WO2025019631A1

WO2025019631A1 - Immunogenic compositions containing inactivated influenza a virus and cpg oligonucleotide adjuvant and uses thereof

Info

Publication number: WO2025019631A1
Application number: PCT/US2024/038471
Authority: WO
Inventors: Florian KRAMMER; Eduard PUENTE-MASSAGUER; Peter Palese; Adolfo Garcia-Sastre
Original assignee: Icahn School of Medicine at Mount Sinai
Current assignee: Icahn School of Medicine at Mount Sinai
Priority date: 2023-07-19
Filing date: 2024-07-18
Publication date: 2025-01-23
Anticipated expiration: 2026-01-19

Abstract

Provided herein are immunogenic compositions comprising a chimeric influenza A virus HA and a CpG oligonucleotide adjuvant. Also provided herein are immunogenic compositions comprising an inactivated influenza A virus described herein or inactivated split influenza A virus described herein and a CpG oligonucleotide adjuvant described herein, wherein the inactivated influenza A virus or inactivated split influenza A virus comprises a chimeric hemagglutinin described herein. The immunogenic compositions may be used in a sequential immunization regimen. Also provided herein are methods of immunizing a subject against influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus) using an immunogenic composition described herein. Further, provided herein are methods of preventing influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus) in a subject using an immunogenic composition described herein.

Description

IMMUNOGENIC COMPOSITIONS CONTAINING INACTIVATED INFLUENZA A VIRUS AND CpG OLIGONUCLEOTIDE ADJUVANT AND USES THEREOF

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63/514,562, filed July 19, 2023, the disclosure of which is incorporated by reference herein in its entirety.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

[0002] This invention was made with government support under award W81XWH-18-1- 0488 awarded by the Department of Defense grant, awards P01 AI097092, R01 AI145870, and R01 AI141226 awarded by the NIH, and the Collaborative Influenza Vaccine Innovation Centers (CIVIC) contract 75N93019C00051. The government has certain rights in this invention.

SEQUENCE LISTING

[0003] This application contains an electronic Sequence Listing which has been submitted in XML file format with this application, the entire content of which is incorporated by reference herein in its entirety. The Sequence Listing XML file submitted with this application is entitled “06923-412-228_SEQ_LISTING.xml”, was created on July 18, 2024, and is 100,015 bytes in size.

1. INTRODUCTION

[0004] Provided herein are immunogenic compositions comprising a chimeric influenza A virus HA and a CpG oligonucleotide adjuvant. Also provided herein are immunogenic compositions comprising an inactivated influenza A virus described herein or inactivated split influenza A virus described herein and a CpG oligonucleotide adjuvant described herein, wherein the inactivated influenza A virus or inactivated split influenza A virus comprises a chimeric hemagglutinin described herein. The immunogenic compositions may be used in a sequential immunization regimen. Also provided herein are methods of immunizing a subject against influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus) using an immunogenic composition described herein. Further, provided herein are methods of preventing influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus) in a subject using an immunogenic composition described herein. 2. BACKGROUND

[0005] Seasonal influenza viruses represent a major public health burden every year. The vaccine effectiveness (VE) of commercially available influenza vaccines is in the range of 10-60%, being generally lower for H3N2 in comparison to H1N1 and influenza B viruses (1, 2). The rapid antigenic evolution of H3N2 viruses (FIG. 1) (3), the acquisition of TV-linked glycans in the immunodominant hemagglutinin (HA) head domain (4), and egg-adaptive mutations (5) may be the main reasons for the lower VE for these vaccines. Additionally, the risk of swine H3N2 influenza virus transmission to humans (6), the existence of other avian and mammalian animal reservoirs for viruses such as H3N8 (7), and sporadic inter-species transmission of other group 2 HA viruses like H7N9 (8) and H10NX (9, 10) pose a potential pandemic threat.

[0006] Current influenza virus vaccines are composed of the matched group 1, group 2, and influenza B virus circulating strains. The immune response elicited by these vaccines mainly targets the immunodominant head domain of the most abundant influenza virus glycoprotein, the HA. The head domain of the HA is subject to strong antigenic drift and can accommodate mutations that facilitate escape from pre-existing immunity, hence annual revaccinations are required. Moreover, seasonal influenza virus vaccines would offer little to no protection against pandemic influenza viruses. The development of broadly protective vaccines is therefore of high importance (11, 12).

3. SUMMARY

[0007] In one aspect, provided herein are immunogenic compositions comprising a chimeric hemagglutinin (HA) described herein and a CpG oligonucleotide adjuvant. In some embodiments, provided herein is an immunogenic composition, comprising: (a) a chimeric hemagglutinin (HA) comprising an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the HA globular head domain of the chimeric HA comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and (b) a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

[0008] In some embodiments, provided herein are immunogenic compositions comprising an inactivated split influenza virus and a CpG oligonucleotide adjuvant, wherein the inactivated influenza virus comprises a chimeric HA. In some embodiments, provided herein is an immunogenic composition, comprising: (a) an inactivated influenza virus comprising a chimeric hemagglutinin (HA), wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the HA globular head domain of the chimeric HA comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and (b) a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3). In some embodiments, the inactivated influenza virus comprises neuraminidase of the group 2 influenza A virus of interest. In some embodiments, the inactivated influenza virus comprises one or more proteins encoded by one or more genes of influenza A virus A/Puerto Rico/8/1934.

[0009] In some embodiments, provided herein are immunogenic compositions comprising an inactivated split influenza virus and a CpG oligonucleotide adjuvant, wherein the inactivated split influenza virus comprises a chimeric HA. In some embodiments, provided herein is an immunogenic composition, comprising: (a) an inactivated split influenza virus comprising a chimeric hemagglutinin (HA), wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the HA globular head domain of the chimeric HA comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and (b) a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3). In some embodiments, the inactivated split influenza virus comprises neuraminidase of the group 2 influenza A virus of interest. In some embodiments, the inactivated split influenza virus comprises one or more proteins encoded by one or more genes of influenza A virus A/Puerto Rico/8/1934.

[0010] In some embodiments, the group 2 influenza A virus HA of interest is of subtype H3. In some embodiments, the group 2 influenza A virus HA of interest is A/Hong Kong/4801/2014, NYMC X-263 HA or A/Hong Kong/4801/2014-like HA. [0011] In some embodiments, the influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest is a group 1 influenza A virus HA. In some embodiments, the influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest is of subtype H2, H5, H6, H8, H9, Hl 1, H12, H13, H16, H17, or H18. In some embodiments, the influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest is of subtype H4, H7, H10, H14, or H15. In some embodiments, the influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest is the HA of an avian influenza virus subtype which does not circulate in humans (e.g., an avian influenza A virus subtype H4 or Hl 5). In some embodiments, the influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest is A/wedge-tailed shearwater/Western Australia/2576/1979 HA or A/wedge-tailed shearwater/We stern Australia/2576/1979-like HA. In some embodiments, the influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest is A/Duck/Czechoslovakia/1956 HA or A/Duck/Czechoslovakia/1956-like HA.

[0012] In some embodiments, provided herein is an immunogenic composition, comprising: (a) an inactivated influenza virus comprising a chimeric hemagglutinin (HA), wherein the chimeric HA comprises an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:5, 6, 7 or 8, or the amino acid sequence of SEQ ID NO:5, 6, 7, or 8; and (b) a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3). In some embodiments, provided herein is an immunogenic composition, comprising: (a) an inactivated split influenza virus comprising a chimeric hemagglutinin (HA), wherein the chimeric HA comprises an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:5, 6, 7 or 8, or the amino acid sequence of SEQ ID NO:5, 6, 7, or 8; and (b) a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

[0013] In some embodiments, the oligonucleotide comprises the nucleotide sequence of 5’-TGACTGTGAACGTTCGAGATGA-3’ (SEQ ID NO:4). In some embodiments, the oligonucleotide is 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 nucleotides in length. In some embodiments, the oligonucleotide is a single stranded oligodeoxynucleotide. In some embodiments, the oligonucleotide comprises only phosphorothioate linkages, or a combination of one or more phosphodiester linkages and one or more phosphorothioate linkages. In some embodiments, the oligonucleotide is fully RNA or is an RNA/DNA chimera.

[0014] In some embodiments, the immunogenic composition further comprises an aluminum salt. In some embodiments, the aluminum salt comprises one or more selected from the group consisting of amorphous aluminum hydroxyphosphate sulfate, aluminum hydroxide, aluminum phosphate, and potassium aluminum sulfate. In some embodiments, the aluminum salt comprises aluminum hydroxide or aluminum phosphate.

[0015] In another aspect, provided herein are methods for preventing influenza virus disease in a subject, comprising administering to the subject the immunogenic composition described herein. In another aspect, provided herein are methods of immunizing a subject against influenza virus disease, comprising administering to the subject the immunogenic composition described herein. In another aspect, provided herein are methods of inducing a cross-reactive immune response to at least two group 2 influenza A viruses in a subject, comprising administering to the subject the immunogenic composition described herein. In some embodiments, the immunogenic composition is administered intramuscularly to the subject. In some embodiments, the immunogenic composition is administered intranasally to the subject.

[0016] In another aspect, provided herein are methods for preventing influenza virus disease in a subject, comprising administering to the subject two or more immunogenic compositions described herein. In another aspect, provided herein are methods of immunizing a subject against influenza virus disease, comprising administering to the subject two or more immunogenic compositions described herein. In another aspect, provided herein are methods of inducing a cross-reactive immune response to at least two group 2 influenza A viruses in a subject, comprising administering to the subject two or more immunogenic compositions described herein. In some embodiments, the two or more immunogenic compositions are administered intramuscularly to the subject. In some embodiments, the two or more immunogenic compositions are administered intranasally to the subject.

[0017] In some embodiments, provided herein is a method for preventing influenza virus disease in a subject, comprising: (a) administering to the subject a first immunogenic composition comprising a first inactivated influenza virus and a CpG oligonucleotide adjuvant, wherein the first inactivated influenza virus comprises a first chimeric HA, wherein the first chimeric HA comprises a first influenza virus HA globular head domain and a first influenza virus HA stalk domain, wherein the first HA stalk domain comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and (b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second inactivated influenza virus and a CpG oligonucleotide adjuvant, wherein the second inactivated influenza virus comprises a second chimeric HA, wherein the second chimeric HA comprises a second influenza virus HA globular head domain and a second influenza virus HA stalk domain, wherein the second HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA of interest, and wherein the second HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the second HA globular head domain, and wherein each CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3). In some embodiments, the method further comprises administering to the subject a third immunogenic composition a certain time after the administration of the second immunogenic composition to the subject, wherein the third immunogenic composition comprises a third inactivated influenza virus and a CpG oligonucleotide adjuvant, wherein the third inactivated influenza virus comprises a third chimeric HA, wherein the third chimeric HA comprises a third influenza virus HA globular head domain and a third influenza virus HA stalk domain, wherein the third HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA of interest, wherein the third HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest, and wherein the third HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the first HA globular head domain and the second HA globular head domain.

[0018] In some embodiments, provided herein is a method of immunizing a subject against influenza virus disease, comprising: (a) administering to the subject a first immunogenic composition comprising a first inactivated influenza virus and a CpG oligonucleotide adjuvant, wherein the first inactivated influenza virus comprises a first chimeric HA, wherein the first chimeric HA comprises a first influenza virus HA globular head domain and a first influenza virus HA stalk domain, wherein the first HA stalk domain comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and (b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second inactivated influenza virus and a CpG oligonucleotide adjuvant, wherein the second inactivated influenza virus comprises a second chimeric HA, wherein the second chimeric HA comprises a second influenza virus HA globular head domain and a second influenza virus HA stalk domain, wherein the second HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA of interest, and wherein the second HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the second HA globular head domain, and wherein each CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3). In some embodiments, the method further comprises administering to the subject a third immunogenic composition a certain time after the administration of the second immunogenic composition to the subject, wherein the third immunogenic composition comprises a third inactivated influenza virus and a CpG oligonucleotide adjuvant, wherein the third inactivated influenza virus comprises a third chimeric HA, wherein the third chimeric HA comprises a third influenza virus HA globular head domain and a third influenza virus HA stalk domain, wherein the third HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA of interest, wherein the third HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest, and wherein the third HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the first HA globular head domain and the second HA globular head domain.

[0019] In some embodiments, provided herein is a method of inducing a cross-reactive immune response to at least two group 2 influenza A viruses in a subject, comprising: (a) administering to the subject a first immunogenic composition comprising a first inactivated influenza virus and a CpG oligonucleotide adjuvant, wherein the first inactivated influenza virus comprises a first chimeric HA, wherein the first chimeric HA comprises a first influenza virus HA globular head domain and a first influenza virus HA stalk domain, wherein the first HA stalk domain comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and (b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second inactivated influenza virus and a CpG oligonucleotide adjuvant, wherein the second inactivated influenza virus comprises a second chimeric HA, wherein the second chimeric HA comprises a second influenza virus HA globular head domain and a second influenza virus HA stalk domain, wherein the second HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA of interest, and wherein the second HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the second HA globular head domain, and wherein each CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3). In some embodiments, the method further comprises administering to the subject a third immunogenic composition a certain time after the administration of the second immunogenic composition to the subject, wherein the third immunogenic composition comprises a third inactivated influenza virus and a CpG oligonucleotide adjuvant, wherein the third inactivated influenza virus comprises a third chimeric HA, wherein the third chimeric HA comprises a third influenza virus HA globular head domain and a third influenza virus HA stalk domain, wherein the third HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA of interest, wherein the third HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest, and wherein the third HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the first HA globular head domain and the second HA globular head domain.

[0020] In some embodiments, the first inactivated influenza virus and the second inactivated influenza virus each comprise neuraminidase of the group 2 influenza A virus of interest. In some embodiments, the group 2 influenza A virus of interest is an H3. In some embodiment, the group 2 influenza A virus of interest is A/Hong Kong/4801/2014 (H3N2) NYMC X-263. In some embodiments, the first inactivated influenza virus and the second inactivated influenza virus each comprise one or more proteins encoded by one or more genes of influenza A virus A/Puerto Rico/8/1934.

[0021] In some embodiments, provided herein is a method of preventing influenza virus disease in a subject, comprising: (a) administering to the subject a first immunogenic composition comprising a first inactivated split influenza virus and a CpG oligonucleotide adjuvant, wherein the first inactivated split influenza virus comprises a first chimeric HA, wherein the first chimeric HA comprises a first influenza virus HA globular head domain and a first influenza virus HA stalk domain, wherein the first HA stalk domain comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and (b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second inactivated split influenza virus and a CpG oligonucleotide adjuvant, wherein the second inactivated split influenza virus comprises a second chimeric HA, and wherein the second chimeric HA comprises a second influenza virus HA globular head domain and a second influenza virus HA stalk domain, wherein the second HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA of interest, and wherein the second HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the second HA globular head domain, and wherein each CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3). In some embodiments, the method further comprises administering to the subject a third immunogenic composition a certain time after the administration of the second immunogenic composition to the subject, wherein the third immunogenic composition comprises a third inactivated split influenza virus and a CpG oligonucleotide adjuvant, wherein the third inactivated split influenza virus comprises a third chimeric HA, and wherein the third chimeric HA comprises a third influenza virus HA globular head domain and a third influenza virus HA stalk domain, wherein the third HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA of interest, wherein the third HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest, and wherein the third HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the first HA globular head domain and the second HA globular head domain.

[0022] In some embodiments, provided herein is a method of immunizing a subject against influenza virus disease, comprising: (a) administering to the subject a first immunogenic composition comprising a first inactivated split influenza virus and a CpG oligonucleotide adjuvant, wherein the first inactivated split influenza virus comprises a first chimeric HA, wherein the first chimeric HA comprises a first influenza virus HA globular head domain and a first influenza virus HA stalk domain, wherein the first HA stalk domain comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and (b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second inactivated split influenza virus and a CpG oligonucleotide adjuvant, wherein the second inactivated split influenza virus comprises a second chimeric HA, wherein the second chimeric HA comprises a second influenza virus HA globular head domain and a second influenza virus HA stalk domain, wherein the second HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA of interest, and wherein the second HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the second HA globular head domain, and wherein each CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3). In some embodiments, the method further comprises administering to the subject a third immunogenic composition a certain time after the administration of the second immunogenic composition to the subject, wherein the third immunogenic composition comprises a third inactivated split influenza virus and a CpG oligonucleotide adjuvant, wherein the third inactivated split influenza virus comprises a third chimeric HA, and wherein the third chimeric HA comprises a third influenza virus HA globular head domain and a third influenza virus HA stalk domain, wherein the third HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA of interest, wherein the third HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest, and wherein the third HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the first HA globular head domain and the second HA globular head domain.

[0023] In some embodiments, provided herein is a method of inducing a cross-reactive immune response to at least two group 2 influenza A viruses in a subject, comprising: (a) administering to the subject a first immunogenic composition comprising a first inactivated split influenza virus and a CpG oligonucleotide adjuvant, wherein the first inactivated split influenza virus comprises a first chimeric HA, wherein the first chimeric HA comprises a first influenza virus HA globular head domain and a first influenza virus HA stalk domain, wherein the first HA stalk domain comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and (b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second inactivated split influenza virus and a CpG oligonucleotide adjuvant, wherein the second inactivated split influenza virus comprises a second chimeric HA, wherein the second chimeric HA comprises a second influenza virus HA globular head domain and a second influenza virus HA stalk domain, wherein the second HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA of interest, and wherein the second HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the second HA globular head domain, and wherein each CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3). In some embodiments, the method further comprises administering to the subject a third immunogenic composition a certain time after the administration of the second immunogenic composition to the subject, wherein the third immunogenic composition comprises a third inactivated split influenza virus and a CpG oligonucleotide adjuvant, wherein the third inactivated split influenza virus comprises a third chimeric HA, and wherein the third chimeric HA comprises a third influenza virus HA globular head domain and a third influenza virus HA stalk domain, wherein the third HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA of interest, wherein the third HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest, and wherein the third HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the first HA globular head domain and the second HA globular head domain. [0024] In some embodiments, the first inactivated split influenza virus and the second inactivated split influenza virus each comprise neuraminidase of the group 2 influenza A virus of interest. In some embodiments, the group 2 influenza A virus of interest is an H3. In some embodiment, the group 2 influenza A virus of interest is A/Hong Kong/4801/2014 (H3N2) NYMC X-263. In some embodiments, the first inactivated split influenza virus and the second inactivated split influenza virus each comprise one or more proteins encoded by one or more genes of influenza A virus A/Puerto Rico/8/1934.

[0025] In some embodiments, provided herein is a method of preventing influenza virus disease in a subject, comprising: (a) administering to the subject a first immunogenic composition comprising a first chimeric hemagglutinin (HA) and a CpG oligonucleotide adjuvant, wherein the first chimeric HA comprises a first influenza virus HA globular head domain and a first influenza virus HA stalk domain, wherein the first HA stalk domain comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and (b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second chimeric HA and a CpG oligonucleotide adjuvant, wherein the second chimeric HA comprises a second influenza virus HA globular head domain and a second influenza virus HA stalk domain, wherein the second HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA of interest, and wherein the second HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest, and wherein the first globular head comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the second HA globular head domain, and wherein each CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

[0026] In some embodiments, provided herein is a method of immunizing a subject against influenza virus disease, comprising: (a) administering to the subject a first immunogenic composition comprising a first chimeric hemagglutinin (HA) and a CpG oligonucleotide adjuvant, wherein the first chimeric HA comprises a first influenza virus HA globular head domain and a first influenza virus HA stalk domain, wherein the first HA stalk domain comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and (b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second chimeric HA and a CpG oligonucleotide adjuvant, wherein the second chimeric HA comprises a second influenza virus HA globular head domain and a second influenza virus HA stalk domain, wherein the second HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA of interest, and wherein the second HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the second HA globular head domain, and wherein each CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

[0027] In some embodiments, provided herein is a method of inducing a cross-reactive immune response to at least two group 2 influenza A viruses in a subject, comprising: (a) administering to the subject a first immunogenic composition comprising a first chimeric hemagglutinin (HA) and a CpG oligonucleotide adjuvant, wherein the first chimeric HA comprises a first influenza virus HA globular head domain and a first influenza virus HA stalk domain, wherein the first HA stalk domain comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and (b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second chimeric HA and a CpG oligonucleotide adjuvant, wherein the second chimeric HA comprises a second influenza virus HA globular head domain and a second influenza virus HA stalk domain, wherein the second HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA of interest, and wherein the second HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest, and wherein the first globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the second HA globular head domain, and wherein each CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3). [0028] In some embodiments, the group 2 influenza A virus HA of interest is of subtype H3. In some embodiments, the group 2 influenza A virus HA of interest is A/Hong Kong/4801/2014, NYMC X-263 HA, or A/Hong Kong/4801/2014-like HA.

[0029] In some embodiments, the first HA globular head domain or the second HA globular head domain is the HA globular head domain of a group 1 influenza A virus HA. In some embodiments, the first HA globular head domain and the second HA globular head domain are the HA globular head domain of group 1 influenza A virus HAs. In some embodiments, provided herein is the first HA globular head domain or the second HA globular head domain is the HA globular head domain of an HA of subtype H2, H5, H6, H8, H9, Hl 1, H12, H13, H16, H17, or H18. In some embodiments, the first HA globular head domain and the second HA globular head domain are the HA globular head domain of an HA of subtype H2, H5, H6, H8, H9, Hl l, H12, H13, H16, H17, or H18. In some embodiments, the first HA globular head domain and the second HA globular head domain are the HA globular head domain of subtype H4, H7, H10, H14, or H15. In some embodiments, the first HA globular head domain and the second HA globular head domain are the HA globular head domains of HAs of avian influenza viruses which do not circulate in humans (e.g., an avian influenza A virus subtype H4 or Hl 5). In some embodiments, the first HA globular head domain is the HA globular head domain of A/wedge-tailed shearwater/We stern Australia/2576/1979 HA or A/wedge-tailed shearwater/Westem Australia/2576/1979-like HA. In some embodiments, the second HA globular head domain is the HA globular head domain of A/Duck/Czechoslovakia/1956 HA or A/Duck/Czechoslovakia/1956-like HA.

[0030] In some embodiments, the first HA globular head domain is the HA globular head domain of A/wedge-tailed shearwater/Westem Australia/2576/1979 HA or A/wedge-tailed shearwater/Westem Australia/2576/1979-like HA and the first HA stalk domain is the HA stalk domain of A/Hong Kong/4801/2014, NYMC X-263 HA, or A/Hong Kong/4801/2014- like HA. In some embodiments, the second HA globular head domain is the HA globular head domain of A/Duck/Czechoslovakia/1956 HA or A/Duck/Czechoslovakia/1956-like HA and the second HA stalk domain is the HA stalk domain of A/Hong Kong/4801/2014, NYMC X-263 HA, or A/Hong Kong/4801/2014-like HA.

[0031] In some embodiments, provided herein is a method of preventing influenza vims disease in a subject, comprising: (a) administering to the subject a first immunogenic composition comprising a first inactivated influenza vims and a CpG oligonucleotide adjuvant, wherein the first inactivated influenza vims comprises a first chimeric HA, and wherein the first chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8; and (b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second inactivated influenza virus and a CpG oligonucleotide adjuvant, wherein the second inactivated influenza virus comprises a second chimeric HA, and wherein the second chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8, wherein (i) the second chimeric HA comprises the amino acid sequence of SEQ ID NO: 5 or 6, if the first chimeric HA comprises the amino acid sequence of SEQ ID NO: 7 or 8; or (ii) the second chimeric HA comprises the amino acid sequence of SEQ ID NO: 7 or 8, if the first chimeric HA comprises the amino acid sequence of SEQ ID NO:5 or 6, and wherein each CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3). In some embodiments, the CpG oligonucleotide adjuvant comprises the nucleotide sequence of SEQ ID NO: 4, or CpG 1018® adjuvant.

[0032] In some embodiments, provided herein is a method of immunizing a subject against influenza virus disease, comprising: (a) administering to the subject a first immunogenic composition comprising a first inactivated influenza virus and a CpG oligonucleotide adjuvant, wherein the first inactivated influenza virus comprises a first chimeric HA, and wherein the first chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8; and (b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition, wherein the second immunogenic composition comprises a second inactivated influenza virus and a CpG oligonucleotide adjuvant, wherein the second inactivated influenza virus comprises a second chimeric HA, and wherein the second chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8, wherein (i) the second chimeric HA comprises the amino acid sequence of SEQ ID NO: 5 or 6, if the first chimeric HA comprises the amino acid sequence of SEQ ID NO: 7 or 8; or (ii) the second chimeric HA comprises the amino acid sequence of SEQ ID NO:7 or 8, if the first chimeric HA comprises the amino acid sequence of SEQ ID NO:5 or 6, and wherein each CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3). In some embodiments, the CpG oligonucleotide adjuvant comprises the nucleotide sequence of SEQ ID NO: 4, or CpG 1018® adjuvant.

[0033] In some embodiments, provided herein is a method of inducing a cross-reactive immune response to at least two group 2 influenza A viruses in a subject, comprising: (a) administering to the subject a first immunogenic composition comprising a first inactivated influenza virus and a CpG oligonucleotide adjuvant, wherein the first inactivated influenza virus comprises a first chimeric HA, and wherein the first chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8; and (b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition, wherein the second immunogenic composition comprises a second inactivated split influenza virus and a CpG oligonucleotide adjuvant, wherein the second inactivated split influenza virus comprises a second chimeric HA, and wherein the second chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8, wherein (i) the second chimeric HA comprises the amino acid sequence of SEQ ID NO:5 or 6, if the first chimeric HA comprises the amino acid sequence of SEQ ID NO:7 or 8; or (ii) the second chimeric HA comprises the amino acid sequence of SEQ ID NO:7 or 8, if the first chimeric HA comprises the amino acid sequence of SEQ ID NO:5 or 6, and wherein each CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3). In some embodiments, the CpG oligonucleotide adjuvant comprises the nucleotide sequence of SEQ ID NO: 4, or CpG 1018® adjuvant.

[0034] In some embodiments, provided herein is a method of preventing influenza virus disease in a subject, comprising: (a) administering to the subject a first immunogenic composition comprising a first inactivated split influenza virus and a CpG oligonucleotide adjuvant, wherein the first inactivated split influenza virus comprises a first chimeric HA, and wherein the first chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8; and (b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second inactivated split influenza virus and a CpG oligonucleotide adjuvant, wherein the second inactivated split influenza virus comprises a second chimeric HA, and wherein the second chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8, wherein (i) the second chimeric HA comprises the amino acid sequence of SEQ ID NO:5 or 6, if the first chimeric HA comprises the amino acid sequence of SEQ ID NO:7 or 8; or (ii) the second chimeric HA comprises the amino acid sequence of SEQ ID NO:7 or 8, if the first chimeric HA comprises the amino acid sequence of SEQ ID NO:5 or 6, and wherein each CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3). In some embodiments, the CpG oligonucleotide adjuvant comprises the nucleotide sequence of SEQ ID NO: 4, or CpG 1018® adjuvant. [0035] In some embodiments, provided herein is a method of immunizing a subject against influenza virus disease, comprising: (a) administering to the subject a first immunogenic composition comprising a first inactivated split influenza virus and a CpG oligonucleotide adjuvant, wherein the first inactivated split influenza virus comprises a first chimeric HA, and wherein the first chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8; and (b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second inactivated split influenza virus and a CpG oligonucleotide adjuvant, wherein the second inactivated split influenza virus comprises a second chimeric HA, and wherein the second chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8, wherein (i) the second chimeric HA comprises the amino acid sequence of SEQ ID NO:5 or 6, if the first chimeric HA comprises the amino acid sequence of SEQ ID NO:7 or 8; or (ii) the second chimeric HA comprises the amino acid sequence of SEQ ID NO: 7 or 8, if the first chimeric HA comprises the amino acid sequence of SEQ ID NO: 5 or 6, and wherein each CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3). In some embodiments, the CpG oligonucleotide adjuvant comprises the nucleotide sequence of SEQ ID NO: 4, or CpG 1018® adjuvant.

[0036] In some embodiments, provided herein is a method of inducing a cross-reactive immune response to at least two group 2 influenza A viruses in a subject, comprising: (a) administering to the subject a first immunogenic composition comprising a first inactivated split influenza virus and a CpG oligonucleotide adjuvant, wherein the first inactivated split influenza virus comprises a first chimeric HA, and wherein the first chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8; and (b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second inactivated split influenza virus and a CpG oligonucleotide adjuvant, wherein the second inactivated split influenza virus comprises a second chimeric HA, and wherein the second chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8, wherein (i) the second chimeric HA comprises the amino acid sequence of SEQ ID NO:5 or 6, if the first chimeric HA comprises the amino acid sequence of SEQ ID NO:7 or 8; or (ii) the second chimeric HA comprises the amino acid sequence of SEQ ID NO:7 or 8, if the first chimeric HA comprises the amino acid sequence of SEQ ID NO:5 or 6, and wherein each CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3). In some embodiments, the CpG oligonucleotide adjuvant comprises the nucleotide sequence of SEQ ID NO: 4, or CpG 1018® adjuvant. [0037] In some embodiments, provided herein is a method of preventing influenza virus disease in a subject, comprising: (a) administering to the subject a first immunogenic composition comprising a first chimeric HA and a CpG oligonucleotide adjuvant, wherein the first chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8; and (b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second chimeric HA and a CpG oligonucleotide adjuvant, wherein the second chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8, wherein (i) the second chimeric HA comprises the amino acid sequence of SEQ ID NO: 5 or 6, if the first chimeric HA comprises the amino acid sequence of SEQ ID NO: 7 or 8; or (ii) the second chimeric HA comprises the amino acid sequence of SEQ ID NO: 7 or 8, if the first chimeric HA comprises the amino acid sequence of SEQ ID NO:5 or 6, and wherein each CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3). In some embodiments, the CpG oligonucleotide adjuvant comprises the nucleotide sequence of SEQ ID NO: 4, or CpG 1018® adjuvant.

[0038] In some embodiments, provided herein is a method of immunizing a subject against influenza virus disease, comprising: (a) administering to the subject a first immunogenic composition comprising a first chimeric HA and a CpG oligonucleotide adjuvant, wherein the first chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8; and (b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second chimeric HA and a CpG oligonucleotide adjuvant, wherein the second chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8, wherein (i) the second chimeric HA comprises the amino acid sequence of SEQ ID NO: 5 or 6, if the first chimeric HA comprises the amino acid sequence of SEQ ID NO: 7 or 8; or (ii) the second chimeric HA comprises the amino acid sequence of SEQ ID NO:7 or 8, if the first chimeric HA comprises the amino acid sequence of SEQ ID NO:5 or 6, and wherein each CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3). In some embodiments, the CpG oligonucleotide adjuvant comprises the nucleotide sequence of SEQ ID NO: 4, or CpG 1018® adjuvant. [0039] In some embodiments, provided herein is a method of inducing a cross-reactive immune response to at least two group 2 influenza A viruses in a subject, comprising: (a) administering to the subject a first immunogenic composition comprising a first chimeric HA and a CpG oligonucleotide adjuvant, wherein the first chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8; and (b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second chimeric HA and a CpG oligonucleotide adjuvant, wherein the second chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8, wherein (i) the second chimeric HA comprises the amino acid sequence of SEQ ID NO:5 or 6, if the first chimeric HA comprises the amino acid sequence of SEQ ID NO:7 or 8; or (ii) the second chimeric HA comprises the amino acid sequence of SEQ ID NO: 7 or 8, if the first chimeric HA comprises the amino acid sequence of SEQ ID NO: 5 or 6, and wherein each CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3). In some embodiments, the CpG oligonucleotide adjuvant comprises the nucleotide sequence of SEQ ID NO: 4, or CpG 1018® adjuvant.

[0040] In some embodiments, the second immunogenic composition is administered to the subject about 21 days to about 6 months after the administration of the first immunogenic composition to the subject.

[0041] In some embodiments, the oligonucleotide comprises the nucleotide sequence of 5’-TGACTGTGAACGTTCGAGATGA-3’ (SEQ ID NO:4). In some embodiments, the oligonucleotide is 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 nucleotides in length. In some embodiments, the oligonucleotide is a single stranded oligodeoxynucleotide. In some embodiments, the oligonucleotide comprises only phosphorothioate linkages, or a combination of one or more phosphodiester linkages and one or more phosphorothioate linkages. In some embodiments, the oligonucleotide is fully RNA or is an RNA/DNA chimera.

[0042] In some embodiments, the composition further comprises an aluminum salt. In some embodiments, the aluminum salt comprises one or more selected from the group consisting of amorphous aluminum hydroxyphosphate sulfate, aluminum hydroxide, aluminum phosphate, and potassium aluminum sulfate. In some embodiments, the aluminum salt comprises aluminum hydroxide or aluminum phosphate.

[0043] In some embodiments, the first immunogenic composition or second immunogenic is administered to the subject intramuscularly or intranasally. In some embodiments, the first immunogenic composition and second immunogenic are administered to the subject intramuscularly or intranasally.

[0044] In some embodiments, the subject is human.

[0045] In another aspect, provided herein are methods for preventing an influenza virus disease in a subject, comprising administering to the subject an immunogenic composition comprising a chimeric HA described herein, and administering to the subject a CpG oligonucleotide adjuvant described herein. In another aspect, provided herein are methods of immunizing a subject against influenza virus disease, comprising administering to the subject an immunogenic composition comprising a chimeric HA described herein, and administering to the subject a CpG oligonucleotide adjuvant described herein. In another aspect, provided herein are methods of inducing a cross-reactive immune response to at least two group 2 influenza A viruses in a subject, comprising administering to the subject an immunogenic composition comprising a chimeric HA described herein, and administering to the subject a CpG oligonucleotide adjuvant described herein. In some embodiments, the CpG oligonucleotide adjuvant is administered to the subject first. In some embodiments, the immunogenic composition is administered to the subject first.

[0046] In some embodiments, provided herein is a method of preventing an influenza virus disease in a subject, comprising: (a) administering to the subject an immunogenic composition comprising a chimeric hemagglutinin (HA), wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises an amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, wherein the HA globular head domain of the chimeric HA is heterologous to the HA stalk domain of the group 2 influenza A virus HA of interest, and wherein the HA globular head domain of the chimeric HA is from an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and (b) administering to the subject a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

[0047] In some embodiments, provided herein is a method of immunizing a subject against influenza virus disease, comprising: (a) administering to the subject an immunogenic composition comprising a chimeric hemagglutinin (HA), wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises an amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, wherein the HA globular head domain of the chimeric HA is heterologous to the HA stalk domain of the group 2 influenza A virus HA of interest, and wherein the HA globular head domain of the chimeric HA is from an influenza A virus HA of a different strain, subtype, or group than the globular head domain of the group 2 influenza A virus HA of interest; and (b) administering to the subject a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

[0048] In some embodiments, provided herein is a method of inducing a cross-reactive immune response to at least two group 2 influenza A viruses in a subject, comprising: (a) administering to the subject an immunogenic composition comprising a chimeric hemagglutinin (HA), wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises an amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, wherein the HA globular head domain of the chimeric HA is heterologous to the HA stalk domain of the group 2 influenza A virus HA of interest, and wherein the HA globular head domain of the chimeric HA is from an influenza A virus HA of a different strain, subtype, or group than the globular head domain of the group 2 influenza A virus HA of interest; and (b) administering to the subject a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

[0049] In some embodiments, the group 2 influenza A virus HA of interest is of subtype H3. In some embodiments, the group 2 influenza A virus HA of interest is A/Hong Kong/4801/2014, NYMC X-263 HA or A/Hong Kong/4801/2014-like HA.

[0050] In some embodiments, the influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest is a group 1 influenza A virus HA. In some embodiments, the influenza A virus HA of a different strain, subtype, or group is subtype than the group 2 influenza A virus HA of interest is HA of subtype H2, H5, H6, H8, H9, Hl 1, H12, H13, H16, H17, or H18. In some embodiments, the influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest is HA of subtype H4, H7, H10, H14, or H15. In some embodiments, the influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest is the HA of an avian influenza virus which does not circulate in humans. In some embodiments, the influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest is A/wedge-tailed shearwater/Westem Australia/2576/1979 HA or A/wedge-tailed shearwater/We stern Australia/2576/1979-like HA. In some embodiments, the influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest is A/Duck/Czechoslovakia/1956 HA or A/Duck/Czechoslovakia/1956- like HA.

[0051] In some embodiments, the HA globular head domain is the HA globular head domain of A/wedge-tailed shearwater/Westem Australia/2576/1979 HA or A/wedge-tailed shearwater/Westem Australia/2576/1979-like HA and the HA stalk domain is the HA stalk domain of A/Hong Kong/4801/2014, NYMC X-263 HA, or A/Hong Kong/4801/2014-like HA. The term “ A/shearwater/West Australia/2576/1979” is used interchangeably herein for the term “A/wedge-tailed shearwater/We stern Australia/2576/1979”. In some embodiments, the HA globular head domain is the HA globular head domain of A/Duck/Czechoslovakia/1956 HA or A/Duck/Czechoslovakia/1956-like HA and the HA stalk domain is the HA stalk domain of A/Hong Kong/4801/2014, NYMC X-263 HA, or A/Hong Kong/4801/2014-like HA.

[0052] In some embodiments, the oligonucleotide comprises the nucleotide sequence of 5’-TGACTGTGAACGTTCGAGATGA-3’ (SEQ ID NO:4). In some embodiments, the oligonucleotide is 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 nucleotides in length. In some embodiments, the oligonucleotide is a single stranded oligodeoxynucleotide. In some embodiments, the oligonucleotide comprises only phosphorothioate linkages, or a combination of one or more phosphodiester linkages and one or more phosphorothioate linkages. In some embodiments, the oligonucleotide is fully RNA or is an RNA/DNA chimera.

[0053] In some embodiments, the immunogenic composition, the CpG oligonucleotide adjuvant, or both are administered intramuscularly to the subject. In some embodiments, the immunogenic composition, the CpG oligonucleotide adjuvant, or both are administered intranasally to the subject.

[0054] In some embodiments, the immunogenic composition further comprises an aluminum salt. In some embodiments, the CpG oligonucleotide adjuvant further comprises an aluminum salt. In some embodiments, the aluminum salt comprises one or more selected from the group consisting of amorphous aluminum hydroxyphosphate sulfate, aluminum hydroxide, aluminum phosphate, and potassium aluminum sulfate. In some embodiments, the aluminum salt comprises aluminum hydroxide or aluminum phosphate.

[0055] In some embodiments, the subject is human. [0056] In some embodiments, the immunogenic composition and CpG oligonucleotide adjuvant are administered concurrently to the subject. In some embodiments, the immunogenic composition and CpG oligonucleotide adjuvant are administered to the subject within 30 minutes of each other. In some embodiments, the immunogenic composition and CpG oligonucleotide adjuvant are administered to the subject within 15 minutes of each other.

[0057] In another aspect, provided herein are methods for preventing an influenza virus disease in a subject, comprising administering to the subject an immunogenic composition comprising an inactivated influenza virus, wherein the inactivated influenza virus comprises a chimeric HA described herein, and administering to the subject a CpG oligonucleotide adjuvant described herein. In another aspect, provided herein are methods of immunizing a subject against influenza virus disease, comprising administering to the subject an immunogenic composition comprising an inactivated influenza virus, wherein the inactivated influenza virus comprises a chimeric HA described herein, and administering to the subject a CpG oligonucleotide adjuvant described herein. In another aspect, provided herein are methods of inducing a cross-reactive immune response to at least two group 2 influenza A viruses in a subject, comprising administering to the subject an immunogenic composition comprising an inactivated influenza virus, wherein the inactivated influenza virus comprises a chimeric HA described herein, and administering to the subject a CpG oligonucleotide adjuvant described herein. In some embodiments, the CpG oligonucleotide adjuvant is administered to the subject first. In some embodiments, the immunogenic composition is administered to the subject first.

[0058] In some embodiments, provided herein is a method of preventing an influenza virus disease in a subject, comprising: (a) administering to the subject an immunogenic composition comprising an inactivated influenza virus in an admixture with a pharmaceutically acceptable carrier, wherein the inactivated influenza virus comprises a chimeric hemagglutinin (HA), wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises an amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the HA globular head domain of the chimeric HA comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and (b) administering to the subject a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

[0059] In some embodiments, provided herein is a method of immunizing a subject against influenza virus disease, comprising: (a) administering to the subject an immunogenic composition comprising an inactivated influenza virus in an admixture with a pharmaceutically acceptable carrier, wherein the inactivated influenza virus comprises a chimeric hemagglutinin (HA), wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises an amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and the HA globular head domain of the chimeric HA comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and (b) administering to the subject a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

[0060] In some embodiments, provided herein is a method of inducing a cross-reactive immune response to at least two group 2 influenza A viruses in a subject, comprising: (a) administering to the subject an immunogenic composition comprising an inactivated influenza virus in an admixture with a pharmaceutically acceptable carrier, wherein the inactivated influenza virus comprises a chimeric hemagglutinin (HA), wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises an amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the HA globular head domain of the chimeric HA comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and (b) administering to the subject a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

[0061] In some embodiments, the inactivated influenza virus comprises neuraminidase of the group 2 influenza A virus of interest. In some embodiments, the group 2 influenza A virus of interest is of subtype H3. In some embodiments, the group 2 influenza A virus of interest is A/Hong Kong/4801/2014, NYMC X-263 HA or A/Hong Kong/4801/2014-like HA. [0062] In some embodiments, the inactivated influenza virus comprises one or more proteins encoded by one or more genes of influenza A virus A/Puerto Rico/8/1934.

[0063] In some embodiments, the group 2 influenza A virus HA of interest is of subtype H3. In some embodiments, the group 2 influenza A virus HA of interest is A/Hong Kong/4801/2014, NYMC X-263 HA or A/Hong Kong/4801/2014-like HA.

[0064] In some embodiments, the influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest is a group 1 influenza A virus HA. In some embodiments, the influenza A virus HA of a different strain, subtype, or group is subtype than the group 2 influenza A virus HA of interest is HA of subtype H2, H5, H6, H8, H9, Hl 1, H12, H13, H16, H17, or H18. In some embodiments, the influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest is HA of subtype H4, H7, H10, H14, or H15. In some embodiments, the influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest is the HA of an avian influenza virus which does not circulate in humans. In some embodiments, the influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest is A/wedge-tailed shearwater/Westem Australia/2576/1979 HA or A/wedge-tailed shearwater/We stern Australia/2576/1979-like HA. In some embodiments, the influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest is A/Duck/Czechoslovakia/1956 HA or A/Duck/Czechoslovakia/1956- like HA.

[0065] In some embodiments, the HA globular head domain is the HA globular head domain of A/wedge-tailed shearwater/Westem Australia/2576/1979 HA or A/wedge-tailed shearwater/Westem Australia/2576/1979-like HA and the HA stalk domain is the HA stalk domain of A/Hong Kong/4801/2014, NYMC X-263 HA, or A/Hong Kong/4801/2014-like HA. In some embodiments, the HA globular head domain is the HA globular head domain of A/Duck/Czechoslovakia/1956 HA or A/Duck/Czechoslovakia/1956-like HA and the HA stalk domain is the HA stalk domain of A/Hong Kong/4801/2014, NYMC X-263 HA, or A/Hong Kong/4801/2014-like HA.

[0066] In some embodiments, the oligonucleotide comprises the nucleotide sequence of 5’-TGACTGTGAACGTTCGAGATGA-3’ (SEQ ID NO:4). In some embodiments, the oligonucleotide is 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 nucleotides in length. In some embodiments, the oligonucleotide is a single stranded oligodeoxynucleotide. In some embodiments, the oligonucleotide comprises only phosphorothioate linkages, or a combination of one or more phosphodiester linkages and one or more phosphorothioate linkages. In some embodiments, the oligonucleotide is fully RNA or is an RNA/DNA chimera.

[0067] In some embodiments, the immunogenic composition, the CpG oligonucleotide adjuvant, or both are administered intramuscularly to the subject. In some embodiments, the immunogenic composition, the CpG oligonucleotide adjuvant, or both are administered intranasally to the subject.

[0068] In some embodiments, the immunogenic composition further comprises an aluminum salt. In some embodiments, the CpG oligonucleotide adjuvant further comprises an aluminum salt. In some embodiments, the aluminum salt comprises one or more selected from the group consisting of amorphous aluminum hydroxyphosphate sulfate, aluminum hydroxide, aluminum phosphate, and potassium aluminum sulfate. In some embodiments, the aluminum salt comprises aluminum hydroxide or aluminum phosphate.

[0069] In some embodiments, the subject is human.

[0070] In some embodiments, the immunogenic composition and CpG oligonucleotide adjuvant are administered concurrently to the subject. In some embodiments, the immunogenic composition and CpG oligonucleotide adjuvant are administered to the subject within 30 minutes of each other. In some embodiments, the immunogenic composition and CpG oligonucleotide adjuvant are administered to the subject within 15 minutes of each other.

[0071] In another aspect, provided herein are methods for preventing an influenza virus disease in a subject, comprising administering to the subject an immunogenic composition comprising an inactivated split influenza virus, wherein the inactivated split influenza virus comprises a chimeric HA described herein, and administering to the subject a CpG oligonucleotide adjuvant described herein. In another aspect, provided herein are methods of immunizing a subject against influenza virus disease, comprising administering to the subject an immunogenic composition comprising an inactivated split influenza virus, wherein the inactivated split influenza virus comprises a chimeric HA described herein, and administering to the subject a CpG oligonucleotide adjuvant described herein. In another aspect, provided herein are methods of inducing a cross-reactive immune response to at least two group 2 influenza A viruses in a subject, comprising administering to the subject an immunogenic composition comprising an inactivated split influenza virus, wherein the inactivated split influenza virus comprises a chimeric HA described herein, and administering to the subject a CpG oligonucleotide adjuvant described herein. In some embodiments, the CpG oligonucleotide adjuvant is administered to the subject first. In some embodiments, the immunogenic composition is administered to the subject first.

[0072] In some embodiments, provided herein is a method of preventing an influenza virus disease in a subject, comprising: (a) administering to the subject an immunogenic composition comprising an inactivated split influenza virus in an admixture with a pharmaceutically acceptable carrier, wherein the inactivated split influenza virus comprises a chimeric hemagglutinin (HA), wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises an amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the HA globular head domain of the chimeric HA comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and (b) administering to the subject a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

[0073] In some embodiments, provided herein is a method of immunizing a subject against influenza virus disease, comprising: (a) administering to the subject an immunogenic composition comprising an inactivated split influenza virus in an admixture with a pharmaceutically acceptable carrier, wherein the inactivated split influenza virus comprises a chimeric hemagglutinin (HA), wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises an amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the HA globular head domain of the chimeric HA comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and (b) administering to the subject a CpG oligonucleotide adjuvant, wherein the CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

[0074] In some embodiments, provided herein is a method of inducing a cross-reactive immune response to at least two group 2 influenza A viruses in a subject, comprising: (a) administering to the subject an immunogenic composition comprising an inactivated split influenza virus in an admixture with a pharmaceutically acceptable carrier, wherein the inactivated split influenza virus comprises a chimeric hemagglutinin (HA), wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises an amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the HA globular head domain of the chimeric HA comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and (b) administering to the subject a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

[0075] In some embodiments, the inactivated split influenza virus comprises neuraminidase of the group 2 influenza A virus of interest. In some embodiments, the group 2 influenza A virus of interest is of subtype H3. In some embodiments, the group 2 influenza A virus of interest is A/Hong Kong/4801/2014, NYMC X-263 HA or A/Hong Kong/4801/2014-like HA.

[0076] In some embodiments, the inactivated split influenza virus comprises one or more proteins encoded by one or more genes of influenza A virus A/Puerto Rico/8/1934.

[0077] In some embodiments, the group 2 influenza A virus HA of interest is of subtype H3. In some embodiments, the group 2 influenza A virus HA of interest is A/Hong Kong/4801/2014, NYMC X-263 HA or A/Hong Kong/4801/2014-like HA.

[0078] In some embodiments, the influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest is a group 1 influenza A virus HA. In some embodiments, the influenza A virus HA of a different strain, subtype, or group is subtype than the group 2 influenza A virus HA of interest is HA of subtype H2, H5, H6, H8, H9, Hl 1, H12, H13, H16, H17, or H18. In some embodiments, the influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest is HA of subtype H4, H7, H10, H14, or H15. In some embodiments, the influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest is the HA of an avian influenza virus which does not circulate in humans. In some embodiments, the influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest is A/wedge-tailed shearwater/Westem Australia/2576/1979 HA or A/wedge-tailed shearwater/We stern Australia/2576/1979-like HA. In some embodiments, the influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest is A/Duck/Czechoslovakia/1956 HA or A/Duck/Czechoslovakia/1956- like HA.

[0079] In some embodiments, the HA globular head domain is the HA globular head domain of A/wedge-tailed shearwater/Westem Australia/2576/1979 HA or A/wedge-tailed shearwater/Westem Australia/2576/1979-like HA and the HA stalk domain is the HA stalk domain of A/Hong Kong/4801/2014, NYMC X-263 HA, or A/Hong Kong/4801/2014-like HA. In some embodiments, the HA globular head domain is the HA globular head domain of A/Duck/Czechoslovakia/1956 HA or A/Duck/Czechoslovakia/1956-like HA and the HA stalk domain is the HA stalk domain of A/Hong Kong/4801/2014, NYMC X-263 HA, or A/Hong Kong/4801/2014-like HA.

[0080] In some embodiments, the oligonucleotide comprises the nucleotide sequence of 5’-TGACTGTGAACGTTCGAGATGA-3’ (SEQ ID NO:4). In some embodiments, the oligonucleotide is 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 nucleotides in length. In some embodiments, the oligonucleotide is a single stranded oligodeoxynucleotide. In some embodiments, the oligonucleotide comprises only phosphorothioate linkages, or a combination of one or more phosphodiester linkages and one or more phosphorothioate linkages. In some embodiments, the oligonucleotide is fully RNA or is an RNA/DNA chimera.

[0081] In some embodiments, the immunogenic composition, the CpG oligonucleotide adjuvant, or both are administered intramuscularly to the subject. In some embodiments, the immunogenic composition, the CpG oligonucleotide adjuvant, or both are administered intranasally to the subject.

[0082] In some embodiments, the immunogenic composition further comprises an aluminum salt. In some embodiments, the CpG oligonucleotide adjuvant further comprises an aluminum salt. In some embodiments, the aluminum salt comprises one or more selected from the group consisting of amorphous aluminum hydroxyphosphate sulfate, aluminum hydroxide, aluminum phosphate, and potassium aluminum sulfate. In some embodiments, the aluminum salt comprises aluminum hydroxide or aluminum phosphate.

[0083] In some embodiments, the subject is human.

[0084] In some embodiments, the immunogenic composition and CpG oligonucleotide adjuvant are administered concurrently to the subject. In some embodiments, the immunogenic composition and CpG oligonucleotide adjuvant are administered to the subject within 30 minutes of each other. In some embodiments, the immunogenic composition and CpG oligonucleotide adjuvant are administered to the subject within 15 minutes of each other.

[0085] In another aspect, provided herein are kits comprising an immunogenic composition described herein. In some embodiments, provided herein is a kit comprising two or more containers, wherein each container comprises a different immunogenic composition described herein. In some embodiments, provided herein is a kit comprising at least two containers, wherein one container comprises an immunogenic composition comprising a chimeric HA described herein, and the second container comprises a CpG oligonucleotide adjuvant described herein. In some embodiments, provided herein is a kit comprising at least two containers, wherein one container comprises an immunogenic composition comprising an inactivated influenza virus, wherein the inactivated influenza virus comprises a chimeric HA described herein, and the second container comprises a CpG oligonucleotide adjuvant described herein. In some embodiments, provided herein is a kit comprising at least two containers, wherein one container comprises an immunogenic composition comprising an inactivated split influenza virus, wherein the inactivated split influenza virus comprises a chimeric HA described herein, and the second container comprises a CpG oligonucleotide adjuvant described herein.

[0086] In some embodiments, provided herein is a kit comprising a container containing an immunogenic composition comprising a chimeric hemagglutinin (HA) and a CpG oligonucleotide adjuvant, wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises an amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, wherein the HA globular head domain of the chimeric HA is heterologous to the HA stalk domain of the group 2 influenza A virus HA of interest, wherein the HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest, and wherein the CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

[0087] In some embodiments, provided herein is a kit comprising a container containing an immunogenic composition comprising an inactivated influenza virus and a CpG oligonucleotide adjuvant, wherein the inactivated influenza virus comprises a first chimeric HA, and wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, wherein the HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest, and wherein the CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

[0088] In some embodiments, provided herein is a kit comprising a container containing an immunogenic composition comprising an inactivated split influenza virus and a CpG oligonucleotide adjuvant, wherein the inactivated split influenza virus comprises a first chimeric HA, and wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, wherein the HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest, and wherein the CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

[0089] In some embodiments, provided herein is a kit comprising: (a) a first container containing an immunogenic composition comprising a chimeric HA, wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises an amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, wherein the HA globular head domain of the chimeric HA is heterologous to the HA stalk domain of the group 2 influenza A virus HA of interest, wherein the HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and (b) a second container containing a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

[0090] In some embodiments, provided herein is a kit comprising: (a) a first container containing an immunogenic composition comprising a first inactivated influenza virus, wherein the first inactivated influenza virus comprises a first chimeric HA, wherein the first chimeric HA comprises a first influenza virus HA globular head domain and a first influenza virus HA stalk domain, wherein the first HA stalk domain comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and (b) a second container containing a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

[0091] In some embodiments, provided herein is a kit comprising: (a) a first container containing an immunogenic composition comprising a first inactivated split influenza virus, wherein the first inactivated split influenza virus comprises a first chimeric HA, and wherein the first chimeric HA comprises a first influenza virus HA globular head domain and a first influenza virus HA stalk domain, wherein the first HA stalk domain comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and (b) a second container containing a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

[0092] In some embodiments, provided herein is a kit comprising: (a) a first container containing a first immunogenic composition comprising a first inactivated influenza virus and a CpG oligonucleotide adjuvant, wherein the first inactivated influenza virus comprises a first chimeric HA, and wherein the first chimeric HA comprises a first influenza virus HA globular head domain and a first influenza virus HA stalk domain, wherein the first HA stalk domain comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and (b) a second container containing a second immunogenic composition comprising a second inactivated influenza virus and a CpG oligonucleotide adjuvant, wherein the second inactivated influenza virus comprises a second chimeric HA, and wherein the second chimeric HA comprises a second influenza virus HA globular head domain and a second influenza virus HA stalk domain, wherein the second HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA of interest, and wherein the second HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest, wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the second HA globular head domain, and wherein the CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

[0093] In some embodiments, provided herein is a kit comprising: (a) a first container containing a first immunogenic composition comprising a first inactivated split influenza virus and a CpG oligonucleotide adjuvant, wherein the first inactivated split influenza virus comprises a first chimeric HA, and wherein the first chimeric HA comprises a first influenza virus HA globular head domain and a first influenza virus HA stalk domain, wherein the first HA stalk domain comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and (b) a second container containing a second immunogenic composition comprising a second inactivated influenza virus and a CpG oligonucleotide adjuvant, wherein the second inactivated influenza virus comprises a second chimeric HA, and wherein the second chimeric HA comprises a second influenza virus HA globular head domain and a second influenza virus HA stalk domain, wherein the second HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA of interest, and the second HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest, wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the second HA globular head domain, and wherein the CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

3.1 Terminology

[0094] As used herein, the term “about” or “approximately” when used in conjunction with a number refers to any number within 1%, 5%, or 10% of the referenced number and includes the referenced number.

[0095] The term “and/or” as used in a phrase such as “A and/or B” herein is intended to include both A and B; A or B; A (alone); and B (alone). Likewise, the term “and/or” as used in a phrase such as “A, B, and/or C” is intended to encompass each of the following embodiments: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0096] The terms "chimeric influenza virus hemagglutinin," "chimeric influenza virus HA polypeptide," "chimeric hemagglutinin," "chimeric HA," "chimeric influenza hemagglutinin", “chimeric HA polypeptide”, and “cHA” are used herein interchangeably. [0097] As used herein, the terms “comprising” and “including” can be used interchangeably. The terms “comprising” and “including” are to be interpreted as specifying the presence of the stated features or components as referred to, but does not preclude the presence or addition of one or more features, or components, or groups thereof. Additionally, the terms “comprising” and “including” are intended to include examples encompassed by the term “consisting of’. Consequently, the term “consisting of’ can be used in place of the terms “comprising” and “including” to provide for more specific embodiments.

[0098] The terms “CpG,” “CpG motif,” and “cytosine-phosphate-guanosine,” as used herein, refer to an unmethylated cytidine-phospho-guanosine dinucleotide, which when present in an oligonucleotide contributes to a measurable immune response in vitro, in vivo and/or ex vivo. Examples of measurable immune responses include, but are not limited to, antigen-specific antibody production, secretion of cytokines, activation or expansion of lymphocyte populations, such as NK cells, CD4+ T lymphocytes, CD8+ T lymphocytes, B lymphocytes, and the like. Preferably, the CpG oligonucleotide preferentially activates a Th 1 -type response.

[0099] As used herein, the term “elderly human” refers to a human that is 65 years old or older.

[00100] As used herein, the terms "HA" and "hemagglutinin" refer to any influenza virus hemagglutinin known to those of skill in the art or a derivative thereof. Typically, a precursor influenza A virus hemagglutinin comprises domains including a signal peptide, a stem domain (or stalk domain), a globular head domain, a transmembrane domain, and a cytoplasmic domain. In some embodiments, a hemagglutinin consists of a single polypeptide chain, such as HAO. In some embodiments, a hemagglutinin consists of more than one polypeptide chain in quaternary association, e.g., HA1 and HA2. Those of skill in the art will recognize that an immature HAO may be cleaved to release a signal peptide (generally approximately 15 to approximately 20 amino acids) to yield a mature hemagglutinin HAO (z.e., HAO without a signal peptide). In the context of an influenza A virus hemagglutinin, a mature hemagglutinin HAO is generally cleaved by proteolytic enzymes to yield an HA1 subunit (generally approximately 320 to approximately 327 amino acids, including the globular head domain and a portion of the stem domain) and an HA2 subunit (generally approximately 220 to approximately 222 amino acids, including the remainder of the stem domain, a transmembrane domain and a cytoplasmic domain). The terms "hemagglutinin" and "HA", as used herein, encompass an influenza virus HA monomer as well as trimers of influenza virus HA. In addition, the terms "hemagglutinin" and "HA", as used herein, encompass influenza virus hemagglutinin that are modified by, e.g., glycosylation (e.g., N- linked glycosylation) and lipid modification (e.g., S-palmitoylation).

[00101] The terms “influenza virus globular head domain”, “influenza virus HA globular head domain”, “influenza HA globular head domain”, “globular head domain”, “head domain”, “HA head domain”, “HA globular head”, and “HA globular head domain” are used herein interchangeably.

[00102] The terms “influenza virus stem domain”, “influenza stem domain”, “influenza HA stem domain”, “stem domain”, “stalk domain”, ’’influenza virus HA stem domain”, “HA stalk”, “HA stalk domain”, and “HA stem domain” are used herein interchangeably.

[00103] As used herein, the term “HA1” refers to the HA1 of an influenza virus hemagglutinin. Typically, an HA1 includes the globular head domain and a portion of the stem domain of influenza virus hemagglutinin (see, e.g., Sriwilaijaroen and Suzuki, Proc Jpn Acad Ser B Phys Biol Sci. 2012 Jun 11; 88(6): 226-249, the contents of which is incorporated by reference in its entirety).

[00104] As used herein, the term “HA2" refers to the HA2 of an influenza virus hemagglutinin. Typically, an HA2 includes a portion of the stem domain, a transmembrane domain, and a cytoplasmic domain of influenza virus hemagglutinin (see, e.g., Sriwilaijaroen and Suzuki, Proc Jpn Acad Ser B Phys Biol Sci. 2012 Jun 11; 88(6): 226-249, the contents of which is incorporated by reference in its entirety).

[00105] As used herein, the term “HA2 stem domain” refers to the stem domain of the HA2 domain of an influenza virus hemagglutinin. An exemplary HA2 stem domain may be found in Table 5 (see SEQ ID NO: 14).

[00106] As used herein, the term "HA1 C-terminal stem segment" refers to a polypeptide segment that corresponds to the carboxy -terminal portion of the stem domain of HA1. In some embodiments, an HA1 C-terminal stem segment consists of amino acid residues corresponding approximately to amino acids Aq through Acterm of an HA1 of an influenza A virus hemagglutinin. Aq is the cysteine residue in the HA1 C-terminal stem segment that forms or is capable of forming a disulfide bond with a cysteine residue in an influenza A virus HA1 N-terminal stem segment. Acterm or otherwise referred to herein as HAlc-term is the C-terminal amino acid of the HA1 domain as recognized by those of skill in the art. Residue Aq is identified in influenza A hemagglutinin polypeptides in FIGS. 11 A-l ID (z.e., Aq is Cys at amino acid position 277 of an HA1 according to H3 numbering; see also SEQ ID NOS: 70-74 in the sequence table below (Table 5)). In some embodiments, an HA1 C- terminal stem segment consists of amino acid residues corresponding approximately to amino acids 277-329 of HA1 according to H3 numbering. Note that, in this numbering system, 1 refers to the N-terminal amino acid of the mature HAO protein, from which the signal peptide has been removed. Those of skill in the art will readily be able to recognize the amino acid residues that correspond to the HA1 C-terminal stem segment of other influenza HA polypeptides, e.g., the amino acid residues that correspond to the HA1 C-terminal stem segment of HA1 from an Hl hemagglutinin (see, e.g., FIGS. 11 A-l ID; see also SEQ ID NOS: 70-74 in the sequence table below (Table 5)). Amino acid residues that correspond to the HA1 C-terminal stem segment may be identified by aligning the amino acid sequence of an influenza A virus HA for which the HA1 C-terminal stem segment has been identified with the amino acid sequence of the influenza A virus HA of interest. In some embodiments, the three-dimensional structure of HA may also be considered in determining the HA1 C- terminal stem segment of the influenza A virus of interest.

[00107] As used herein, the term "HA1 N-terminal stem segment" refers to a polypeptide segment that corresponds to the amino-terminal portion of the stem domain of an influenza virus hemagglutinin HA1. In some embodiments, an HA1 N-terminal stem segment consists of amino acid residues corresponding approximately to amino acids Ax-term through A_P of an HA1 of an influenza A virus hemagglutinin. Ax-term otherwise referred to herein as HAlx- term is the N-terminal amino acid of HA1 as recognized by those of skill in the art. A_P is the cysteine residue in the HA1 N-terminal stem segment that forms or is capable of forming a disulfide bond with a cysteine residue in an influenza A virus HA1 C-terminal stem segment. Residue A_P is identified in influenza A hemagglutinin polypeptides in FIGS. 11 A-l ID (i.e., A_P is Cys at amino acid position 52 of an HA1 according to H3 numbering; see also SEQ ID NOS: 70-74 in the sequence table below (Table 5)). In some embodiments, an HA1 N- terminal stem segment consists of amino acid residues corresponding approximately to amino acids 1-52 of HA1 according to H3 numbering. Note that, in this numbering system, 1 refers to the N-terminal amino acid of the mature HAO protein, from which the signal peptide has been removed. Those of skill in the art will readily be able to recognize the amino acid residues that correspond to the HA1 N-terminal stem segment of other influenza HA polypeptides, e.g., the amino acid residues that correspond to the HA1 N-terminal stem segment of HA1 from an Hl hemagglutinin (see, e.g., FIGS. 11 A-l ID; see also SEQ ID NOS: 70-74 in the sequence table below (Table 5)). Amino acid residues that correspond to the HA1 N-terminal stem segment of HA1 may be identified by aligning the amino acid sequence of an influenza A virus HA for which the HA1 N-terminal stem segment has been identified with the amino acid sequence of the influenza A virus HA of interest. In some embodiments, the three-dimensional structure of HA may also be considered in determining the HA1 N-terminal stem segment of the influenza A virus of interest.

[00108] As used herein, the term "heterologous" in the context of a polypeptide, nucleic acid or virus refers to a polypeptide, nucleic acid or virus, respectively, that is not normally found in nature or not normally associated in nature with a polypeptide, nucleic acid or virus of interest. For example, an HA globular head domain that is heterologous to an HA stem domain refers to an HA globular head domain that would not be found in nature associated with the HA stem domain or would not normally be associated in nature with the HA stem domain.

[00109] As used herein, the term “human adult” refers to a human 18 years old and older. [00110] As used herein, the term “human child” refers to a human 1 years old to 18 years old.

[00111] As used herein, the term “human infant” refers to a newborn human to 1 years old. [00112] Immunologically distinct: In some embodiments, the HA globular head domain of a chimeric HA is immunologically distinct from the HA globular head domain normally associated with an HA stem domain if there is no cross-reactivity in an immunoassay described herein or known to one of skill in the art. In some embodiments, the HA globular head domain of a chimeric HA is immunologically distinct from the HA globular head domain normally associated with an HA stem domain if there is no cross-reactivity in a hemagglutinin inhibition assay known to one of skill in the art. In some embodiments, the HA globular head domain of a chimeric HA is immunologically distinct from the HA globular head domain normally associated with an HA stem domain if there is no crossreactivity in an immunoassay and a hemagglutinin assay described herein or known to one of skill in the art. In some embodiments, the HA globular head domain of a chimeric HA is immunologically distinct from the HA globular head domain normally associated with an HA stem domain if the HA globular head domain of the chimeric HA is considered of a different influenza A virus subtype than the HA globular head domain normally associated with the HA stem domain using CDC, FDA, or WHO criteria. [00113] As used herein, the term “nucleic acid” and “nucleotide” is intended to include DNA molecules (e.g., cDNA or genomic DNA) and RNA molecules (e.g., mRNA) and analogs of the DNA or RNA generated using nucleotide analogs. In specific embodiments, the nucleic acid is a negative-sense single RNA. In some embodiments, the nucleic acid is cDNA.

[00114] As used herein, the term “or” is to be interpreted as an inclusive “or” meaning any one or any combination. Therefore, “A, B or C” means any of the following: “A; B; C; A and B; A and C; B and C; A, B and C”. An exception to this definition will occur only when a combination of elements, functions, steps or acts are in some way inherently mutually exclusive.

[00115] Percent identity: Techniques known to one of skill in the art can be used to determine the percent identity between two amino acid sequences or between two nucleotide sequences. Generally, to determine the percent identity of two amino acid sequences or of two nucleic acid sequences, the sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced in the sequence of a first amino acid or nucleic acid sequence for optimal alignment with a second amino acid or nucleic acid sequence). The amino acid residues or nucleotides at corresponding amino acid positions or nucleotide positions are then compared. When a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence, then the molecules are identical at that position. The percent identity between the two sequences is a function of the number of identical positions shared by the sequences (z.e., % identity = number of identical overlapping positions/total number of positions X 100%). In some embodiments, the two sequences are the same length. In some embodiments, the percent identity is determined over the entire length of an amino acid sequence or nucleotide sequence. The determination of percent identity between two sequences (e.g., amino acid sequences or nucleic acid sequences) can also be accomplished using a mathematical algorithm. A nonlimiting example of a mathematical algorithm utilized for the comparison of two sequences is the algorithm of Karlin and Altschul, 1990, Proc. Natl. Acad. Sci. U.S.A.87:22642268, modified as in Karlin and Altschul, 1993, Proc. Natl. Acad. Sci. U.S.A.90:58735877. Such an algorithm is incorporated into the NBLAST and XBLAST programs of Altschul et al., 1990, J. Mol. Biol.215:403.

[00116] BLAST nucleotide searches can be performed with the NBLAST nucleotide program parameters set, e.g., for score=100, wordlength=12 to obtain nucleotide sequences homologous to nucleic acid molecules described herein. BLAST protein searches can be performed with the XBLAST program parameters set, e.g., to score 50, wordlength=3 to obtain amino acid sequences homologous to a protein molecule described herein. To obtain gapped alignments for comparison purposes, Gapped BLAST can be utilized as described in Altschul et al., 1997, Nucleic Acids Res.25:33893402. Alternatively, PSI BLAST can be used to perform an iterated search which detects distant relationships between molecules (Id). When utilizing BLAST, Gapped BLAST, and PSI Blast programs, the default parameters of the respective programs (e.g., of XBLAST and NBLAST) can be used (see, e.g., National Center for Biotechnology Information (NCBI) on the worldwide web, ncbi.nlm.nih.gov). In another non-limiting example of a mathematical algorithm utilized for the comparison of sequences is the algorithm of Myers and Miller, 1988, CABIOS 4: 1117. Such an algorithm is incorporated in the ALIGN program (version 2.0) which is part of the GCG sequence alignment software package. When utilizing the ALIGN program for comparing amino acid sequences, a PAM 120 weight residue table, a gap length penalty of 12, and a gap penalty of 4 can be used. The percent identity between two sequences can be determined using techniques similar to those described above, with or without allowing gaps. In calculating percent identity, typically only exact matches are counted. In some embodiments, two sequences are aligned using Clustal Omega.

[00117] As used interchangeably herein, the terms “polynucleotide” and “oligonucleotide” are oligomers of nucleic acids and include single-stranded DNA (ssDNA), double-stranded DNA (dsDNA), single-stranded RNA (ssRNA) and double-stranded RNA (dsRNA), modified oligonucleotides and oligonucleosides or combinations thereof. The oligonucleotide can be linearly or circularly configured, or the oligonucleotide can contain both linear and circular segments. Oligonucleotides are polymers of nucleosides joined, generally, through phosphodiester linkages, although alternate linkages, such as phosphorothioate esters may also be used in oligonucleotides. A nucleoside consists of a purine (adenine (A) or guanine (G) or derivative thereof) or pyrimidine (thymine (T), cytosine (C) or uracil (U), or derivative thereof) base bonded to a sugar. The four nucleoside units (or bases) in DNA are called deoxyadenosine, deoxyguanosine, thymidine, and deoxy cytidine.

[00118] As used herein, the terms “purified” and “isolated” when used in the context of a polypeptide (including an antibody) that is obtained from a natural source, e.g., cells, refers to a polypeptide which is substantially free of contaminating materials from the natural source, e.g., minerals, chemicals from the environment, and/or cellular materials from the natural source, such as but not limited to cell debris, cell wall materials, membranes, organelles, the bulk of the nucleic acids, carbohydrates, proteins, and/or lipids present in cells. Thus, a polypeptide that is isolated includes preparations of a polypeptide having less than about 30%, 20%, 10%, 5%, 2%, or 1% (by dry weight) of cellular materials and/or contaminating materials. As used herein, the terms “purified” and “isolated” when used in the context of a polypeptide (including an antibody) that is chemically synthesized refers to a polypeptide which is substantially free of chemical precursors or other chemicals which are involved in the syntheses of the polypeptide. In a specific embodiment, a chimeric HA is chemically synthesized. In another specific embodiment, a chimeric HA is isolated.

[00119] As used herein, the terms "replication," "viral replication" and "virus replication" in the context of a virus refer to one or more, or all, of the stages of a viral life cycle which result in the propagation of virus. The steps of a viral life cycle include, but are not limited to, virus attachment to the host cell surface, penetration or entry of the host cell (e.g., through receptor mediated endocytosis or membrane fusion), uncoating (the process whereby the viral capsid is removed and degraded by viral enzymes or host enzymes thus releasing the viral genomic nucleic acid), genome replication, synthesis of viral messenger RNA (mRNA), viral protein synthesis, and assembly of viral ribonucleoprotein complexes for genome replication, assembly of virus particles, post-translational modification of the viral proteins, and release from the host cell by lysis or budding and acquisition of a phospholipid envelope which contains embedded viral glycoproteins. In some embodiments, the terms "replication," "viral replication" and "virus replication" refer to the replication of the viral genome. In some embodiments, the terms "replication," "viral replication" and "virus replication" refer to the synthesis of viral proteins.

[00120] As used herein, terms “subject” or “patient” are used interchangeably to refer to an animal (e.g., birds, reptiles, and mammals). In some embodiments, a subject is a bird. In some embodiments, a subject is a mammal including a non-primate (e.g., a camel, donkey, zebra, cow, pig, horse, goat, sheep, cat, dog, rat, and mouse) and a primate (e.g. , a monkey, chimpanzee, and a human). In some embodiments, a subject is a non-human animal. In some embodiments, a subject is a farm animal or pet. In specific embodiments, a subject is a human. In some embodiments, a subject is a human adult. In some embodiments, a subject is an elderly human. In some embodiments, a subject is a human child. In some embodiments, a subject is a human infant.

[00121] As used herein, the term “seasonal influenza virus strain” refers to a strain of influenza virus to which a subject population is exposed to on a seasonal basis. In specific embodiments, the term seasonal influenza virus strain refers to a strain of influenza A virus. In some embodiments, the term seasonal influenza virus strain refers to a strain of influenza A virus that belongs to the H3 subtype, z.e., one of the two subtypes that presently persist in the human subject population.

[00122] The terms “tertiary structure” and “quaternary structure” have the meanings understood by those of skill in the art. Tertiary structure refers to the three-dimensional structure of a single polypeptide chain. Quaternary structure refers to the three dimensional structure of a polypeptide having multiple polypeptide chains.

[00123] As used herein, in some embodiments, the phrase “wild-type” in the context of a viral polypeptide refers to a viral polypeptide that is found in nature and is associated with a naturally occurring virus.

[00124] In some embodiments, the phrase “wild-type” in the context of a virus refers to a virus that is prevalent, circulating naturally and producing typical outbreaks of disease. In some embodiments, the term “wild-type” in the context of a virus refers to a parental virus.

4. DESCRIPTION OF THE FIGURES

[00125] FIG. 1 depicts a timeline of global evolutionary frequencies of H3N2 viruses (02- Dec-2010 to 03-Jun-2022). The graph was adapted from nextstrain/flu/seasonal/h3n2/ha/12y (accessed on November 10, 2022) (78).

[00126] FIGS. 2A-2C depict Group 2 cHA vaccination strategy and experimental design. FIG. 2A depicts a schematic of sequential vaccination with group 2 cHA constructs to induce antibodies that target the immunosubdominant HA stalk domain, as contemplated to be present in humans with pre-existing immunity to H3N2. FIG. 2B depicts a cladogram of HAs from the influenza viruses used in this study for challenge and of recombinant HA proteins used for serology analysis. HAs from challenge viruses were marked with an asterisk. The tree was constructed using amino acid sequences aligned in Clustal Omega (79) and visualized with the FigTree software (tree.bio.ed.ac.uk/software/figtree/). Bris07 (H1N1): A/Brisbane/59/2007 (H1N1), Cal09 (H1N1): A/California/07/2009 (H1N1), Singl5 (H1N1): A/Singapore/GP 1908/2015 (H1N1), canine (H3N2): A/canine/Illinois/41915/2015 (H3N2), HK14 (H3N2): A/Hong Kong/4801/2014 (H3N2), HK68 (H3N2): A/Hong Kong/1/1968 (H3N2), Switzl3 (H3N2): A/Switzerland/9715293/2013 (H3N2), X-79 (H3N2): A/Philippines/2/1982 (H3N2, X-79), Wisc05 (H3N2): A/Wisconsin/67/2005 (H3N2), duck (H4N6): A/duck/Czechoslovakia/1956 (H4N6), swine (H4N6): A/swine/Missouri/AO 1727926/2915 (H4N6), H7N9: A/Shanghai/1/2013 (H7N9), H10N7: A/mallard/Interior Alaska/9BM3355R0/2009 (H10N7), H10N8: A/Jiangxi-Donghu/346/2013 (H10N8), H15N5: A/shearwater/West Australia/2576/1979 (H15N9), B/Coll7: B/Colorado/06/2017. FIG. 2C depicts experimental design; different groups of BALB/c mice (n = 10) were primed intranasally (i.n.) with either a sublethal infection of the B-cH5/l virus (10⁵ PFU/mouse) or PBS. After four weeks, mice were vaccinated with CH15/3HKI4N2HKI4 split vaccine (1 pg HA/mouse), bovine serum albumin (BSA), or whole inactivated A/Philippines/2/1982 (H3N2, X-79) virus or A/Hunan/02285/2017 (H7N1) virus (WIV, positive control) via the intramuscular (i.m.) route. Five mice per group were used for WIV control groups. Alternatively, mice were also vaccinated with CH15/3HKI4N2HKI4 LAIV (10⁵ PFU/mouse) i.n., or with allantoic fluid (AF), or PBS delivered i.n. After four additional weeks, mice were vaccinated in the same manner but with CH4/3HKI4N2HKI4 split vaccine or LAIV. Groups co-administered with the CpG 1018® adjuvant (Adj) received a dose of 30 pg CpG 1018® adjuvant/mouse. Six weeks after the second boost, mice were bled and challenged with 5*LD50 of the heterologous A/Philippines/2/1982 (H3N2, X-79) virus. This vaccination experiment was performed in two sets of independent mice (n = 5 mice/set) for serum analysis. Only one set of mice was challenged.

[00127] FIGS. 3A-3J show that sequential vaccination with group 2 cHA constructs protects mice from lethal challenge and elicits cross-reactive and functional antibodies six weeks after the second vaccination. FIG. 3 A depicts weight loss and survival plots of mice (n = 5) challenged with 5*LD50 of the A/Philippines/2/1982 (H3N2, X-79) virus. Average weight values and the standard deviation (SD) are shown (y-axis of the weight loss plot). Statistical comparison of Split and Split/CpG weight loss curves is also indicated (right side of the weight loss plot). Lines in the survival graphs are nudged to allow for distinction between the lines which would otherwise overlap. FIG. 3B depicts geometric mean titers (GMT) of total serum IgG responses of the two sets of mice (n = 10) against a variety of influenza A and B virus HA proteins and against the matched vaccine NA protein analyzed by ELISA. For group 2 HAs, at least one HA protein representative was tested by subtype. Serum from mice vaccinated with the WIV A/Hunan/02285/2017 (H7N1) virus (n = 5) following the same regimen of vaccination as previously shown was also included as serology control. Comparisons between groups of mice were performed by considering all IgG responses to all tested influenza virus antigens in the split/CpG group and comparing these to the total IgG responses of the other groups. FIG. 3C depicts results from a competition ELISA of individual serum samples from the two sets of vaccinated mice (n = 10) with the trimer interface monoclonal antibody (mAb) FluA-20 against the H3 HK14 protein. FIGS. 3D-3E show GMT titers of individual serum IgGl and IgG2a responses against the vaccine matched A/Hong Kong/4801/2014 H3 (H3 HK14) protein from one set of mice (n = 5). FIG. 3F depicts the ratio of individual IgG2a to IgGl responses against the H3 HK14 protein. As shown in FIG. 3G, serum from the two sets of vaccinated mice (n = 10) were analyzed for antibody dependent cell mediated cytotoxicity (ADCC) activity against the A/Hong Kong/4801/2014 (H3N2) virus using a reporter assay. The fold induction of the reporter signal from individual mouse serum over those from blanks were analyzed. FIG. 3H depicts results from a neuraminidase inhibition (NAI) assay of sera from the two sets of mice (n = 10) against an H6N2 reassortant virus expressing the N2 of the A/Hong Kong/4801/2014 (H3N2) virus. Serum dilutions inhibiting 50% of the NA activity (IC50) were plotted. FIGS. 3I-3J show neutralizing activity of mouse sera against A/Philippines/2/1982 (H3N2, X-79) and A/Hong Kong/4801/2014 (H3N2) viruses. Mouse sera from each one of the sets of vaccinated mice (n = 5) were pooled within each group from each set and analyzed in technical duplicate. The A/Philippines/2/1982 H3 head mAb 1F12 was used as a positive control (30 pg/mL). The GMT readout values per mouse group are represented in each graph with a black line. The limit of detection (LoD) was defined as 1 for ELISA and for the ADCC assay, as 476 (GMT of PBS group) for competition ELISA, as 2 for the NAI assay, and as 10 for the microneutralization assays. Half the value of the LoD was assigned for negative samples. Statistical analyses were performed using one-way ANOVA corrected for Dunnett’s multiple comparison test. Only statistically significant p-values (<0.05) are shown. [00128] FIGS. 4A-4G show that split vaccination reduces viral load in lungs and protects mice in serum passive transfer and dose-de-escalation experiments. FIG. 4A depicts viral load in the lungs of mice vaccinated following the same vaccination regimen as shown in the previous experiment. Lungs of a subset of BALB/c mice from each group (n = 6) were collected on day 3 and 6 post challenge with the A/Philippines/2/1982 (H3N2, X-79) virus. Whole lungs were homogenized in 1 mL of PBS. Viral titers were measured on MDCK cells by the plaque assay method and plotted as PFU/mL. The limit of detection was defined as 50 PFU/mL. A titer of 25 PFU/mL was assigned to negative samples. The GMT of viral titers are also shown. FIG. 4B show analysis results for sera from sequentially vaccinated DBA/2J mice that were pooled and transferred into naive DBA/2J mice (n = 5). Two to three hours after the transfer, mice were challenged with the heterologous A/Switzerland/9715293/2013 (H3N2) virus and monitored for weight loss and survival. Average weight values and SD are shown (y-axis of the weight loss plot). Statistical comparison of Split and Split/CpG weight loss curves is also indicated (right side of the weight loss plot). Lines in the survival graphs are nudged to allow for distinction between the lines which would otherwise overlap, i.p. = intraperitoneal. FIGS. 4C and 4D depict GMT of total serum IgG responses from the dose- de-escalation experiment of CpG 1018® adjuvant and combination with alum against the H3 HK14 protein and a stabilized headless H3 protein (mini H3) from the A/Wisconsin/67/2005 (H3N2) virus, respectively. FIGS. 4E-4F depict serum IgGl and IgG2a responses from the dose-de-escalation experiment of CpG 1018® adjuvant and combination with alum against the H3 HK14 protein. FIG. 4G shows the ratio of IgG2a to IgGl responses against the H3 HK14 protein. The GMT of readout values per mouse group are represented in each graph with a black line. The limit of detection for ELISA (LoD) was defined as 1. Half the value of the LoD was assigned for negative samples. In all cases, mice vaccinated with split vaccines and BSA were initially primed with the B-cH5/l virus. Statistical analyses were performed using one-way ANOVA corrected with the non-parametric Dunn’s test for viral titers, and one-way ANOVA corrected for Dunnett’s multiple comparison test for the rest of assays. Only statistically significant p-values (<0.05) are shown.

[00129] FIGS. 5A-5C depict results of systemic and local CD4+ effector memory (EM) T-cell responses induced by split vaccines. FIG. 5 A depicts vaccination strategy and experimental design. FIG. 5B depicts representative flow cytometry plots showing the percentage of IFNy- and TNFa-producing CD4+ EM T lymphocytes in mouse spleens and lungs 6 days after challenge with A/Philippines/2/1982 (H3N2, X-79) virus (n = 3 mice/group). T-cells were stimulated with overlapping peptide libraries covering the H3 protein sequence from A/Perth/16/2009 (H3N2) virus, the N2 protein from A/Perth/ 16/2009 (H3N2) virus, and the NP protein from A/Puerto Rico/8/1934 (H1N1) virus. Different groups of BALB/c mice were sequentially vaccinated with PBS, BSA + 10 pg/mouse of CpG 1018® adjuvant, or 1 pg/mouse of split vaccine + 10 pg/mouse of CpG 1018® adjuvant following vaccination regimen as shown in previous experiments. FIG. 5C depicts the percentage of different cytokine producing cell populations within the total CD4+ EM T-cell subset (n = 3) after background subtraction. Average and SD values are shown. In all cases, mice vaccinated with split vaccines and BSA were initially primed with the B-cH5/l virus. Statistical analyses were performed using one-way ANOVA corrected for Dunn’s multiple comparison test. Only statistically significant p-values (<0.05) are shown.

[00130] FIGS. 6A-6I show that sequential vaccination with group 2 cHA split vaccines protects mice from challenge with a broad spectrum of influenza A viruses. FIG. 6A depicts experimental design. Different groups of mice (n = 5) were sequentially vaccinated with 1 pg/mouse of split vaccine adjuvanted with 10 pg/mouse of CpG 1018® adjuvant as shown in previous experiments and challenged with the heterologous A/Switzerland/9715293/2013 (H3N2) and A/canine/Illinois/41915/2015 (H3N2) viruses (FIGS. 6B and 6C, respectively), the heterologous group 2 A/swine/Missouri/AO 1727926/2015 (H4N6) (FIG. 6D), A/Shanghai/1/2013 (H7N9) (FIG. 6E), A/Jiangxi-Donghu/346/2013 (H10N8) (FIG. 6F), A/mallard/Gurjev/263/1982 (H14N1) (FIG. 6G), A/wedge-tailed shearwater/Western Australia/2576/1979 (H15N5) viruses (FIG. 6H), and the group 1 A/Singapore/GP1908/2015 (H1N1) virus (FIG. 61). Body weight and survival were monitored over the course of 14 days after challenge. Vaccination and challenge experiments with H3N2, H4N6, and H14N1 viruses were conducted in DBA/2J mice, whereas H7N9, H10N8, H15N5, and H1N1 challenge experiments were performed in BALB/c mice. The average weight values and SD are shown (y-axes of the weight loss plots). In all cases, mice vaccinated with split vaccines and BSA were initially primed with the B-cH5/l virus. Comparison of Split/CpG and BSA/CpG weight loss curves are shown (right sides of the weight loss plots). Statistical analyses were performed using one-way ANOVA corrected with the non-parametric Dunn’s test for viral titers, and one-way ANOVA corrected for Dunnett’s multiple comparison test for the rest of assays. Lines in the survival graphs are nudged to allow for distinction between the lines which would otherwise overlap.

[00131] FIG. 7 show that infection with B-cH5/l virus induces IgG titers against the influenza B NA. GMT of total serum IgG responses against B/Colorado/06/2017 NA from one set of BALB/c mice (n = 5) primed with B-cH5/l virus or PBS analyzed by ELISA are shown. Black lines represent the GMT.

[00132] FIG. 8 depicts results of serum from one set of vaccinated BALB/c mice (n = 5) that was analyzed for antibody dependent cell mediated cytotoxicity (ADCC) activity against the A/Philippines/2/1982 (H3N2, X-79) virus using a reporter assay. The fold induction of the reporter signal from individual mouse serum over those from blanks were analyzed. The H3 stalk mAb 9H10 was used as a positive control (30 pg/mL). Black lines represent the GMT.

[00133] FIGS. 9A-9C depict results of dose-de-escalation experiments of split vaccine and CpG 1018® adjuvant. FIG. 9A shows dose-de-escalation of split vaccine. Different groups of BALB/c mice (n = 5) were sequentially vaccinated with different doses of split vaccine (3, 1, 0.3, 0.1 pg/mouse) adjuvanted with 30 pg/mouse of CpG 1018® adjuvant following the same vaccination regimen as in previous experiments, and were challenged with the A/Philippines/2/1982 (H3N2, X-79) virus. Weight loss and survival were monitored (left and right side, respectively). Average weight values and SD are shown. FIG. 9B shows dose-de-escalation of CpG 1018® adjuvant and combination of CpG 1018® adjuvant and aluminum hydroxide gel 2% (alum). Different groups of BALB/c mice (n = 5) were sequentially vaccinated with 1 pg/mouse of split vaccine and different doses of CpG 1018® adjuvant (30, 10, 3 pg/mouse) with and without the combination with alum (50, 15, 5 pg/mouse) at a ratio 1 :5 following the same vaccination regimen as in previous experiments. Mice were challenged with the A/Philippines/2/1982 (H3N2, X-79) virus. The same group of mice vaccinated with 1 pg/mouse of split vaccine and 30 pg/mouse (the first set on the left, FIG. 4C) was included for comparison. Average weight values and SD are shown. FIG. 9C depicts the gating strategy utilized for the identification of cytokine-producing T-cells. Splenocytes from immunized mice were stimulated 6h with 1 pL/well of peptide pool library containing 15-mer peptides with 11 amino acid overlap (5 pg/mL) covering the whole sequences of HA of the A/Perth/ 16/2009 (H3N2) influenza virus strain in the presence of 5 pg/mL Brefeldin A (Biolegend), 2 pM Monensin (Biolegend), and 25 pg/mL of costimulatory anti-CD28 antibodies (Biolegend). Live CD3+ cells were isolated after the exclusion of doublets, debris (based on the FSC-A/SSC-A and FSCA/FSC-H light scattering), and dead cells (Zombie Aqua+). T-lymphocytes were further subdivided into CD8+ and CD4+ T cell populations. CD4+ and CD8+ effector memory (EM) cells were identified as CD44+CD62L-. TNFa+, IL-2+, and IFNy+ events were selected, and Boolean gating was applied to obtain the subpopulations producing all possible combinations of analyzed cytokines.

[00134] FIGS. 10A-10B FIG. 10A depicts representative flow cytometry plots showing the percentage of IL-2- and TNFa-producing CD8+ effector memory (EM) T- lymphocytes in BALB/c mouse spleens and lungs 6 days after challenge with A/Philippines/2/1982 (H3N2, X-79) virus (n = 3 mice/group). T-cells were stimulated with overlapping peptide libraries covering the H3 protein sequence from A/Perth/16/2009 (H3N2) virus, the N2 protein from A/Perth/16/2009 (H3N2) virus, and the NP protein from A/Puerto Rico/8/1934 (H1N1) virus. Different groups of BALB/c mice were sequentially vaccinated with PBS, BSA + 10 pg/mouse of CpG 1018® adjuvant, or 1 pg HA/mouse of split vaccine + 10 pg/mouse of CpG 1018® adjuvant. FIG. 10B depicts the percentage of different cytokineproducing cell populations within the total CD8+ EM T-cell subset (n = 3) after background subtraction. Average and SD values are shown. Statistical analyses were performed using one-way ANOVA corrected for Dunn’s multiple comparison test. Only statistically significant p-values (<0.05) are shown.

[00135] FIGS. 11A-11D show an alignment of influenza A virus HAs (SEQ ID NOS:53- 69). The start of the mature HA sequence is indicated, the Ap is indicated, the Aq is indicated, and the start of the HA2 domain is indicated. Ap designates cysteine at amino acid position 52 of mature influenza A virus HA according to H3 numbering. Aq designates cysteine at amino acid position 277 of mature influenza A virus HA according to H3 numbering.

5. DETAILED DESCRIPTION

[00136] In one aspect, provided herein are immunogenic compositions comprising a chimeric hemagglutinin and a CpG oligonucleotide adjuvant described herein In a specific embodiment, provided herein are immunogenic compositions comprising an inactivated influenza A virus or inactivated split influenza A virus and a CpG oligonucleotide adjuvant described herein, wherein the inactivated influenza A virus or inactivated split influenza A virus comprises a chimeric hemagglutinin described herein. In another aspect, provided herein are methods of immunizing a subject against influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus) using an immunogenic composition described herein. In another aspect, provided herein are methods of preventing influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g, group 2 influenza A virus) in a subject using an immunogenic composition described herein.

5.1 Immunogenic Compositions

[00137] In one aspect, provided herein are immunogenic compositions comprising a chimeric hemagglutinin (HA) and a CpG oligonucleotide adjuvant described herein. In some embodiments, provided herein are immunogenic compositions comprising a chimeric HA and a CpG oligonucleotide adjuvant described herein in an admixture with a pharmaceutically acceptable carrier. In some embodiments, provided herein are immunogenic compositions comprising an inactivated influenza virus and a CpG oligonucleotide adjuvant described herein, wherein the inactivated influenza virus comprises a chimeric HA described herein. In some embodiments, provided herein are immunogenic compositions comprising an inactivated influenza virus and a CpG oligonucleotide adjuvant described herein in an admixture with a pharmaceutically acceptable carrier, wherein the inactivated influenza virus comprises a chimeric HA described herein. In some embodiments, provided herein are immunogenic compositions comprising an inactivated influenza virus and a CpG oligonucleotide adjuvant described herein in an admixture with a pharmaceutically acceptable carrier, wherein the inactivated influenza A virus comprises a chimeric HA described herein. In some embodiments, provided herein are immunogenic compositions comprising an inactivated split influenza virus and a CpG oligonucleotide adjuvant described herein, wherein the inactivated split influenza virus comprises a chimeric HA described herein. In some embodiments, provided herein are immunogenic compositions comprising an inactivated split influenza virus and a CpG oligonucleotide adjuvant described herein in an admixture with a pharmaceutically acceptable carrier, wherein the inactivated split influenza virus comprises a chimeric HA described herein. In some embodiments, provided herein are immunogenic compositions comprising an inactivated split influenza virus and a CpG oligonucleotide adjuvant described herein in an admixture with a pharmaceutically acceptable carrier, wherein the inactivated split influenza A virus comprises a chimeric HA described herein. In specific embodiments, the chimeric HA is one described in this Section or Section 5.3 or 6, infra. In specific embodiments, the CpG oligonucleotide adjuvant is one described in this Section or Section 5.2 or 6, infra. In some embodiments, the immunogenic composition does not comprise an aluminum salt (e.g., aluminum hydroxide, amorphous aluminum hydroxyphosphate sulfate, aluminum hydroxide, aluminum phosphate, or potassium aluminum sulfate, or a combination thereof). In some embodiments, the immunogenic composition comprises an aluminum salt (e.g., aluminum hydroxide, amorphous aluminum hydroxyphosphate sulfate, aluminum hydroxide, aluminum phosphate, or potassium aluminum sulfate, or a combination thereof).

[00138] In some embodiments, provided herein is an immunogenic composition comprising: (a) a chimeric HA comprising an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises an amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA, wherein the HA globular head domain of the chimeric HA is heterologous to the HA stalk domain, and wherein the HA globular head domain of the chimeric HA is immunologically distinct from the globular head domain of the group 2 influenza A virus HA; and (b) a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3). In some embodiments, provided herein is an immunogenic composition comprising: (a) a chimeric HA comprising an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises an amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA, wherein the HA globular head domain of the chimeric HA is heterologous to the HA stalk domain, and wherein the HA globular head domain of the chimeric HA is immunologically distinct from the globular head domain of the group 2 influenza A virus HA; and (b) a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3), in an admixture with a pharmaceutically acceptable carrier. In specific embodiments, the chimeric HA is one described in this Section or Section 5.3 or 6, infra. In specific embodiments, the CpG oligonucleotide adjuvant is one described in this Section or Section 5.2 or 6, infra. In some embodiments, the immunogenic composition described herein does not comprise an aluminum salt (e.g., aluminum hydroxide, amorphous aluminum hydroxyphosphate sulfate, aluminum hydroxide, aluminum phosphate, or potassium aluminum sulfate, or a combination thereof). In some embodiments, the immunogenic composition described herein comprises an aluminum salt (e.g., aluminum hydroxide, amorphous aluminum hydroxyphosphate sulfate, aluminum hydroxide, aluminum phosphate, or potassium aluminum sulfate, or a combination thereof).

[00139] In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated influenza virus comprising a chimeric HA, wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises an amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA, wherein the HA globular head domain of the chimeric HA is heterologous to the HA stalk domain, and wherein the HA globular head domain of the chimeric HA is immunologically distinct from the globular head domain of the group 2 influenza A virus HA; and (b) a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3). In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated influenza virus comprising a chimeric HA, wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises an amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA, wherein the HA globular head domain of the chimeric HA is heterologous to the HA stalk domain, and wherein the HA globular head domain of the chimeric HA is immunologically distinct from the globular head domain of the group 2 influenza A virus HA; and (b) a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3). In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated influenza virus comprising a chimeric HA, wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises an amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA, wherein the HA globular head domain of the chimeric HA is heterologous to the HA stalk domain, and wherein the HA globular head domain of the chimeric HA is immunologically distinct from the globular head domain of the group 2 influenza A virus HA; and (b) a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3), in an admixture with a pharmaceutically acceptable carrier. In specific embodiments, the chimeric HA is one described in this Section or Section 5.3 or 6, infra. In specific embodiments, the CpG oligonucleotide adjuvant is one described in this Section or Section 5.2 or 6, infra. In some embodiments, the immunogenic composition described herein does not comprise an aluminum salt (e.g., aluminum hydroxide, amorphous aluminum hydroxyphosphate sulfate, aluminum hydroxide, aluminum phosphate, or potassium aluminum sulfate, or a combination thereof). In some embodiments, the immunogenic composition described herein comprises an aluminum salt e.g., aluminum hydroxide, amorphous aluminum hydroxyphosphate sulfate, aluminum hydroxide, aluminum phosphate, or potassium aluminum sulfate, or a combination thereof).

[00140] In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated influenza virus comprising a chimeric HA, wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA, and wherein the HA globular head domain of the chimeric HA comprises the amino acid sequence of an HA globular head of an influenza A virus of a different strain, subtype, or group than the group 2 influenza A virus HA; and (b) a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3). In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated influenza virus comprising a chimeric HA, wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA, and wherein the HA globular head domain of the chimeric HA comprises the amino acid sequence of an HA globular head of an influenza A virus of a different strain, subtype, or group than the group 2 influenza A virus HA; and (b) a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3), in an admixture with a pharmaceutically acceptable carrier. In specific embodiments, the chimeric HA is one described in this Section or Section 5.3 or 6, infra. In specific embodiments, the CpG oligonucleotide adjuvant is one described in this Section or Section 5.2 or 6, infra. In some embodiments, the immunogenic composition described herein does not comprise an aluminum salt (e.g., aluminum hydroxide, amorphous aluminum hydroxyphosphate sulfate, aluminum hydroxide, aluminum phosphate, or potassium aluminum sulfate, or a combination thereof). In some embodiments, the immunogenic composition described herein comprises an aluminum salt (e.g., aluminum hydroxide, amorphous aluminum hydroxyphosphate sulfate, aluminum hydroxide, aluminum phosphate, or potassium aluminum sulfate, or a combination thereof).

[00141] In some embodiments, provided herein are immunogenic compositions comprising an inactivated split influenza virus and a CpG oligonucleotide adjuvant described herein, wherein the inactivated split influenza virus comprises a chimeric hemagglutinin described herein. In some embodiments, provided herein are immunogenic compositions comprising an inactivated split influenza A virus and a CpG oligonucleotide adjuvant described herein in an admixture with a pharmaceutically acceptable carrier, wherein the inactivated split influenza virus comprises a chimeric hemagglutinin described herein. In specific embodiments, the chimeric HA is one described in this Section or Section 5.3 or 6, infra. In specific embodiments, the CpG oligonucleotide adjuvant is one described in this Section or Section 5.2 or 6, infra. In some embodiments, the immunogenic composition does not comprise an aluminum salt (e.g., aluminum hydroxide, amorphous aluminum hydroxyphosphate sulfate, aluminum hydroxide, aluminum phosphate, or potassium aluminum sulfate, or a combination thereof). In some embodiments, the immunogenic composition comprises an aluminum salt (e.g., aluminum hydroxide, amorphous aluminum hydroxyphosphate sulfate, aluminum hydroxide, aluminum phosphate, or potassium aluminum sulfate, or a combination thereof).

[00142] In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated split influenza virus comprising a chimeric HA, wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises an amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA, wherein the HA globular head domain of the chimeric HA is heterologous to the HA stalk domain, and wherein the HA globular head domain of the chimeric HA is immunologically distinct from the globular head domain of the group 2 influenza A virus HA; and (b) a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3). In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated split influenza virus comprising a chimeric hemagglutinin (HA), wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises an amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA, wherein the HA globular head domain of the chimeric HA is heterologous to the HA stalk domain, and wherein the HA globular head domain of the chimeric HA is immunologically distinct from the globular head domain of the group 2 influenza A virus HA; and (b) a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3), in an admixture with a pharmaceutically acceptable carrier. In specific embodiments, the chimeric HA is one described in this Section or Section 5.3 or 6, infra. In specific embodiments, the CpG oligonucleotide adjuvant is one described in this Section or Section 5.2 or 6, infra. In some embodiments, the immunogenic composition described herein does not comprise an aluminum salt (e.g., aluminum hydroxide, amorphous aluminum hydroxyphosphate sulfate, aluminum hydroxide, aluminum phosphate, or potassium aluminum sulfate, or a combination thereof). In some embodiments, the immunogenic composition described herein comprises an aluminum salt (e.g., aluminum hydroxide, amorphous aluminum hydroxyphosphate sulfate, aluminum hydroxide, aluminum phosphate, or potassium aluminum sulfate, or a combination thereof).

[00143] In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated split influenza virus comprising a chimeric hemagglutinin (HA), wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA, and wherein the HA globular head domain of the chimeric HA comprises the amino acid sequence of an HA globular head of an influenza A virus of a different strain, subtype, or group than the group 2 influenza A virus HA; and (b) a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3). In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated split influenza virus comprising a chimeric hemagglutinin (HA), wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA, and wherein the HA globular head domain of the chimeric HA comprises the amino acid sequence of an HA globular head of an influenza A virus of a different strain, subtype, or group than the group 2 influenza A virus HA; and (b) a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3), in an admixture with a pharmaceutically acceptable carrier. In specific embodiments, the chimeric HA is one described in this Section or Section 5.3 or 6, infra. In specific embodiments, the CpG oligonucleotide adjuvant is one described in this Section or Section 5.2 or 6, infra. In some embodiments, the immunogenic composition described herein does not comprise an aluminum salt (e.g., aluminum hydroxide, amorphous aluminum hydroxyphosphate sulfate, aluminum hydroxide, aluminum phosphate, or potassium aluminum sulfate, or a combination thereof). In some embodiments, the immunogenic composition described herein comprises an aluminum salt (e.g., aluminum hydroxide, amorphous aluminum hydroxyphosphate sulfate, aluminum hydroxide, aluminum phosphate, or potassium aluminum sulfate, or a combination thereof).

[00144] In some embodiments, provided herein is an immunogenic composition comprising: (a) a chimeric HA, wherein the chimeric HA comprises the HA globular head domain of influenza virus A/wedged-tailed/shearwater/Western Australia/2576/9134 (H15N9) HA and the HA stalk domain of influenza virus A/Hong Kong/4801/2014 (H3N2) NYMC X-263 HA; and (b) a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3). In some embodiments, provided herein is an immunogenic composition comprising: (a) a chimeric HA, wherein the chimeric HA comprises the HA globular head domain of influenza virus A/wedged- tailed/shearwater/Western Australia/2576/9134 (H15N9) HA and the HA stalk domain of influenza virus A/Hong Kong/4801/2014 (H3N2) NYMC X-263 HA; and (b) a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3), in an admixture with a pharmaceutically acceptable carrier. [00145] In some embodiments, provided herein is an immunogenic composition comprising: (a) a chimeric HA, wherein the chimeric HA comprises the HA globular head domain of influenza virus A/duck/Czechoslovakia/1956 (H4N6) HA and the HA stalk domain of influenza virus A/Hong Kong/4801/2014 (H3N2) NYMC X-263 HA; and (b) a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3). In some embodiments, provided herein is an immunogenic composition comprising: (a) a chimeric HA, wherein the chimeric HA comprises the HA globular head domain of influenza virus A/duck/Czechoslovakia/1956 (H4N6) HA and the HA stalk domain of influenza virus A/Hong Kong/4801/2014 (H3N2) NYMC X-263 HA; and (b) a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3), in an admixture with a pharmaceutically acceptable carrier.

[00146] In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated influenza virus comprising a chimeric HA, wherein the chimeric HA comprises the HA globular head domain of influenza virus A/wedged- tailed/shearwater/Western Australia/2576/9134 (H15N9) HA and the HA stalk domain of influenza virus A/Hong Kong/4801/2014 (H3N2) NYMC X-263 HA; and (b) a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3). In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated influenza virus comprising a chimeric HA, wherein the chimeric HA comprises the HA globular head domain of influenza virus A/wedged-tailed/shearwater/Western Australia/2576/9134 (H15N9) HA and the HA stalk domain of influenza virus A/Hong Kong/4801/2014 (H3N2) NYMC X-263 HA; and (b) a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3), in an admixture with a pharmaceutically acceptable carrier. In some embodiments, the inactivated influenza virus comprises the NA of influenza virus A/Hong Kong/4801/2014 (H3N2) NYMC X-263. In some embodiments, the inactivated influenza virus comprises one or more, or all proteins other than HA and NA encoded by one or more, or all genes of influenza virus A/Puerto Rico/8/1934 (H1N1). In some embodiments, the inactivated influenza virus comprises the non- structural proteins and matrix protein of influenza virus A/Puerto Rico/8/1934 (H1N1). [00147] In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated split influenza virus comprising a chimeric HA, wherein the chimeric HA comprises the HA globular head domain of influenza virus A/wedged- tailed/shearwater/Western Australia/2576/9134 (H15N9) HA and the HA stalk domain of influenza virus A/Hong Kong/4801/2014 (H3N2) NYMC X-263 HA; and (b) a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3). In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated split influenza virus comprising a chimeric HA, wherein the chimeric HA comprises the HA globular head domain of influenza virus A/wedged-tailed/shearwater/Western Australia/2576/9134 (H15N9) HA and the HA stalk domain of influenza virus A/Hong Kong/4801/2014 (H3N2) NYMC X-263 HA; and (b) a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3), in an admixture with a pharmaceutically acceptable carrier. In some embodiments, the inactivated split influenza virus comprises the NA of influenza virus A/Hong Kong/4801/2014 (H3N2) NYMC X-263. In some embodiments, the inactivated split influenza virus comprises one or more, or all proteins other than HA and NA encoded by one or more, or all genes of influenza virus A/Puerto Rico/8/1934 (H1N1). In some embodiments, the inactivated split influenza virus comprises the non- structural proteins and matrix protein of influenza virus A/Puerto Rico/8/1934 (H1N1).

[00148] In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated influenza virus comprising a chimeric HA, wherein the chimeric HA comprises the HA globular head domain of influenza virus A/duck/Czechoslovakia/1956 (H4N6) HA and the HA stalk domain of influenza virus A/Hong Kong/4801/2014 (H3N2) NYMC X-263 HA; and (b) a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3). In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated influenza virus comprising a chimeric HA, wherein the chimeric HA comprises the HA globular head domain of influenza virus A/duck/Czechoslovakia/1956 (H4N6) HA and the HA stalk domain of influenza virus A/Hong Kong/4801/2014 (H3N2) NYMC X-263 HA; and (b) a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3), in an admixture with a pharmaceutically acceptable carrier. In some embodiments, the inactivated influenza virus comprises the NA of influenza virus A/Hong Kong/4801/2014 (H3N2) NYMC X-263. In some embodiments, the inactivated influenza virus comprises one or more, or all proteins other than HA and NA encoded by one or more, or all genes (e.g., non- structural and/or matrix encoding genes) of influenza virus A/Puerto Rico/8/1934 (H1N1). In some embodiments, the inactivated influenza virus comprises the non-structural proteins and matrix protein of influenza virus A/Puerto Rico/8/1934 (H1N1).

[00149] In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated split influenza virus comprising a chimeric HA, wherein the chimeric HA comprises the HA globular head domain of influenza virus A A/duck/Czechoslovakia/1956 (H4N6) HA and the HA stalk domain of influenza virus A/Hong Kong/4801/2014 (H3N2) NYMC X-263 HA; and (b) a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3). In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated split influenza virus comprising a chimeric HA, wherein the chimeric HA comprises the HA globular head domain of influenza virus A/duck/Czechoslovakia/1956 (H4N6) HA and the HA stalk domain of influenza virus A/Hong Kong/4801/2014 (H3N2) NYMC X-263 HA; and (b) a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3), in an admixture with a pharmaceutically acceptable carrier. In some embodiments, the inactivated split influenza virus comprises the NA of influenza virus A/Hong Kong/4801/2014 (H3N2) NYMC X-263. In some embodiments, the inactivated split influenza virus comprises one or more, or all proteins other than HA and NA encoded by one or more, or all genes e.g., non- structural and/or matrix encoding genes) of influenza virus A/Puerto Rico/8/1934 (H1N1). In some embodiments, the inactivated split influenza virus comprises the non-structural proteins and matrix protein of influenza virus A/Puerto Rico/8/1934 (H1N1).

[00150] In some embodiments, provided herein is an immunogenic composition comprising: (a) a chimeric HA, wherein the chimeric HA comprises the HA globular head domain of influenza virus A/wedged-tailed/shearwater/Western Australia/2576/9134 (H15N9) HA and the HA stalk domain of influenza virus A/Hong Kong/4801/2014 (H3N2) NYMC X-263 HA; and (b) a CpG oligonucleotide adjuvant comprising the nucleotide sequence of SEQ ID NO:4, or CpG 1018® adjuvant. In some embodiments, provided herein is an immunogenic composition comprising: (a) a chimeric HA, wherein the chimeric HA comprises the HA globular head domain of influenza virus A/wedged- tailed/shearwater/Western Australia/2576/9134 (H15N9) HA and the HA stalk domain of influenza virus A/Hong Kong/4801/2014 (H3N2) NYMC X-263 HA; and (b) a CpG oligonucleotide adjuvant comprising the nucleotide sequence of SEQ ID NO:4, or CpG 1018® adjuvant, in an admixture with a pharmaceutically acceptable carrier.

[00151] In some embodiments, provided herein is an immunogenic composition comprising: (a) a chimeric HA, wherein the chimeric HA comprises the HA globular head domain of influenza virus A/duck/Czechoslovakia/1956 (H4N6) HA and the HA stalk domain of influenza virus A/Hong Kong/4801/2014 (H3N2) NYMC X-263 HA; and (b) a CpG oligonucleotide adjuvant comprising the nucleotide sequence of SEQ ID NO:4, or CpG 1018® adjuvant. In some embodiments, provided herein is an immunogenic composition comprising: (a) a chimeric HA, wherein the chimeric HA comprises the HA globular head domain of influenza virus A/duck/Czechoslovakia/1956 (H4N6) HA and the HA stalk domain of influenza virus A/Hong Kong/4801/2014 (H3N2) NYMC X-263 HA; and (b) a CpG oligonucleotide adjuvant comprising the nucleotide sequence of SEQ ID NO:4, or CpG 1018® adjuvant, in an admixture with a pharmaceutically acceptable carrier.

[00152] In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated influenza virus comprising a chimeric HA, wherein the chimeric HA comprises the HA globular head domain of influenza virus A/wedged- tailed/shearwater/Western Australia/2576/9134 (H15N9) HA and the HA stalk domain of influenza virus A/Hong Kong/4801/2014 (H3N2) NYMC X-263 HA; and (b) a CpG oligonucleotide adjuvant comprising the nucleotide sequence of SEQ ID NO:4, or CpG 1018® adjuvant. In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated influenza virus comprising a chimeric HA, wherein the chimeric HA comprises the HA globular head domain of influenza virus A/wedged- tailed/shearwater/Western Australia/2576/9134 (H15N9) HA and the HA stalk domain of influenza virus A/Hong Kong/4801/2014 (H3N2) NYMC X-263 HA; and (b) a CpG oligonucleotide adjuvant comprising the nucleotide sequence of SEQ ID NO:4, or CpG 1018® adjuvant, in an admixture with a pharmaceutically acceptable carrier. In some embodiments, the inactivated influenza virus comprises the NA of influenza virus A/Hong Kong/4801/2014 (H3N2) NYMC X-263. In some embodiments, the inactivated influenza virus comprises one or more, or all proteins other than HA and NA encoded by one or more, or all genes of influenza virus A/Puerto Rico/8/1934 (H1N1). In some embodiments, the inactivated influenza virus comprises the non- structural proteins and matrix protein of influenza virus A/Puerto Rico/8/1934 (H1N1).

[00153] In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated split influenza virus comprising a chimeric HA, wherein the chimeric HA comprises the HA globular head domain of influenza virus A/wedged- tailed/shearwater/Western Australia/2576/9134 (H15N9) HA and the HA stalk domain of influenza virus A/Hong Kong/4801/2014 (H3N2) NYMC X-263 HA; and (b) a CpG oligonucleotide adjuvant comprising the nucleotide sequence of SEQ ID NO:4, or CpG 1018® adjuvant In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated split influenza virus comprising a chimeric HA, wherein the chimeric HA comprises the HA globular head domain of influenza virus A/wedged- tailed/shearwater/Western Australia/2576/9134 (H15N9) HA and the HA stalk domain of influenza virus A/Hong Kong/4801/2014 (H3N2) NYMC X-263 HA; and (b) a CpG oligonucleotide adjuvant comprising the nucleotide sequence of SEQ ID NO:4, or CpG 1018® adjuvant, in an admixture with a pharmaceutically acceptable carrier. In some embodiments, the inactivated split influenza virus comprises the NA of influenza virus A/Hong Kong/4801/2014 (H3N2) NYMC X-263. In some embodiments, the inactivated split influenza virus comprises one or more, or all proteins other than HA and NA encoded by one or more, or all genes of influenza virus A/Puerto Rico/8/1934 (H1N1). In some embodiments, the inactivated split influenza virus comprises the non- structural proteins and matrix protein of influenza virus A/Puerto Rico/8/1934 (H1N1).

[00154] In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated influenza virus comprising a chimeric HA, wherein the chimeric HA comprises the HA globular head domain of influenza virus A/duck/Czechoslovakia/1956 (H4N6) HA and the HA stalk domain of influenza virus A/Hong Kong/4801/2014 (H3N2) NYMC X-263 HA; and (b) a CpG oligonucleotide adjuvant comprising the nucleotide sequence of SEQ ID NO:4, or CpG 1018® adjuvant. In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated influenza virus comprising a chimeric HA, wherein the chimeric HA comprises the HA globular head domain of influenza virus A/duck/Czechoslovakia/1956 (H4N6) HA and the HA stalk domain of influenza virus A/Hong Kong/4801/2014 (H3N2) NYMC X-263 HA; and (b) a CpG oligonucleotide adjuvant comprising the nucleotide sequence of SEQ ID NO:4, or CpG 1018® adjuvant, in an admixture with a pharmaceutically acceptable carrier. In some embodiments, the inactivated influenza virus comprises the NA of influenza virus A/Hong Kong/4801/2014 (H3N2) NYMC X-263. In some embodiments, the inactivated influenza virus comprises one or more, or all proteins other than HA and NA encoded by one or more, or all genes (e.g., non-structural and/or matrix encoding genes) of influenza virus A/Puerto Rico/8/1934 (H1N1). In some embodiments, the inactivated influenza virus comprises the non-structural proteins and matrix protein of influenza virus A/Puerto Rico/8/1934 (H1N1).

In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated split influenza virus comprising a chimeric HA, wherein the chimeric HA comprises the HA globular head domain of influenza virus A A/duck/Czechoslovakia/1956 (H4N6) HA and the HA stalk domain of influenza virus A/Hong Kong/4801/2014 (H3N2) NYMC X-263 HA; and (b) a CpG oligonucleotide adjuvant comprising the nucleotide sequence of SEQ ID NO:4, or CpG 1018® adjuvant. In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated split influenza virus comprising a chimeric HA, wherein the chimeric HA comprises the HA globular head domain of influenza virus A/duck/Czechoslovakia/1956 (H4N6) HA and the HA stalk domain of influenza virus A/Hong Kong/4801/2014 (H3N2) NYMC X-263 HA; and (b) a CpG oligonucleotide adjuvant comprising the nucleotide sequence of SEQ ID NO:4, or CpG 1018® adjuvant, in an admixture with a pharmaceutically acceptable carrier. In some embodiments, the inactivated split influenza virus comprises the NA of influenza virus A/Hong Kong/4801/2014 (H3N2) NYMC X-263. In some embodiments, the inactivated split influenza virus comprises one or more, or all proteins other than HA and NA encoded by one or more, or all genes (e.g., non-structural and/or matrix encoding genes) of influenza virus A/Puerto Rico/8/1934 (H1N1). In some embodiments, the inactivated split influenza virus comprises the non-structural proteins and matrix protein of influenza virus A/Puerto Rico/8/1934 (H1N1).

[00155] In some embodiments, provided herein is an immunogenic composition comprising: (a) a chimeric HA comprising the amino acid sequence of SEQ ID NO: 5 or 6; and (b) a CpG oligonucleotide adjuvant comprising the nucleotide sequence of SEQ ID NO: 4, or CpG 1018® adjuvant. In some embodiments, provided herein is an immunogenic composition comprising: (a) a chimeric HA comprising the amino acid sequence of SEQ ID NO: 7 or 8; and (b) a CpG oligonucleotide adjuvant comprising the nucleotide sequence of SEQ ID NO: 4, or CpG 1018® adjuvant.

[00156] In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated influenza virus comprising a chimeric HA, wherein the chimeric HA comprises the amino acid sequence of SEQ ID NO: 5 or 6; and (b) a CpG oligonucleotide adjuvant comprising the nucleotide sequence of SEQ ID NO: 4, or CpG 1018® adjuvant. In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated influenza virus comprising a chimeric HA, wherein the chimeric HA comprises the amino acid sequence of SEQ ID NO: 7 or 8; and (b) a CpG oligonucleotide adjuvant comprising the nucleotide sequence of SEQ ID NO: 4, or CpG 1018® adjuvant. In some embodiments, the inactivated influenza virus comprises the NA of influenza virus A/Hong Kong/4801/2014 (H3N2) NYMC X-263. In some embodiments, the inactivated influenza virus comprises one or more, or all proteins other than HA and NA encoded by one or more, or all genes of influenza virus A/Puerto Rico/8/1934 (H1N1). In some embodiments, the inactivated influenza virus comprises the non-structural proteins and matrix protein of influenza virus A/Puerto Rico/8/1934 (H1N1).

[00157] In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated split influenza virus comprising a chimeric HA, wherein the chimeric HA comprises the amino acid sequence of SEQ ID NO: 5 or 6; and (b) a CpG oligonucleotide adjuvant comprising the nucleotide sequence of SEQ ID NO: 4, or CpG 1018® adjuvant. In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated split influenza virus comprising a chimeric HA, wherein the chimeric HA comprises the amino acid sequence of SEQ ID NO: 7 or 8; and (b) a CpG oligonucleotide adjuvant comprising the nucleotide sequence of SEQ ID NO: 4, or CpG 1018® adjuvant. In some embodiments, the inactivated influenza virus comprises the NA of influenza virus A/Hong Kong/4801/2014 (H3N2) NYMC X-263. In some embodiments, the inactivated split influenza virus comprises one or more, or all proteins other than HA and NA encoded by one or more, or all genes of influenza virus A/Puerto Rico/8/1934 (H1N1). In some embodiments, the inactivated split influenza virus comprises the non-structural proteins and matrix protein of influenza virus A/Puerto Rico/8/1934 (H1N1).

[00158] In some embodiments, provided herein is an immunogenic composition comprising a live attenuated influenza A virus, wherein the live attenuated influenza A virus comprises a chimeric HA, wherein the chimeric HA comprises the HA globular head domain of influenza virus A/wedged-tailed/shearwater/Western Australia/2576/9134 (H15N9) HA and the HA stalk domain of influenza virus A/Hong Kong/4801/2014 (H3N2) NYMC X-263 HA). In some embodiments, provided herein is an immunogenic composition comprising a live attenuated influenza A virus, wherein the live attenuated influenza A virus comprises a chimeric HA, wherein the chimeric HA comprises the HA globular head domain of influenza virus A/wedged-tailed/shearwater/Western Australia/2576/9134 (H15N9) HA and the HA stalk domain of influenza virus A/Hong Kong/4801/2014 (H3N2) NYMC X-263 HA, in an admixture with a pharmaceutically acceptable carrier. In some embodiments, the live attenuated influenza A virus comprises the NA of influenza virus A/Hong Kong/4801/2014 (H3N2) NYMC X-263. In some embodiments, the live attenuated influenza A virus comprises one or more, or all proteins other than HA and NA encoded by one or more, or all genes of influenza virus A/Puerto Rico/8/1934 (H1N1). In some embodiments, the live attenuated influenza A virus comprises the non- structural proteins and matrix protein of influenza virus A/Puerto Rico/8/1934 (H1N1).

[00159] In some embodiments, provided herein is an immunogenic composition comprising a live attenuated influenza A virus, wherein the live attenuated influenza A virus comprises a chimeric HA, wherein the chimeric HA comprises the HA globular head domain of influenza virus A/duck/Czechoslovakia/1956 (H4N6) HA and the HA stalk domain of influenza virus A/Hong Kong/4801/2014 (H3N2) NYMC X-263 HA. In some embodiments, provided herein is an immunogenic composition comprising a live attenuated influenza A virus, wherein the live attenuated influenza A virus comprises a chimeric HA, wherein the chimeric HA comprises the HA globular head domain of influenza virus A/duck/Czechoslovakia/1956 (H4N6) HA and the HA stalk domain of influenza virus A/Hong Kong/4801/2014 (H3N2) NYMC X-263 HA, in an admixture with a pharmaceutically acceptable carrier. In some embodiments, the live attenuated influenza A virus comprises the NA of influenza virus A/Hong Kong/4801/2014 (H3N2) NYMC X-263. In some embodiments, the live attenuated influenza A virus comprises one or more, or all proteins other than HA and NA encoded by one or more, or all genes (e.g. , non-structural and/or matrix encoding genes) of influenza virus A/Puerto Rico/8/1934 (H1N1). In some embodiments, the live attenuated influenza A virus comprises the non-structural proteins and matrix protein of influenza virus A/Puerto Rico/8/1934 (H1N1).

[00160] In some embodiments, provided herein is an immunogenic composition comprising a chimeric HA described herein. In some embodiments, the chimeric HA comprises the HA globular head domain of influenza virus A/wedged- tailed/shearwater/Western Australia/2576/9134 (H15N9) HA and the HA stalk domain of influenza virus A/Hong Kong/4801/2014 (H3N2) NYMC X-263 HA). In some embodiments, the chimeric HA comprises the HA globular head domain of influenza virus A/duck/Czechoslovakia/1956 (H4N6) HA and the HA stalk domain of influenza virus A/Hong Kong/4801/2014 (H3N2) NYMC X-263 HA. In some embodiments, provided herein is an immunogenic composition comprising an inactivated influenza virus described herein (e.g., on Section 6). In some embodiments, provided herein is an immunogenic composition comprising an inactivated split influenza virus described herein (e.g., on Section 6). In some embodiments, provided herein is an immunogenic composition comprising the live attenuated influenza virus described in Section 6. In some embodiments, provided herein is an immunogenic composition described in Section 6.

[00161] In another aspect, provided herein are immunogenic compositions comprising a chimeric HA described herein, a CpG oligonucleotide adjuvant described herein, and an aluminum salt. In some embodiments, provided herein are immunogenic compositions comprising a chimeric HA described herein, a CpG oligonucleotide adjuvant described herein, and an aluminum salt in an admixture with a pharmaceutically acceptable carrier. In some embodiments, provided herein are immunogenic compositions comprising an inactivated influenza virus, a CpG oligonucleotide adjuvant described herein, and an aluminum salt, wherein the inactivated influenza virus comprises a chimeric HA described herein. In some embodiments, provided herein are immunogenic compositions comprising an inactivated influenza virus, a CpG oligonucleotide adjuvant described herein, and an aluminum salt in an admixture with a pharmaceutically acceptable carrier, wherein the inactivated influenza virus comprises a chimeric HA described herein. In some embodiments, provided herein are immunogenic compositions comprising an inactivated split influenza virus, a CpG oligonucleotide adjuvant described herein, and an aluminum salt, wherein the inactivated split influenza virus comprises a chimeric HA described herein. In some embodiments, provided herein are immunogenic compositions comprising an inactivated split influenza virus, a CpG oligonucleotide adjuvant described herein, and an aluminum salt in an admixture with a pharmaceutically acceptable carrier, wherein the inactivated split influenza virus comprises a chimeric HA described herein. In specific embodiments, the chimeric HA is one described in this Section or Section 5.3 or 6, infra. In some embodiments, the CpG oligonucleotide adjuvant is one described in this Section or Section 5.2 or 6, infra. In some embodiment, the aluminum salt is one described in this Section or Section 6, infra.

[00162] In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated influenza virus comprising a chimeric HA, wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises an amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA, wherein the HA globular head domain of the chimeric HA is heterologous to the HA stalk domain, and wherein the HA globular head domain of the chimeric HA is immunologically distinct from the globular head domain of the group 2 influenza A virus HA; (b) a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3); and (c) an aluminum salt, in an admixture with a pharmaceutically acceptable carrier. In specific embodiments, the chimeric HA is one described in this Section or Section 5.3 or 6, infra. In some embodiments, the CpG oligonucleotide adjuvant is one described in this Section or Section 5.2 or 6, infra. In some embodiment, the aluminum salt is one described in this Section or Section 6, infra.

[00163] In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated influenza virus comprising a chimeric HA, wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA, and wherein the HA globular head domain of the chimeric HA comprises the amino acid sequence of an HA globular head of an influenza A virus of a different strain, subtype, or group than the group 2 influenza A virus HA; (b) a CpG oligonucleotide adjuvant, wherein the CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3); and (c) an aluminum adjuvant, in an admixture with a pharmaceutically acceptable carrier. In specific embodiments, the chimeric HA is one described in this Section or Section 5.3 or 6, infra. In some embodiments, the CpG oligonucleotide adjuvant is one described in this Section or Section 5.2 or 6, infra. In some embodiments, the aluminum adjuvant is an aluminum salt. In some embodiment, the aluminum salt is one described in this Section or Section 6, infra.

[00164] In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated split influenza virus comprising a chimeric hemagglutinin (HA), wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises an amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA, wherein the HA globular head domain of the chimeric HA is heterologous to the HA stalk domain, and wherein the HA globular head domain of the chimeric HA is immunologically distinct from the globular head domain of the group 2 influenza A virus HA; (b) a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID N0:3); and (c) an aluminum salt, in an admixture with a pharmaceutically acceptable carrier. In specific embodiments, the chimeric HA is one described in this Section or Section 5.3 or 6, infra. In some embodiments, the CpG oligonucleotide adjuvant is one described in this Section or Section 5.2 or 6, infra. In some embodiment, the aluminum salt is one described in this Section or Section 6, infra.

[00165] In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated split influenza virus comprising a chimeric hemagglutinin (HA), wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA, and wherein the HA globular head domain of the chimeric HA comprises the amino acid sequence of an HA globular head of an influenza A virus of a different strain, subtype, or group than the group 2 influenza A virus HA; (b) a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3); and (c) an aluminum adjuvant, in an admixture with a pharmaceutically acceptable carrier. In specific embodiments, the chimeric HA is one described in this Section or Section 5.3 or 6, infra. In some embodiments, the CpG oligonucleotide adjuvant is one described in this Section or Section 5.2 or 6, infra. In some embodiments, the aluminum adjuvant is an aluminum salt. In some embodiment, the aluminum salt is one described in this Section or Section 6, infra.

[00166] In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated influenza virus comprising a chimeric HA, wherein the chimeric HA comprises the HA globular head domain of influenza virus A/wedged- tailed/shearwater/Western Australia/2576/9134 (H15N9) HA and the HA stalk domain of influenza virus A/Hong Kong/4801/2014 (H3N2) NYMC X-263 HA; (b) a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3); and (c) an aluminum salt. In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated influenza virus comprising a chimeric HA, wherein the chimeric HA comprises the HA globular head domain of influenza virus A/wedged- tailed/shearwater/Western Australia/2576/9134 (H15N9) HA and the HA stalk domain of influenza virus A/Hong Kong/4801/2014 (H3N2) NYMC X-263 HA; (b) a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3); and (c) an aluminum salt, in an admixture with a pharmaceutically acceptable carrier. In some embodiments, the inactivated influenza virus comprises the NA of influenza virus A/Hong Kong/4801/2014 (H3N2) NYMC X-263. In some embodiments, the inactivated influenza virus comprises one or more, or all proteins other than HA and NA encoded by one or more, or all genes of influenza virus A/Puerto Rico/8/1934 (H1N1). In some embodiments, the inactivated influenza virus comprises the non- structural proteins and matrix protein of influenza virus A/Puerto Rico/8/1934 (H1N1). In some embodiments, the aluminum salt comprises one or more selected from the group consisting of amorphous aluminum hydroxyphosphate sulfate, aluminum hydroxide, aluminum phosphate, potassium aluminum sulfate, and a combination thereof.

[00167] In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated split influenza virus comprising a chimeric HA, wherein the chimeric HA comprises the HA globular head domain of influenza virus A/wedged- tailed/shearwater/Western Australia/2576/9134 (H15N9) HA and the HA stalk domain of influenza virus A/Hong Kong/4801/2014 (H3N2) NYMC X-263 HA; (b) a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3); and (c) an aluminum salt. In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated split influenza virus comprising a chimeric HA, wherein the chimeric HA comprises the HA globular head domain of influenza virus A/wedged- tailed/shearwater/Western Australia/2576/9134 (H15N9) HA and the HA stalk domain of influenza virus A/Hong Kong/4801/2014 (H3N2) NYMC X-263 HA; (b) a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3); and (c) an aluminum salt, in an admixture with a pharmaceutically acceptable carrier. In some embodiments, the inactivated split influenza virus comprises the NA of influenza virus A/Hong Kong/4801/2014 (H3N2) NYMC X-263. In some embodiments, the inactivated split influenza virus comprises one or more, or all proteins other than HA and NA encoded by one or more, or all genes of influenza virus A/Puerto Rico/8/1934 (H1N1). In some embodiments, the inactivated split influenza virus comprises the non- structural proteins and matrix protein of influenza virus A/Puerto Rico/8/1934 (H1N1).

[00168] In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated influenza virus comprising a chimeric HA, wherein the chimeric HA comprises the HA globular head domain of influenza virus A/duck/Czechoslovakia/1956 (H4N6) HA and the HA stalk domain of influenza virus A/Hong Kong/4801/2014 (H3N2) NYMC X-263 HA; (b) a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3); and (c) an aluminum salt. In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated influenza virus comprising a chimeric HA, wherein the chimeric HA comprises the HA globular head domain of influenza virus A/duck/Czechoslovakia/1956 (H4N6) HA and the HA stalk domain of influenza virus A/Hong Kong/4801/2014 (H3N2) NYMC X-263 HA; (b) a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3); and (c) an aluminum salt, in an admixture with a pharmaceutically acceptable carrier. In some embodiments, the inactivated influenza virus comprises the NA of influenza virus A/Hong Kong/4801/2014 (H3N2) NYMC X-263. In some embodiments, the inactivated influenza virus comprises one or more, or all proteins other than HA and NA encoded by one or more, or all genes of influenza virus A/Puerto Rico/8/1934 (H1N1). In some embodiments, the inactivated influenza virus comprises the non- structural proteins and matrix protein of influenza virus A/Puerto Rico/8/1934 (H1N1). In some embodiments, the aluminum salt comprises one or more selected from the group consisting of amorphous aluminum hydroxyphosphate sulfate, aluminum hydroxide, aluminum phosphate, potassium aluminum sulfate, and a combination thereof.

[00169] In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated split influenza virus comprising a chimeric HA, wherein the chimeric HA comprises the HA globular head domain of influenza virus A A/duck/Czechoslovakia/1956 (H4N6) HA and the HA stalk domain of influenza virus A/Hong Kong/4801/2014 (H3N2) NYMC X-263 HA; (b) a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3); and (c) an aluminum salt. In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated split influenza virus comprising a chimeric HA, wherein the chimeric HA comprises the HA globular head domain of influenza virus A/duck/Czechoslovakia/1956 (H4N6) HA and the HA stalk domain of influenza virus A/Hong Kong/4801/2014 (H3N2) NYMC X-263 HA; (b) a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3); and (c) an aluminum salt, in an admixture with a pharmaceutically acceptable carrier. In some embodiments, the inactivated split influenza virus comprises the NA of influenza virus A/Hong Kong/4801/2014 (H3N2) NYMC X-263. In some embodiments, the inactivated split influenza virus comprises one or more, or all proteins other than HA and NA encoded by one or more, or all genes of influenza virus A/Puerto Rico/8/1934 (H1N1). In some embodiments, the inactivated split influenza virus comprises the non- structural proteins and matrix protein of influenza virus A/Puerto Rico/8/1934 (H1N1). In some embodiments, the aluminum salt comprises one or more selected from the group consisting of amorphous aluminum hydroxyphosphate sulfate, aluminum hydroxide, aluminum phosphate, potassium aluminum sulfate, and a combination thereof

[00170] In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated influenza virus comprising a chimeric HA, wherein the chimeric HA comprises the HA globular head domain of influenza virus A/wedged- tailed/shearwater/Western Australia/2576/9134 (H15N9) HA and the HA stalk domain of influenza virus A/Hong Kong/4801/2014 (H3N2) NYMC X-263 HA; (b) a CpG oligonucleotide adjuvant comprising the nucleotide sequence of SEQ ID NO:4, or CpG 1018® adjuvant; and (c) an aluminum salt. In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated influenza virus comprising a chimeric HA, wherein the chimeric HA comprises the HA globular head domain of influenza virus A/wedged-tailed/shearwater/Western Australia/2576/9134 (H15N9) HA and the HA stalk domain of influenza virus A/Hong Kong/4801/2014 (H3N2) NYMC X-263 HA; (b) a CpG oligonucleotide adjuvant comprising the nucleotide sequence of SEQ ID NO:4, or CpG 1018® adjuvant; and (c) an aluminum salt, in an admixture with a pharmaceutically acceptable carrier. In some embodiments, the inactivated influenza virus comprises the NA of influenza virus A/Hong Kong/4801/2014 (H3N2) NYMC X-263. In some embodiments, the inactivated influenza virus comprises one or more, or all proteins other than HA and NA encoded by one or more, or all genes of influenza virus A/Puerto Rico/8/1934 (H1N1). In some embodiments, the inactivated influenza virus comprises the non-structural proteins and matrix protein of influenza virus A/Puerto Rico/8/1934 (H1N1). In some embodiments, the aluminum salt comprises one or more selected from the group consisting of amorphous aluminum hydroxyphosphate sulfate, aluminum hydroxide, aluminum phosphate, potassium aluminum sulfate, and a combination thereof.

[00171] In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated split influenza virus comprising a chimeric HA, wherein the chimeric HA comprises the HA globular head domain of influenza virus A/wedged- tailed/shearwater/Western Australia/2576/9134 (H15N9) HA and the HA stalk domain of influenza virus A/Hong Kong/4801/2014 (H3N2) NYMC X-263 HA; (b) a CpG oligonucleotide adjuvant comprising the nucleotide sequence of SEQ ID NO:4, or CpG 1018® adjuvant; and (c) an aluminum salt. In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated split influenza virus comprising a chimeric HA, wherein the chimeric HA comprises the HA globular head domain of influenza virus A/wedged-tailed/shearwater/Western Australia/2576/9134 (H15N9) HA and the HA stalk domain of influenza virus A/Hong Kong/4801/2014 (H3N2) NYMC X-263 HA; (b) a CpG oligonucleotide adjuvant comprising the nucleotide sequence of SEQ ID NO:4, or CpG 1018® adjuvant; and (c) an aluminum salt, in an admixture with a pharmaceutically acceptable carrier. In some embodiments, the inactivated split influenza virus comprises the NA of influenza virus A/Hong Kong/4801/2014 (H3N2) NYMC X-263. In some embodiments, the inactivated split influenza virus comprises one or more, or all proteins other than HA and NA encoded by one or more, or all genes of influenza virus A/Puerto Rico/8/1934 (H1N1). In some embodiments, the inactivated split influenza virus comprises the non-structural proteins and matrix protein of influenza virus A/Puerto Rico/8/1934 (H1N1). In some embodiments, the aluminum salt comprises one or more selected from the group consisting of amorphous aluminum hydroxyphosphate sulfate, aluminum hydroxide, aluminum phosphate, potassium aluminum sulfate, and a combination thereof.

[00172] In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated influenza virus comprising a chimeric HA, wherein the chimeric HA comprises the HA globular head domain of influenza virus A/duck/Czechoslovakia/1956 (H4N6) HA and the HA stalk domain of influenza virus A/Hong Kong/4801/2014 (H3N2) NYMC X-263 HA; (b) a CpG oligonucleotide adjuvant comprising the nucleotide sequence of SEQ ID NO:4, or CpG 1018® adjuvant; and (c) an aluminum salt. In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated influenza virus comprising a chimeric HA, wherein the chimeric HA comprises the HA globular head domain of influenza virus A/duck/Czechoslovakia/1956 (H4N6) HA and the HA stalk domain of influenza virus A/Hong Kong/4801/2014 (H3N2) NYMC X-263 HA; (b) a CpG oligonucleotide adjuvant comprising the nucleotide sequence of SEQ ID NO:4, or CpG 1018® adjuvant; and (c) an aluminum salt, in an admixture with a pharmaceutically acceptable carrier. In some embodiments, the inactivated influenza virus comprises the NA of influenza virus A/Hong Kong/4801/2014 (H3N2) NYMC X-263. In some embodiments, the inactivated influenza virus comprises one or more, or all proteins other than HA and NA encoded by one or more, or all genes of influenza virus A/Puerto Rico/8/1934 (H1N1). In some embodiments, the inactivated influenza virus comprises the non- structural proteins and matrix protein of influenza virus A/Puerto Rico/8/1934 (H1N1). In some embodiments, the aluminum salt comprises one or more selected from the group consisting of amorphous aluminum hydroxyphosphate sulfate, aluminum hydroxide, aluminum phosphate, potassium aluminum sulfate, and a combination thereof.

[00173] In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated split influenza virus comprising a chimeric HA, wherein the chimeric HA comprises the HA globular head domain of influenza virus A A/duck/Czechoslovakia/1956 (H4N6) HA and the HA stalk domain of influenza virus A/Hong Kong/4801/2014 (H3N2) NYMC X-263 HA; (b) a CpG oligonucleotide adjuvant comprising the nucleotide sequence of SEQ ID NO:4, or CpG 1018® adjuvant; and (c) an aluminum salt. In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated split influenza virus comprising a chimeric HA, wherein the chimeric HA comprises the HA globular head domain of influenza virus A/duck/Czechoslovakia/1956 (H4N6) HA and the HA stalk domain of influenza virus A/Hong Kong/4801/2014 (H3N2) NYMC X-263 HA; (b) a CpG oligonucleotide adjuvant comprising the nucleotide sequence of SEQ ID NO:4, or CpG 1018® adjuvant; and (c) an aluminum salt, in an admixture with a pharmaceutically acceptable carrier. In some embodiments, the inactivated split influenza virus comprises the NA of influenza virus A/Hong Kong/4801/2014 (H3N2) NYMC X-263. In some embodiments, the inactivated split influenza virus comprises one or more, or all proteins other than HA and NA encoded by one or more, or all genes of influenza virus A/Puerto Rico/8/1934 (H1N1). In some embodiments, the inactivated split influenza virus comprises the non- structural proteins and matrix protein of influenza virus A/Puerto Rico/8/1934 (H1N1). In some embodiments, the aluminum salt comprises one or more selected from the group consisting of amorphous aluminum hydroxyphosphate sulfate, aluminum hydroxide, aluminum phosphate, potassium aluminum sulfate, and a combination thereof

[00174] In some embodiments, provided herein is an immunogenic composition comprising: (a) a chimeric HA comprising the amino acid sequence of SEQ ID NO: 5 or 6; (b) a CpG oligonucleotide adjuvant comprising the nucleotide sequence of SEQ ID NO: 4, or CpG 1018® adjuvant; and (c) an aluminum salt. In some embodiments, provided herein is an immunogenic composition comprising: (a) a chimeric HA comprising the amino acid sequence of SEQ ID NO: 7 or 8; (b) a CpG oligonucleotide adjuvant comprising the nucleotide sequence of SEQ ID NO: 4, or CpG 1018® adjuvant; and (c) an aluminum salt. In some embodiments, the aluminum salt comprises one or more selected from the group consisting of amorphous aluminum hydroxyphosphate sulfate, aluminum hydroxide, aluminum phosphate, potassium aluminum sulfate, and a combination thereof.

[00175] In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated influenza virus comprising a chimeric HA, wherein the chimeric HA comprises the amino acid sequence of SEQ ID NO: 5 or 6; (b) a CpG oligonucleotide adjuvant comprising the nucleotide sequence of SEQ ID NO: 4, or CpG 1018® adjuvant; and (c) an aluminum salt. In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated influenza virus comprising a chimeric HA, wherein the chimeric HA comprises the amino acid sequence of SEQ ID NO: 7 or 8; (b) a CpG oligonucleotide adjuvant comprising the nucleotide sequence of SEQ ID NO: 4, or CpG 1018® adjuvant; and (c) an aluminum salt. In some embodiments, the inactivated influenza virus comprises the NA of influenza virus A/Hong Kong/4801/2014 (H3N2) NYMC X-263. In some embodiments, the inactivated influenza virus comprises one or more, or all proteins other than HA and NA encoded by one or more, or all genes of influenza virus A/Puerto Rico/8/1934 (H1N1). In some embodiments, the inactivated influenza virus comprises the non- structural proteins and matrix protein of influenza virus A/Puerto Rico/8/1934 (H1N1). In some embodiments, the aluminum salt comprises one or more selected from the group consisting of amorphous aluminum hydroxyphosphate sulfate, aluminum hydroxide, aluminum phosphate, potassium aluminum sulfate, and a combination thereof.

[00176] In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated split influenza virus comprising a chimeric HA, wherein the chimeric HA comprises the amino acid sequence of SEQ ID NO: 5 or 6; (b) a CpG oligonucleotide adjuvant comprising the nucleotide sequence of SEQ ID NO: 4, or CpG 1018® adjuvant; and (c) an aluminum salt. In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated split influenza virus comprising a chimeric HA, wherein the chimeric HA comprises the amino acid sequence of SEQ ID NO: 7 or 8; (b) a CpG oligonucleotide adjuvant comprising the nucleotide sequence of SEQ ID NO: 4, or CpG 1018® adjuvant; and (c) an aluminum salt. In some embodiments, the inactivated influenza virus comprises the NA of influenza virus A/Hong Kong/4801/2014 (H3N2) NYMC X-263. In some embodiments, the inactivated split influenza virus comprises one or more, or all proteins other than HA and NA encoded by one or more, or all genes of influenza virus A/Puerto Rico/8/1934 (H1N1). In some embodiments, the inactivated split influenza virus comprises the non-structural proteins and matrix protein of influenza virus A/Puerto Rico/8/1934 (H1N1). In some embodiments, the aluminum salt comprises one or more selected from the group consisting of amorphous aluminum hydroxyphosphate sulfate, aluminum hydroxide, aluminum phosphate, potassium aluminum sulfate, and a combination thereof.

[00177] In some embodiments, an immunogenic composition described herein comprises from about 3.75 pg to about 150 pg of HA (e.g., a chimeric HA). In some embodiments, an immunogenic composition described herein comprises from about 3.75 pg to about 75 pg of HA (e.g., a chimeric HA). In some embodiments, an immunogenic composition described herein comprises from about 3.75 pg to about 50 pg of HA (e.g., a chimeric HA). In some embodiments, an immunogenic composition described herein comprises from about 3.75 pg to about 25 pg of HA (e.g., a chimeric HA). In some embodiments, an immunogenic composition described herein comprises from about 3.75 pg to about 15 pg of HA (e.g., a chimeric HA). In some embodiments, an immunogenic composition described herein comprises from about 3.75 pg to about 10 pg of HA (e.g., a chimeric HA). In some embodiments, an immunogenic composition described herein comprises from about 10 pg to about 150 pg of HA (e.g., a chimeric HA). In some embodiments, an immunogenic composition described herein comprises from about 10 pg to about 75 pg of HA (e.g., a chimeric HA). In some embodiments, an immunogenic composition described herein comprises from about 50 pg to about 150 pg of HA (e.g., a chimeric HA). In some embodiments, an immunogenic composition described herein comprises from about 50 pg to about 100 pg of HA (e.g., a chimeric HA). In some embodiments, an immunogenic composition described herein comprises from about 50 pg to about 150 pg of HA (e.g, a chimeric HA). In some embodiments, an immunogenic composition described herein comprises from about 75 pg to about 150 pg of HA (e.g, a chimeric HA). In some embodiments, an immunogenic composition described herein comprises from about 25 pg to about 100 pg of HA (e.g., a chimeric HA). In some embodiments, an immunogenic composition described herein comprises from about 25 pg to about 75 pg of HA (e.g., a chimeric HA). In some embodiments, an immunogenic composition described herein comprises from about 10 pg to about 50 pg of HA (e.g., a chimeric HA). In some embodiments, an immunogenic composition described herein comprises from about 10 pg to about 25 pg of HA (e.g., a chimeric HA). In some embodiments, an immunogenic composition described herein comprises from about 0.1 pg to about 5 pg of HA (e.g., a chimeric HA). In some embodiments, an immunogenic composition described herein comprises from about 10 pg to about 15 pg of HA (e.g., a chimeric HA). In some embodiments, an immunogenic composition described herein comprises from about 10 pg to about 60 pg of HA (e.g., a chimeric HA). In some embodiments, an immunogenic composition described herein comprises from about 5 pg to about 50 pg of HA (e.g., a chimeric HA). In some embodiments, an immunogenic composition described herein comprises from about 5 pg to about 45 pg of HA (e.g., a chimeric HA). In some embodiments, an immunogenic composition described herein comprises from about 5 pg to about 40 pg of HA (e.g., a chimeric HA). In some embodiments, an immunogenic composition described herein comprises from about 10 pg to about 40 pg of HA (e.g., a chimeric HA). In some embodiments, an immunogenic composition described herein comprises from about 10 pg to about 35 pg of HA (e.g., a chimeric HA). In some embodiments, an immunogenic composition described herein comprises from about 15 pg to about 35 pg of HA (e.g., a chimeric HA). In some embodiments, an immunogenic composition described herein comprises from about 15 pg to about 30 pg of HA (e.g., a chimeric HA). In some embodiments, an immunogenic composition described herein comprises about 3.75 pg of HA (e.g., a chimeric HA). In some embodiments, an immunogenic composition described herein comprises about 5 pg of HA (e.g., a chimeric HA). In some embodiments, an immunogenic composition described herein comprises about 10 pg of HA (e.g., a chimeric HA). In some embodiments, an immunogenic composition described herein comprises about 15 pg of HA (e.g., a chimeric HA). In some embodiments, an immunogenic composition described herein comprises about 20 pg of HA (e.g., a chimeric HA). In some embodiments, an immunogenic composition described herein comprises from about 25 pg of HA (e.g., a chimeric HA). In some embodiments, an immunogenic composition described herein comprises from about 30 pg of HA (e.g., a chimeric HA). In some embodiments, an immunogenic composition described herein comprises from about 60 pg of HA (e.g., a chimeric HA).

[00178] In some embodiments, the chimeric HA comprises the HA globular head domain and HA stem domain of a chimeric HA set forth in Table 1.

[00179] In some embodiments, the chimeric HA comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of the H3 subtype. In some embodiments, the chimeric HA comprises the amino acid sequence of the HA stalk domain of group 2 influenza A virus A/Hong Kong/4801/2014, NYMC X-263 HA or A/Hong Kong/4801/2014-like HA.

[00180] In some embodiments, the chimeric HA comprises the amino acid sequence of the HA globular head domain of a group 1 influenza A virus HA. In some embodiments, the chimeric HA comprises the amino acid sequence of the HA globular head domain of an H2, H5, H6, H8, H9, Hl l, H12, H13, H16, H17, or H18 subtype. In some embodiments, the chimeric HA comprises the amino acid sequence of the HA globular head domain of an H4, H7, H10, H14, or H15 subtype. In some embodiments, the chimeric HA comprises the amino acid sequence of the HA globular head domain of an avian influenza virus HA (e.g., avian influenza A virus HA) which does not circulate in humans. In some embodiments, the chimeric HA comprises the amino acid sequence of the HA globular head domain of influenza A virus A/wedge-tailed shearwater/Westem Australia/2576/1979 HA or A/wedge- tailed shearwater/Westem Australia/2576/1979-like HA. In some embodiments, the chimeric HA comprises the amino acid sequence of the HA globular head domain of influenza A vims A/Duck/Czechoslovakia/1956 HA or A/Duck/Czechoslovakia/1956-like HA.

[00181] In some embodiments, the chimeric HA comprises the amino acid sequence of the HA globular head domain of an H4 and the amino acid sequence of the HA stem domain of an H3. In some embodiments, the chimeric HA comprises the amino acid sequence of the HA globular head domain of an Hl 5 and the amino acid sequence of the HA stem domain of an H3. In some embodiments, the chimeric HA comprises the amino acid sequence of the HA globular head domain of influenza A virus A/Duck/Czechoslovakia/1956 HA or A/Duck/Czechoslovakia/1956-like HA and the amino acid sequence of the HA stem domain of influenza A virus A/Hong Kong/4801/2014 H3N2, NYMC X-263 HA or A/Hong Kong/4801/2014-like HA. In some embodiments, the chimeric HA comprises the amino acid sequence of the HA globular head domain of influenza A virus A/wedge-tailed shearwater/Western Australia/2576/1979 HA or A/wedge-tailed shearwater/We stern Australia/2576/1979-like HA and the amino acid sequence of HA stem domain of influenza A virus A/Hong Kong/4801/2014 H3N2, NYMC X-263 HA or A/Hong Kong/4801/2014-like HA.

[00182] In some embodiments, the chimeric HA comprises an amino acid sequence that is at least 90%, at least 95%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 5. In some embodiments, the chimeric HA comprises an amino acid sequence that is at least 90%, at least 95%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:6. In some embodiments, the chimeric HA comprises an amino acid sequence that is at least 90%, at least 95%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:7. In some embodiments, the chimeric HA comprises an amino acid sequence that is at least 90%, at least 95%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 8.

[00183] In specific embodiments, the chimeric HA comprises the amino acid sequence of SEQ ID NO:5. In specific embodiments, the chimeric HA comprises the amino acid sequence of SEQ ID NO:6. In specific embodiments, the chimeric HA comprises the amino acid sequence of SEQ ID NO:7. In specific embodiments, the chimeric HA comprises the amino acid sequence of SEQ ID NO: 8.

[00184] In some embodiments, the inactivated influenza virus comprises neuraminidase from the same group 2 influenza A virus from which the HA stem domain of the chimeric domain is derived. In some embodiments, the inactivated influenza virus comprises proteins encoded by genes of influenza A virus A/Puerto Rico/8/1934. In some embodiments, the inactivated influenza A virus comprises non- structural proteins and matrix protein encoded by genes of influenza A virus A/Puerto Rico/8/1934. In some embodiments, the inactivated influenza virus comprises: (a) neuraminidase from the same group 2 influenza A virus from which the HA stem domain of the chimeric domain is derived; and (b) proteins encoded by genes of influenza A virus A/Puerto Rico/8/1934. In some embodiments, the inactivated influenza virus comprises: (a) neuraminidase from the same group 2 influenza A virus from which the HA stem domain of the chimeric domain is derived; and (b) non- structural proteins and matrix protein encoded by genes of influenza A virus A/Puerto Rico/8/1934.

[00185] In some embodiments, the inactivated split influenza virus comprises neuraminidase from the same group 2 influenza A virus from which the HA stem domain of the chimeric domain is derived. In some embodiments, the inactivated split influenza virus comprises proteins encoded by genes of influenza A virus A/Puerto Rico/8/1934. In some embodiments, the inactivated split influenza virus comprises non- structural proteins and matrix protein encoded by genes of influenza A virus A/Puerto Rico/8/1934. In some embodiments, the inactivated split influenza virus comprises: (a) neuraminidase from the same group 2 influenza A virus from which the HA stem domain of the chimeric domain is derived; and (b) proteins encoded by genes of influenza A virus A/Puerto Rico/8/1934. In some embodiments, the inactivated split influenza virus comprises: (a) neuraminidase from the same group 2 influenza A virus from which the HA stem domain of the chimeric domain is derived; and (b) non-structural proteins and matrix protein encoded by genes of influenza A virus A/Puerto Rico/8/1934. [00186] In some embodiments, an immunogenic composition described herein comprises from about 1 pg to about 50 pg of a CpG oligonucleotide adjuvant. In some embodiments, an immunogenic composition described herein comprises from about 5 pg to about 50 pg of a CpG oligonucleotide adjuvant. In some embodiments, an immunogenic composition described herein comprises from about 5 pg to about 40 pg of a CpG oligonucleotide adjuvant. In some embodiments, an immunogenic composition described herein comprises from about 5 pg to about 30 pg of a CpG oligonucleotide adjuvant. In some embodiments, an immunogenic composition described herein comprises from about 5 pg to about 25 pg of a CpG oligonucleotide adjuvant. In some embodiments, an immunogenic composition described herein comprises from about 5 pg to about 20 pg of a CpG oligonucleotide adjuvant. In some embodiments, an immunogenic composition described herein comprises from about 5 pg to about 10 pg of a CpG oligonucleotide adjuvant. In some embodiments, an immunogenic composition described herein comprises about 1 pg, about 2 pg, about 3 pg, about 4 pg, or about 5 pg of a CpG oligonucleotide adjuvant. In some embodiments, an immunogenic composition described herein comprises about 6 pg, about 7 pg, about 8 pg, about 9 pg, or about 10 pg of a CpG oligonucleotide adjuvant. In some embodiments, an immunogenic composition described herein comprises about 11 pg, about 12 pg, about 13 pg, about 14 pg, or about 15 pg of a CpG oligonucleotide adjuvant. In some embodiments, an immunogenic composition described herein comprises about 20 pg, about 25 pg, about 30 pg, about 40 pg, or about 50 pg of a CpG oligonucleotide adjuvant.

[00187] In some embodiments, an immunogenic composition described herein comprises from about 50 pg to about 400 pg of a CpG oligonucleotide adjuvant. In some embodiments, an immunogenic composition described herein comprises from about 75 pg of a CpG oligonucleotide adjuvant. In some embodiments, an immunogenic composition described herein comprises from about 100 pg of a CpG oligonucleotide adjuvant. In some embodiments, an immunogenic composition described herein comprises from about 150 pg of a CpG oligonucleotide adjuvant. In some embodiments, an immunogenic composition described herein comprises from about 200 pg of a CpG oligonucleotide adjuvant. In some embodiments, an immunogenic composition described herein comprises from about 250 pg of a CpG oligonucleotide adjuvant. In some embodiments, an immunogenic composition described herein comprises from about 300 pg of a CpG oligonucleotide adjuvant. In some embodiments, an immunogenic composition described herein comprises from about 350 pg of a CpG oligonucleotide adjuvant. In some embodiments, an immunogenic composition described herein comprises from about 400 pg of a CpG oligonucleotide adjuvant. [00188] In some embodiments, an immunogenic composition described herein comprises from about 375 pg to about 6000 pg of a CpG oligonucleotide of a CpG oligonucleotide adjuvant described herein (e.g., in Section 5.2 or Example 1), preferably from about 500 pg to about 5000 pg of the CpG oligonucleotide, preferably from about 750 pg to about 3000 pg of the CpG oligonucleotide. In some embodiments, an immunogenic composition described herein comprises greater than about 250 pg, about 500 pg, about 750 pg, about 1000 pg, or about 1250 pg of the CpG oligonucleotide of a CpG oligonucleotide adjuvant described herein (e.g., in Section 5.2 or Example 1), and less than about 6000 pg, about 5000 pg, about 4000 pg, about 3000 pg, or about 2000 pg of the CpG oligonucleotide. In some embodiments, an immunogenic composition described herein comprises about 375 pg, about 750 pg, about 1500 pg, about 3000 pg or about 6000 pg of the CpG oligonucleotide of a CpG oligonucleotide adjuvant described herein (e.g., in Section 5.2 or Example 1). In some embodiments, an immunogenic composition comprises about 750 pg of the CpG oligonucleotide adjuvant described herein (e.g., in Section 5.2 or Example 1). In some embodiments, an immunogenic composition described herein comprises about 1500 pg of the CpG oligonucleotide of a CpG oligonucleotide adjuvant described herein (e.g., in Section 5.2 or Example 1). In some embodiments, an immunogenic composition described herein comprises about 3000 pg of the CpG oligonucleotide of a CpG oligonucleotide adjuvant described herein (e.g., in Section 5.2 or Example 1). In some embodiments, an immunogenic composition described herein comprises about 6000 pg of the CpG oligonucleotide of a CpG oligonucleotide adjuvant described herein (e.g, in Section 5.2 or Example 1).

[00189] In some embodiments, the oligonucleotide of the CpG oligonucleotide adjuvant comprises the nucleotide sequence of 5’-TGACTGTGAACGTTCGAGATGA-3’ (SEQ ID NO:4). In some embodiments, the oligonucleotide of the CpG oligonucleotide adjuvant is 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 nucleotides in length. In some embodiments, the oligonucleotide of the CpG oligonucleotide adjuvant is a single stranded oligodeoxynucleotide. In some embodiments, the oligonucleotide of the CpG oligonucleotide adjuvant comprises only phosphorothioate linkages, or a combination of one or more phosphodiester linkages and one or more phosphorothioate linkages. In some embodiments, the oligonucleotide of the CpG oligonucleotide adjuvant is fully RNA or is an RNA/DNA chimera.

[00190] In some embodiments, an immunogenic composition described herein comprises from about 5 pg to about 50 pg of an aluminum salt. In some embodiments, an immunogenic composition described herein comprises from about 5 pg to about 25 pg of an aluminum salt. In some embodiments, an immunogenic composition described herein comprises from about 5 pg to about 15 pg of an aluminum salt. In some embodiments, an immunogenic composition described herein comprises from about 15 pg to about 25 pg of an aluminum salt. In some embodiments, an immunogenic composition described herein comprises from about 15 pg to about 50 pg of an aluminum salt. In some embodiments, an immunogenic composition described herein comprises about 5 pg, about 15 pg, about 25 pg, or about 50 pg of an aluminum salt.

[00191] In some embodiments, an immunogenic composition described herein comprises from about 50 pg to about 800 pg of an aluminum salt. In some embodiments, an immunogenic composition described herein comprises from about 100 pg of an aluminum salt. In some embodiments, an immunogenic composition described herein comprises about 150 pg of an aluminum salt. In some embodiments, an immunogenic composition described herein comprises about 200 pg of an aluminum salt. In some embodiments, an immunogenic composition described herein comprises about 250 pg of an aluminum salt. In some embodiments, an immunogenic composition described herein comprises about 300 pg of an aluminum salt. In some embodiments, an immunogenic composition described herein comprises about 350 pg of an aluminum salt. In some embodiments, an immunogenic composition described herein comprises about 400 pg of an aluminum salt. In some embodiments, an immunogenic composition described herein comprises about 450 pg of an aluminum salt. In some embodiments, an immunogenic composition described herein comprises about 500 pg of an aluminum salt. In some embodiments, an immunogenic composition described herein comprises about 550 pg of an aluminum salt. In some embodiments, an immunogenic composition described herein comprises about 600 pg of an aluminum salt. In some embodiments, an immunogenic composition described herein comprises about 650 pg of an aluminum salt. In some embodiments, an immunogenic composition described herein comprises about 700 pg of an aluminum salt. In some embodiments, an immunogenic composition described herein comprises about 750 pg of an aluminum salt. In some embodiments, an immunogenic composition described herein comprises about 800 pg of an aluminum salt.

[00192] In some embodiments, an immunogenic composition described herein comprises from about 0.25 to about 1.25 mg of A13+. In some embodiments, an immunogenic composition comprises from about 0.50 to about 1.00 mg of an A13+. In some embodiments, the immunogenic composition comprises about 0.375 mg, about 0.75 mg, or about 1.00 mg of A13+. In some embodiments, the immunogenic composition comprises about 0.375 mg of A13+.

[00193] In some embodiments, an immunogenic composition described herein comprises about 0.05% to about 3%, or about 1% to about 3% of aluminum salt. In some embodiments, an immunogenic composition described herein comprises about 1%, about 1.5%, about 2%, about 2.5%, or about 3% of aluminum salt. In some embodiments, an immunogenic composition described herein comprises about 1% or about 2% of an aluminum salt.

[00194] In some embodiments, the aluminum salt comprises one or more selected from the group consisting of amorphous aluminum hydroxyphosphate sulfate, aluminum hydroxide, aluminum phosphate, potassium aluminum sulfate, and a combination thereof. In some embodiments, the aluminum salt comprises one or both of aluminum hydroxide and aluminum phosphate. In some embodiments, the aluminum salt comprises aluminum hydroxide. In some embodiments, the aluminum salt comprises aluminum phosphate. In some embodiments, the immunogenic composition described herein does not comprise an aluminum salt.

[00195] In specific embodiments, an aluminum salt functions as an adjuvant.

[00196] In some embodiments, an immunogenic composition described herein further comprises a group 1 chimeric HA, such as, e.g., described in Nachbagauer et al., 2016, npj Vaccines 131 1, 1-10, and/or Nachbagauer et al., 2021, Nature Medicine 27, 106-114. In some embodiments, an immunogenic composition described herein further comprises a group 1 chimeric HA, wherein the group 1 chimeric HA comprises an HA globular head domain of an influenza virus H8 and the HA stem domain of an influenza virus Hl. In some embodiments, an immunogenic composition described herein further comprises a group 1 chimeric HA, wherein the group 1 chimeric HA comprises an HA globular head domain of an influenza virus H8 and the HA stem domain of an influenza A virus A/California/04/09 HA. In some embodiments, an immunogenic composition described herein further comprises a group 1 chimeric HA, wherein the group 1 chimeric HA comprises an HA globular head domain of an influenza A virus A/mallard/Sweden/24/02 HA and the HA stem domain of an influenza A virus A/California/04/09 HA. In some embodiments, an immunogenic composition described herein further comprises a group 1 chimeric HA, wherein the group 1 chimeric HA comprises an HA globular head domain of an influenza virus H5 and the HA stem domain of an influenza A virus A/California/04/09 HA. In some embodiments, an immunogenic composition described herein further comprises a group 1 chimeric HA, wherein the group 1 chimeric HA comprises an HA globular head domain of an influenza A virus A/Vietnam/1203/04 HA and the HA stem domain of an influenza A virus A/California/04/09 HA. In some embodiments, the immunogenic composition described herein further comprises mosaic HA influenza B, such as, e.g., described in Liu et al., 2021, Front Immunol 12, 746447. In some embodiments, the mosaic HA influenza B comprises influenza B virus B/Yamagata/16/1988 (Yam) HA in which the major antigenic sites are replaced by corresponding sequences from H5, H8 or H13.

[00197] In some embodiments, an immunogenic composition described herein further comprises mosaic HA influenza B, such as, e.g., described in Liu et al., 2021, Front Immunol 12, 746447; Sun et al., J. Virol. 93(12):e00333-19; Sun et al., 2019, J. Virol. 93(2):e01673- 18; and Ermler et al., 2017, J. Virol. 91(12):e00286-17. In some embodiments, the mosaic HA influenza B comprises influenza B virus B/Yamagata/16/1988 (Yam) HA in which the major antigenic sites are replaced by corresponding sequences from H5, H8 or Hl 3.

[00198] In some embodiments, an immunogenic composition described herein has a volume of about 0.5 mL to about 2 mL. In some embodiments, an immunogenic composition described herein has a volume of about 0.5 mL, about 1 mL, about 1.5 mL, or about 2 mL. [00199] As used herein, the term “pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopoeia for use in animals, and more particularly in humans. The term “carrier” refers to a diluent, adjuvant, excipient, or vehicle with which the pharmaceutical composition is administered. In specific embodiments, the pharmaceutically acceptable carrier is a diluent, excipient, or vehicle. For example, the pharmaceutically acceptable carrier is a diluent (e.g., saline). Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. Suitable excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. Examples of suitable pharmaceutical carriers are described in “Remington’s Pharmaceutical Sciences” by E.W. Martin. The formulation should suit the mode of administration.

[00200] In specific embodiments, an immunogenic compositions described herein are formulated to be suitable for the intended route of administration to a subject. For example, an immunogenic composition may be formulated to be suitable for parenteral, oral, intradermal, intranasal, transdermal, or intraperitoneal administration. In a specific embodiment, an immunogenic composition may be formulated for intravenous, oral, intraperitoneal, intranasal, intratracheal, subcutaneous, intramuscular, topical, intradermal, transdermal, or pulmonary administration. In a specific embodiment, an immunogenic composition may be formulated for intramuscular administration. In another specific embodiment, an immunogenic composition may be formulated for subcutaneous administration. In another specific embodiment, an immunogenic composition may be formulated for intranasal administration.

[00201] In specific embodiments, provided herein is an immunogenic composition described in Section 6, infra.

[00202] An immunogenic composition described herein may be used to induce an immune response to one, two, or multiple (e.g., 3, 4, 5, 6, or more) influenza viruses (e.g., influenza A viruses) in a subject (e.g., human subject). In specific embodiments, an immunogenic composition described herein may be used to induce a cross-reactive immune response to two or more (e.g., 3, 4, 5, 6, or more) influenza A viruses (e.g., group 2 influenza A viruses) in a subject (e.g., human subject). An immunogenic composition described herein may be used to induce an immune response that provides protection (e.g., full or partial protection) against one, two, or multiple (e.g., 3, 4, 5, 6, or more) influenza viruses (e.g., influenza A virus, such as, e.g., group 2 influenza A viruses) in a subject (e.g., human subject). An immunogenic composition described herein may be used to induce an immune response that provides protection (e.g., full or partial protection) against one, two, or multiple (e.g., 3, 4, 5, 6, or more) influenza virus subtypes (e.g., influenza A virus, such as, e.g., group 2 influenza A virus subtypes) in a subject (e.g., human subject). In some embodiments, the immune response induced provides protection (e.g., full or partial protection) against a homologous influenza A virus. In some embodiments, the immune response induced provides protection (e.g., full or partial protection) against a heterotypic influenza A virus. An immunogenic composition described herein may be used to immunize a subject (e.g., human subject) against influenza virus (e.g., influenza A virus). In some embodiments, an immunogenic composition described herein may be used to immunize a subject (e.g., human subject) against influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus). An immunogenic composition described herein may also be used to prevent an influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus) in a subject (e.g., human subject). In a specific embodiment, an immunogenic composition described herein may be used in a method described herein. In some embodiments, two or more immunogenic compositions described herein may be used in a method described herein (e.g., to prevent an influenza virus disease and/or immunize a subject against an influenza virus disease). In some embodiments, two or more immunogenic compositions described herein may be used in a sequential immunization method described herein

[00203] In some embodiments, provided herein is the use of an immunogenic composition described herein in the manufacture of a medicament for inducing an immune response to one, two, or multiple (e.g., 3, 4, 5, 6, or more) influenza viruses (e.g., influenza A viruses) in a subject (e.g., human subject). In some embodiments, provided herein is the use of an immunogenic composition described herein in the manufacture of a medicament for inducing a cross-reactive immune response to two or more (e.g., 3, 4, 5, 6, or more) influenza A viruses (e.g., group 2 influenza A viruses) in a subject (e.g., human subject). In some embodiments, the immune response induced provides protection (e.g., full or partial protection) against a heterotypic influenza A virus. An immunogenic composition described herein may be used in the preparation of a medicament for immunizing a subject (e.g., human subject) against influenza virus (e.g., influenza A virus). In some embodiments, provided herein is the use of an immunogenic composition described herein in the manufacture of a medicament for immunizing a subject (e.g., human subject) against influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus). In some embodiments, provided herein is the use of an immunogenic composition described herein in the manufacture of a medicament for preventing an influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus) in a subject (e.g., human subject).

[00204] In some embodiments, provided herein is the use of a first immunogenic composition described herein in the manufacture of a medicament for use in combination with a second immunogenic composition described herein to immunize a subject (e.g., human subject) against influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus). In some embodiments, provided herein is the use of an immunogenic composition described herein in the manufacture of a medicament for use in combination with a second immunogenic composition described herein to prevent an influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus) in a subject (e.g., human subject).

[00205] In specific embodiments, an immunogenic composition described herein is a vaccine.

[00206] The immunogenic compositions described herein can be included in a container, pack, or dispenser together with instructions for administration. [00207] In a specific embodiment, provided herein is a composition (e.g., a pharmaceutical composition) comprising an antibody(ies) that binds to influenza virus HA (e.g., a group 2 influenza A virus HA), which was generated using an immunogenic composition described herein. The composition may further comprise a pharmaceutically acceptable carrier. The antibody may be polyclonal or monoclonal. In some embodiments, the antibody is human or humanized. The antibody(ies) may be used to passively immunize a subject (e.g., a human subject).

5.2 CpG Oligonucleotide Adjuvants

[00208] Toll-like receptors are expressed in and on dendritic cells and other innate immune cells and are among the most important receptors for stimulating a response to the presence of invading pathogens. Humans have multiple types of TLRs that are similar in structure but recognize different parts of viruses or bacteria. By activating specific TLRs, it is possible to stimulate and control specific types of innate immune responses that can be harnessed to enhance adaptive responses.

[00209] TLR9 (CD289) recognizes unmethylated cytidine-phospho-guanosine (CpG) motifs found in microbial DNA, which can be mimicked using synthetic CpG-containing oligodeoxynucleotides (CpG-ODNs). CpG-ODNs are known to enhance antibody production and to stimulate T helper 1 (Thl) cell responses (Coffman et al., Immunity, 33:492-503, 2010). Based on structure and biological function, CpG-ODNs have been divided into three general classes: CpG-A, CpG-B, and CpG-C (Campbell, Methods Mol Biol, 1494: 15-27, 2017). The degree of B cell activation varies between the classes with CpG-A ODNs being weak, CpG-C ODNs being good, and CpG-B ODNs being strong B cell activators.

[00210] In specific embodiments, the compositions described herein comprise, or are administered in combination with, a CpG oligonucleotide adjuvant. The CpG oligonucleotide adjuvants of the present disclosure are TLR9 agonists. In specific embodiments, CpG oligonucleotide adjuvants of the present disclosure are good B cell activators (CpG-C ODN) or more preferably strong (CpG-B ODN) B cell activators.

[00211] Optimal oligonucleotide TLR9 agonists often contain a palindromic sequence following the general formula of: 5’-purine-purine-CG-pyrimidine-pyrimidine-3’, or 5’- purine-purine-CG-pyrimidine-pyrimidine-CG-3’ (U.S. Patent No. 6,589,940). TLR9 agonism is also observed with certain non-palindromic CpG-enriched phosphorothioate oligonucleotides, but may be affected by changes in the nucleotide sequence. Additionally, TLR9 agonism is abolished by methylation of the cytosine within the CpG dinucleotide. Accordingly in some embodiments, a CpG oligonucleotide adjuvant comprises an oligonucleotide of from 8 to 35 nucleotides in length comprising the sequence 5’- AACGTTCG-3’ (SEQ ID NO: 1). In some embodiments, the oligonucleotide is greater than 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 nucleotides in length, and the oligonucleotide is less than 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, 25, or 24 nucleotides in length. In some embodiments, a CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the sequence 5’-AACGTTCGAG-3’ (SEQ ID NO:2). In some embodiments, the oligonucleotide is greater than 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 nucleotides in length, and the oligonucleotide is less than 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, 25, or 24 nucleotides in length. In some embodiments, a CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the sequence 5’-GAACGTTCG-3’ (SEQ ID NO:3). In some embodiments, the oligonucleotide is greater than 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 nucleotides in length, and the oligonucleotide is less than 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, 25, or 24 nucleotides in length.

[00212] Researchers at Dynavax Technologies Corporation (Emeryville, CA) have identified a 22-mer phosphorothioate linked oligodeoxynucleotide, CpG 1018® adjuvant, which contains specific sequences that can substantially enhance the immune response to coadministered antigens across species (Campbell JD. Development of the CpG Adjuvant 1018: A Case Study. Methods Mol Biol. 2017;1494: 15-27. doi: 10.1007/978-l-4939-6445-l_2. PMID: 27718183). CpG 1018® adjuvant has a nucleotide sequence of 5’- TGACTGTGAACGTTCGAGATGA-3’ (SEQ ID NO:4) and was chosen after screening a broad panel of oligonucleotides for immunostimulatory activity in vitro and in vivo. CpG 1018® adjuvant is a CpG-B ODN that is active in mice, rabbits, dogs, baboons, cynomolgus monkeys, and humans. CpG 1018® adjuvant is also referred to by the term ODN 1018. In specific embodiments, a CpG oligonucleotide adjuvant (e.g., as described herein Section 5.2 or Example 1) comprises an oligonucleotide comprising the sequence of SEQ ID NO:4. In some embodiments, a CpG oligonucleotide adjuvant comprises an oligonucleotide of from 22 to 35 nucleotides in length comprising the sequence of SEQ ID NO:4. In some embodiments, the oligonucleotide is greater than 22, 23, 24, 25, 26, 27, 28, 29, 30 or 31 nucleotides in length, and the oligonucleotide is less than 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, 25, or 24 nucleotides in length.

[00213] Although the exemplary CpG oligonucleotide adjuvant, CpG 1018® adjuvant, is a CpG-ODN, the present disclosure is not restricted to fully DNA molecules. That is, in some embodiments, the oligonucleotide of the CpG oligonucleotide adjuvant is a DNA/RNA chimeric molecule in which the CpG(s) and the palindromic sequence are deoxyribonucleic acids and one or more nucleic acids outside of these regions are ribonucleic acids. In some embodiments, the oligonucleotide of the CpG oligonucleotide adjuvant is linear. In other embodiments, the oligonucleotide of the CpG oligonucleotide adjuvant is circular or includes hairpin loop(s). The oligonucleotide of the CpG oligonucleotide adjuvant may be single stranded. Alternatively, the oligonucleotide of the CpG oligonucleotide adjuvant may be double stranded.

[00214] In some embodiments, the CpG oligonucleotide of the CpG oligonucleotide adjuvant may contain modifications. Modifications include but are not limited to, modifications of the 3 ’OH or 5 ’OH group, modifications of the nucleotide base, modifications of the sugar component, and modifications of the phosphate group. Modified bases may be included in the palindromic sequence of the CpG oligonucleotide as long as the modified base(s) maintains the same specificity for its natural complement through Watson- Crick base pairing (e.g., the palindromic portion is still self-complementary). In some embodiments, the CpG oligonucleotide comprises a non-canonical base. In some embodiments, the CpG oligonucleotide comprises a modified nucleoside. In some embodiments, the modified nucleoside is selected from the group consisting of 2’-deoxy-7- deazaguanosine, 2’-deoxy-6-thioguanosine, arabinoguanosine, 2’-deoxy-2’substituted- arabinoguanosine, and 2’-O-substituted-arabinoguanosine.

[00215] The CpG oligonucleotide of the CpG oligonucleotide adjuvant may contain a modification of the phosphate group. For example, in addition to phosphodiester linkages, phosphate modifications include, but are not limited to, phosphorothioate (e.g., phosphoromonothioate), phosphorodithioate, methyl phosphonate, phosphoramidate (bridging or non-bridging), and phosphotriester, and may be used in any combination. Other non-phosphate oligomer linkages may also be used. In some embodiments, the oligonucleotides comprise only phosphorothioate backbones. In some embodiments, the oligonucleotides comprise only phosphorodithioate backbones. In some embodiments, the oligonucleotides comprise only phosphodiester backbones. In some embodiments, the oligonucleotide comprises a combination of phosphate linkages in the phosphate backbone such as a combination of phosphodiester and phosphorothioate linkages. In some embodiments, the oligonucleotide comprises a combination of phosphate linkages in the phosphate backbone such as a combination of phosphodiester, phosphorothioate, and phosphorodithioate linkages. Oligonucleotides with thioated phosphate (e.g., phosphorothioate) backbones can be more immunogenic than those with phosphodiester backbones and appear to be more resistant to degradation after injection into the host [18, 19], The CpG oligonucleotide of an CpG oligonucleotide adjuvant of the present disclosure include at least one, two or three intemucleotide phosphorothioate ester linkages. In some embodiments, when a plurality of CpG oligonucleotide molecules are present in a pharmaceutical composition comprising at least one excipient, both stereoisomers of the phosphorothioate ester linkage are present in the plurality of CpG oligonucleotide molecules. In some embodiments, all of the internucleotide linkages of the CpG oligonucleotide are phosphorothioate linkages, or said another way, the CpG oligonucleotide has a phosphorothioate backbone.

[00216] In some embodiments, the CpG oligonucleotide of the CpG oligonucleotide adjuvant is produced synthetically, or is an isolated natural product or fragment thereof. In some embodiments, a CpG oligonucleotide is synthesized using H-phosphonate, phosphotriester, phosphodiester, phosphite-triester, and/or phosphoramidite chemistry. In some embodiments, a the CpG oligonucleotide of the CpG oligonucleotide adjuvant is synthesized using a solid support, optionally controlled pore glass. In some embodiments, a CpG oligonucleotide is thioated using environmental sulfur (S8), Beaucage reagent, a thioazoline derivative (i.e., DtsNH, EDITH, MEDITH, ADTT, DDTT), or sulfurizing reagent II (Glen Research). In some embodiments, the CpG oligonucleotide of the CpG oligonucleotide adjuvant is purified using column chromatography (e.g., HPLC).

[00217] The CpG oligonucleotides are in their pharmaceutically acceptable salt form unless otherwise indicated. In specific embodiments, a CpG oligonucleotide adjuvant described herein comprises a pharmaceutically acceptable salt form. Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, zinc salts, salts with organic bases (for example, organic amines) such as N-Me-D-glucamine, N-[l-(2,3- dioleoyloxy)propyl]-N,N,N-trimethylammonium chloride, choline, tromethamine, dicyclohexylamines, t-butyl amines, and salts with amino acids such as arginine, lysine and the like. In some embodiment, the CpG oligonucleotides are in the ammonium, sodium, lithium, or potassium salt form. In one preferred embodiment, the CpG oligonucleotides are in the sodium salt form. In a specific embodiment, a CpG oligonucleotide adjuvant described herein comprises an aluminum salt. In some embodiments, the aluminum salt comprises one or more selected from the group consisting of amorphous aluminum hydroxyphosphate sulfate, aluminum hydroxide, aluminum phosphate, and potassium aluminum sulfate. The aluminum salt may be aluminum hydroxide or aluminum phosphate. In a specific embodiment, the aluminum salt comprises aluminum hydroxide and aluminum phosphate. In a specific embodiment, the aluminum salt comprises aluminum phosphate. In a specific embodiment, the aluminum salt is aluminum hydroxide. In some embodiments, the CpG oligonucleotide adjuvant described herein does not comprise an aluminum salt.

[00218] In a specific embodiment, a CpG oligonucleotide adjuvant comprises CpG 1018® adjuvant. In a specific embodiment, a CpG oligonucleotide adjuvant is one described in Section 6, infra.

[00219] In some embodiments, a CpG oligonucleotide adjuvant described herein (e.g., in Example 1) enhances or boosts an immune response to influenza virus and does not produce an allergy or other adverse reaction. For example, the CpG oligonucleotide adjuvant can enhance an immune response by several mechanisms including, e.g., lymphocyte recruitment, stimulation of B and/or T cells, and stimulation of macrophages.

5.3 Chimeric HA

[00220] In one aspect, provided herein are chimeric hemagglutinins (cHAs) comprising an influenza virus HA stem domain and an influenza virus HA globular head domain, wherein the influenza virus HA globular head domain is heterologous to the influenza virus HA stem domain. In some embodiments, the influenza virus HA globular head domain is heterologous to the influenza virus HA stem domain if the influenza virus hemagglutinin globular head is less than 80%, less than 75%, less than 70%, less than 65%, or less than 60% identical to the HA globular head domain that would normally be associated with the influenza virus HA stem domain of the chimeric HA. In some embodiments, the influenza virus HA globular head domain is heterologous to the influenza virus HA stem domain if the influenza virus hemagglutinin globular head is less than 55%, less than 50%, less than 45%, less than 40%, or less than 35% identical to the HA globular head domain that would normally be associated with the influenza virus hemagglutinin stem domain of the chimeric HA. In some embodiments, the influenza virus hemagglutinin globular head domain is heterologous to the influenza virus hemagglutinin stem domain if the influenza virus HA globular head is less than 55%, less than 30%, less than 25%, or less than 20% identical to the HA globular head domain that would normally be associated with the influenza virus HA stem domain of the chimeric HA. In some embodiments, the influenza virus HA globular head domain is heterologous to the influenza virus hemagglutinin stem domain if the influenza virus HA globular head is about 70% to about 80%, about 60% to about 80%, about 50% to about 75%, or about 45% to about 70% identical to the HA globular head domain that would normally be associated with the influenza virus HA stem domain of the chimeric HA. In some embodiments, the influenza virus hemagglutinin globular head domain is heterologous to the influenza virus hemagglutinin stem domain if the influenza virus HA globular head that is about 20% to about 50%, about 25 to about 50%, about 20% to about 30%, or about 30% to about 70% identical to the HA globular head domain that would normally be associated with the influenza virus HA stem domain of the chimeric HA. In some embodiments, the influenza virus HA globular head domain is one described in Section 5.3.1 or 6. In some embodiments, the influenza virus HA stem domain is one described in Section 5.3.2 or 6. In specific embodiments, the influenza virus HA stem domain comprise the HA stem domain of an influenza virus H3. In specific embodiments, the influenza virus HA stem domain comprise the HA stem domain of influenza A virus HA is A/Hong Kong/4801/2014, NYMC X-263 HA or A/Hong Kong/4801/2014-like HA.

[00221] In some embodiments, a chimeric HA comprises an influenza virus HA stem domain and an influenza virus HA globular head domain, wherein the influenza virus HA globular head domain is heterologous to the influenza virus HA stem domain, and wherein the influenza virus HA globular head domain of the chimeric HA is immunologically distinct from the globular head domain of the HA that would normally be associated with the influenza virus HA stem domain of the chimeric HA. In some embodiments, the influenza virus HA globular head domain is one described in Section 5.3.1 or 6. In some embodiments, the influenza virus HA stem domain is one described in Section 5.3.2 or 6. In specific embodiments, the influenza virus HA stem domain comprise the HA stem domain of an influenza virus H3. In specific embodiments, the influenza virus HA stem domain comprise the HA stem domain of influenza A virus HA is A/Hong Kong/4801/2014, NYMC X-263 HA or A/Hong Kong/4801/2014-like HA.

[00222] In some embodiments, provided herein are chimeric hemagglutinins (cHAs) comprising a group 2 influenza A virus HA stem domain and an influenza virus HA globular head domain, wherein the influenza virus HA globular head domain is heterologous to the group 2 influenza A virus HA stem domain. In some embodiments, the influenza virus HA globular head domain is heterologous to the group 2 influenza A virus HA stem domain if the influenza virus HA globular head is less than 80%, less than 75%, less than 70%, less than 65%, or less than 60% identical to the HA globular head domain that would normally be associated with the group 2 influenza A virus HA stem domain of the chimeric HA. In some embodiments, the influenza virus HA globular head domain is heterologous to the group 2 influenza A virus HA stem domain the influenza virus HA globular head is less than 55%, less than 50%, less than 45%, less than 40%, or less than 35% identical to the HA globular head domain that would normally be associated with the group 2 influenza A virus hemagglutinin stem domain of the chimeric HA. In some embodiments, the influenza virus HA globular head domain is heterologous to the group 2 influenza A virus HA stem domain the influenza virus HA globular head is less than 55%, less than 30%, less than 25%, or less than 20% identical to the HA globular head domain that would normally be associated with the group 2 influenza A virus hemagglutinin stem domain of the chimeric HA. In some embodiments, the influenza virus HA globular head domain is heterologous to the group 2 influenza A virus HA stem domain the influenza virus hemagglutinin globular head is about 70% to about 80%, about 60% to about 80%, about 50% to about 75%, or about 45% to about 70% identical to the HA globular head domain that would normally be associated with the group 2 influenza A virus hemagglutinin stem domain of the chimeric HA. In some embodiments, the influenza virus HA globular head domain is heterologous to the group 2 influenza A virus HA stem domain the influenza virus HA globular head that is about 20% to about 50%, about 25% to about 50%, about 20% to about 30%, or about 30% to about 70% identical to the HA globular head domain that would normally be associated with the group 2 influenza A virus HA stem domain of the chimeric HA. In some embodiments, the influenza virus HA globular head domain is one described in Section 5.3.1 or 6. In some embodiments, the influenza virus HA stem domain is one described in Section 5.3.2 or 6. In specific embodiments, the influenza virus HA stem domain comprise the HA stem domain of an influenza virus H3. In specific embodiments, the influenza virus HA stem domain comprise the HA stem domain of influenza A virus HA is A/Hong Kong/4801/2014, NYMC X-263 HA or A/Hong Kong/4801/2014-like HA.

[00223] In some embodiments, a chimeric HA comprises a group 2 influenza A virus HA stem domain and an influenza virus HA globular head domain, wherein the influenza virus HA globular head domain is heterologous to the group 2 influenza A virus HA stem domain, and wherein the influenza virus HA globular head domain of the chimeric HA is immunologically distinct from the globular head domain of the HA that would normally be associated with the group 2 influenza A virus HA stem domain of the chimeric HA. In some embodiments, an influenza virus HA globular head domain of a chimeric HA that is immunologically distinct from the globular head domain of the HA that would normally be associated with the group 2 influenza A virus HA stem domain of the chimeric HA is another group 2 influenza A virus HA subtype (e.g., an H4, H7, Hl 0, Hl 4, or Hl 5 subtype). In some embodiments, an influenza virus HA globular head domain of a chimeric HA that is immunologically distinct from the globular head domain of the HA that would normally be associated with the group 2 influenza A virus HA stem domain of the chimeric HA is a group 1 influenza A virus HA subtype. Group 2 influenza A viruses include H3, H4, H7, H10, H14, and H15 subtypes. Group 1 influenza A viruses include Hl, H2, H5, H6, H8, H9, Hl 1, H12, H13, H16, H17, and H18 subtypes.

[00224] In some embodiments, a chimeric HA comprises an influenza virus HA stem domain and an influenza virus HA globular head domain, wherein the influenza virus HA globular head domain of the chimeric HA is from a different strain, subtype, or group of influenza virus than the influenza virus HA stem domain. In some embodiments, a chimeric HA comprises an influenza virus HA stem domain and an influenza virus HA globular head domain, wherein the influenza virus HA globular head domain of the chimeric HA is from a different strain of influenza virus than the influenza virus HA stem domain. In some embodiments, a chimeric HA comprises an influenza virus HA stem domain and an influenza virus HA globular head domain, wherein the influenza virus HA globular head domain of the chimeric HA is from a different subtype of influenza virus than the influenza virus HA stem domain. In some embodiments, a chimeric HA comprises an influenza virus HA stem domain and an influenza virus HA globular head domain, wherein the influenza virus HA globular head domain of the chimeric HA is from a different group of influenza virus than the influenza virus HA stem domain. In some embodiments, a chimeric HA comprises an influenza virus HA stem domain and an influenza virus HA globular head domain, wherein the influenza virus HA stem domain of the chimeric HA comprises the HA stem domain of a seasonal influenza virus HA and the influenza virus globular head domain of the chimeric HA comprises the HA globular head domain of an influenza virus subtype that does not circulate in humans. In some embodiments, a chimeric HA comprises an influenza virus HA stem domain and an influenza virus HA globular head domain, wherein the influenza virus HA stem domain of the chimeric HA comprises the HA stem domain of a seasonal influenza virus HA and the influenza virus globular head domain of the chimeric HA comprises the HA globular head domain of an avian influenza virus subtype that does not circulate in humans. In some embodiments, a chimeric HA comprises an influenza virus HA stem domain and an influenza virus HA globular head domain, wherein the influenza virus HA stem domain of the chimeric HA comprises the HA stem domain of a seasonal influenza virus HA and the influenza virus globular head domain of the chimeric HA comprises the HA globular head domain of an exotic influenza virus that does not circulate in humans. In some embodiments, a chimeric HA comprises an influenza virus HA stem domain and an influenza virus HA globular head domain, wherein the influenza virus HA stem domain of the chimeric HA comprises the HA stem domain of a seasonal influenza virus HA and the influenza virus globular head domain of the chimeric HA comprises the HA globular head domain of an avian influenza virus that does not circulate in humans. In some embodiments, the influenza virus HA globular head domain is one described in Section 5.3.1 or 6. In some embodiments, the influenza virus HA stem domain is one described in Section 5.3.2 or 6. In specific embodiments, the influenza virus HA stem domain comprises the HA stem domain of an influenza A virus H3. In specific embodiments, the influenza virus HA stem domain comprises the HA stem domain of an influenza A virus A/Hong Kong/4801/2014, NYMC X- 263 HA or A/Hong Kong/4801/2014-like HA.

[00225] In some embodiments, the influenza virus HA globular head domain of a chimeric HA is less than 80%, less than 75%, less than 70%, less than 65%, or less than 60% identical to the HA globular head domain that would normally be associated with the HA stem domain of the chimeric HA. In some embodiments, the influenza virus HA globular head domain of a chimeric HA refers to an influenza virus hemagglutinin globular head that is less than 55%, less than 50%, less than 45%, less than 40%, or less than 35% identical to the to the HA globular head domain that would normally be associated with the HA stem domain of the chimeric HA. In some embodiments, the influenza virus HA globular head domain of a chimeric HA is less than 55%, less than 30%, less than 25%, or less than 20% identical to the HA globular head domain that would normally be associated with the HA stem domain of the chimeric HA. In some embodiments, the influenza virus HA globular head domain of a chimeric HA is about 70% to about 80%, about 60% to about 80%, about 50% to about 75%, or about 45% to about 70% identical to the HA globular head domain that would normally be associated with the HA stem domain of the chimeric HA. In some embodiments, the influenza virus HA globular head domain of a chimeric HA is about 20% to about 50%, about 25 to about 50%, about 20% to about 30%, or about 30% to about 70% identical to the HA globular head domain that would normally be associated with the HA stem domain of the chimeric HA. In specific embodiments, the influenza virus HA stem domain comprises the HA stem domain of an influenza A virus H3. In specific embodiments, the influenza virus HA stem domain comprises the HA stem domain of an influenza A virus A/Hong Kong/4801/2014, NYMC X-263 HA or A/Hong Kong/4801/2014-like HA.

[00226] In some embodiments, a chimeric HA comprises a group 2 influenza A virus HA stem domain and an influenza virus HA globular head domain, wherein the influenza virus HA globular head domain of the chimeric HA is from a different strain, subtype, or group of influenza virus than the group 2 influenza A virus HA stem domain. In some embodiments, a chimeric HA comprises a group 2 influenza A virus HA stem domain and an influenza virus HA globular head domain, wherein the influenza virus HA globular head domain of the chimeric HA is from a different strain of influenza virus than the group 2 influenza A virus HA stem domain. In some embodiments, a chimeric HA comprises a group 2 influenza A virus HA stem domain and an influenza virus HA globular head domain, wherein the influenza virus HA globular head domain of the chimeric HA is from a different subtype of influenza virus than the group 2 influenza A virus HA stem domain. In some embodiments, a chimeric HA comprises a group 2 influenza A virus HA stem domain and an influenza virus HA globular head domain, wherein the influenza virus HA globular head domain of the chimeric HA is from a different group of influenza virus than the group 2 influenza A virus HA stem domain. In some embodiments, a chimeric HA comprises a group 2 influenza A virus HA stem domain and an influenza virus HA globular head domain, wherein the group 2 influenza A virus HA stem domain of the chimeric HA comprises the HA stem domain of a seasonal influenza virus HA and the influenza virus globular head domain of the chimeric HA comprises the HA globular head domain of an influenza virus subtype (e.g., an avian influenza A virus subtype) that does not circulate in humans. In some embodiments, a chimeric HA comprises a group 2 influenza A virus HA stem domain and an influenza virus HA globular head domain, wherein the group 2 influenza A virus HA stem domain of the chimeric HA comprises the HA stem domain of a seasonal influenza virus HA and the influenza virus globular head domain of the chimeric HA comprises the HA globular head domain of an exotic influenza virus (e.g., an avian influenza A virus) that does not circulate in humans.

[00227] In some embodiments, the influenza virus HA globular head domain of a chimeric HA is the HA globular head domain of a group 1 influenza A virus HA. In some embodiments, the influenza virus HA globular head domain of a chimeric HA is the HA globular head domain of an Hl, H2, H5, H6, H8, H9, Hl 1, H12, H13, H16, H17, or H18 subtype of influenza A virus HA. In some embodiments, the influenza virus HA globular head domain of a chimeric HA is the HA globular head domain of an H2, H5, H6, H8, H9, Hl 1, H12, H13, H16, H17, or H18 subtype of influenza A virus HA. In some embodiments, the influenza virus HA globular head domain of a chimeric HA is the HA globular head domain of an H5, H8, H9, Hl 1, H12, or H13 subtype of influenza A virus HA. In some embodiments, the influenza virus HA globular head domain of a chimeric HA is the HA globular head domain of an H4, H7, H10, H14, or H15 subtype of influenza A virus HA. In some embodiments, the influenza virus HA globular head domain of a chimeric HA is the HA globular head domain of an avian influenza A virus. In some embodiments, the influenza virus HA globular head domain of a chimeric HA is the HA globular head domain of A/wedge-tailed shearwater/We stern Australia/2576/1979 HA. In some embodiments, the influenza virus HA globular head domain of a chimeric HA is the HA globular head domain of A/wedge-tailed shearwater/Western Australia/2576/1979-like HA. In some embodiments, the influenza virus HA globular head domain of a chimeric HA is the HA globular head domain of A/Duck/Czechoslovakia/1956 HA. In some embodiments, the influenza virus HA globular head domain of a chimeric HA is the HA globular head domain of A/Duck/Czechoslovakia/1956-like HA.

[00228] In some embodiments, the influenza virus HA globular head domain of a chimeric HA is less than 80%, less than 75%, less than 70%, less than 65%, or less than 60% identical to the HA globular head domain that would normally be associated with the group 2 influenza A virus HA stem domain of the chimeric HA. In some embodiments, the influenza virus HA globular head domain of a chimeric HA refers to an influenza virus HA globular head that is less than 55%, less than 50%, less than 45%, less than 40%, or less than 35% identical to the to the HA globular head domain that would normally be associated with the group 2 influenza A virus HA stem domain of the chimeric HA. In some embodiments, the influenza virus HA globular head domain of a chimeric HA is less than 55%, less than 30%, less than 25%, or less than 20% identical to the HA globular head domain that would normally be associated with the group 2 influenza A virus HA stem domain of the chimeric HA. In some embodiments, the influenza virus HA globular head domain of a chimeric HA is about 70% to about 80%, about 60% to about 80%, about 50% to about 75%, or about 45% to about 70% identical to the HA globular head domain that would normally be associated with the group 2 influenza A virus HA stem domain of the chimeric HA. In some embodiments, the influenza virus HA globular head domain of a chimeric HA is about 20% to about 50%, about 25 to about 50%, about 20% to about 30%, or about 30% to about 70% identical to the HA globular head domain that would normally be associated with the group 2 influenza A virus HA stem domain of the chimeric HA.

[00229] In some embodiments, provided herein is provided herein is a chimeric HA comprising: (i) an influenza virus HA stem domain of influenza A virus A/Hong Kong/4801/14 (H3) HA; and (ii) an influenza virus HA globular head domain of the HA globular head domain of an Hl, H2, H3, H4, H5, H6, H7, H8, H9, H10, Hl l, H12, H13, H14, H15, H16, Hl 7, or H18 subtype of an influenza A virus HA, wherein the influenza virus HA globular head domain is heterologous to the influenza virus HA stem domain. In some embodiments, the influenza virus HA globular head domain is an Hl, H2, H3, H4, H5, H6, H7, H8, H9, H10, Hl l, H12, H13, H14, H15, H16, H17, or H18 subtype of an avian influenza A virus HA. In some embodiments, the influenza virus HA globular head domain is an H4, H7, H10, H14, or H15 subtype of an influenza A virus HA. In some embodiments, the influenza virus HA globular head domain is an H5 subtype of influenza A virus HA. In some embodiments, the influenza virus HA globular head domain is the HA globular head domain of influenza A virus A/Vietnam/1203/04 (H5) HA. In some embodiments, the influenza virus HA globular head domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:46. In some embodiments, the influenza virus HA globular head domain comprises the amino acid sequence of SEQ ID NO:46. In some embodiments, the influenza virus HA globular head domain is an H8 subtype of influenza A virus HA. In some embodiments, the influenza virus HA globular head domain is the HA globular head domain of A/mallard/Sweden/24/2002 H8N4. In some embodiments, the influenza virus HA globular head domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:47. In some embodiments, the influenza virus HA globular head domain comprises the amino acid sequence of SEQ ID NO:47. In some embodiments, the influenza virus HA globular head domain of an H4 subtype (e.g., A/duck/Czech/56) of influenza A virus HA, an H10 subtype (e.g., A/mallard/Interior or Alaska/IOBMO 1929/10) of influenza A virus HA, an H14 subtype (e.g., A/mallard/Gurjev/263/82) of influenza A virus HA, or an Hl 5 subtype (e.g., A/wedge tailed shearwater/Western Australia/2576/79) of influenza A virus HA. In some embodiments, the influenza virus HA globular head domain is the HA globular head domain of an H7 subtype (e.g., A/mallard/Alberta/24/01 or A/Anhui/1/13) of an influenza A virus HA. In some embodiments, the influenza virus HA globular head domain is the HA globular head domain of influenza A virus A/Alberta/24/01 (H7) HA. In some embodiments, the influenza virus HA globular head domain is not the HA globular head domain of an Hl subtype of influenza A virus HA. In some embodiments, the influenza virus HA globular head domain is not an H2 subtype of an influenza A virus HA. In some embodiments, the influenza virus HA globular head domain is not an H3 subtype of an influenza A virus HA. In some embodiments, the influenza virus HA globular head domain is not an H5 subtype of an influenza A virus HA. [00230] In some embodiments, provided herein is provided herein is a chimeric HA comprising: (i) an influenza virus HA stem domain of influenza A virus A/Hong Kong/4801/14 (H3) HA; and (ii) an influenza virus HA globular head domain of the HA globular head domain of influenza A virus A/mallard/Sweden/24/2002 H8N4 HA. In some embodiments, provided herein is provided herein is a chimeric HA comprising: (i) an influenza virus HA stem domain of influenza A virus A/Hong Kong/4801/14 (H3) HA; and (ii) an influenza virus HA globular head domain of the HA globular head domain of influenza A virus A/Vietnam/1203/2004 H5N1 HA.

[00231] In some embodiments, provided herein is provided herein is a chimeric HA comprising: (i) an influenza virus HA stem domain of influenza A virus A/Hong Kong/4801/14 (H3) HA; and (ii) an influenza virus HA globular head domain comprising the amino acid sequence of SEQ ID NO:46. In some embodiments, provided herein is provided herein is a chimeric HA comprising: (i) an influenza virus HA stem domain of influenza A virus A/Hong Kong/4801/14 (H3) HA; and (ii) an influenza virus HA globular head domain comprising the amino acid sequence of SEQ ID NO:47.

[00232] In specific embodiments, provided herein is provided herein is a chimeric HA comprising: (i) an influenza virus HA stem domain of influenza A virus A/Hong Kong/4801/14 (H3) HA; and (ii) an influenza virus HA globular head domain of the HA globular head domain of influenza A virus A/Shearwater/West Australia/2576/1979 HA. In specific embodiments, provided herein is provided herein is a chimeric HA comprising: (i) an influenza virus HA stem domain of influenza A virus A/Hong Kong/4801/14 (H3) HA; and (ii) an influenza virus HA globular head domain of the HA globular head domain of influenza A virus A/duck/Czechoslovakia/1956 HA.

[00233] In specific embodiments, provided herein is provided herein is a chimeric HA comprising: (i) an influenza virus HA stem domain of influenza A virus A/Hong Kong/4801/14 (H3)-like HA; and (ii) an influenza virus HA globular head domain of the HA globular head domain of influenza A virus A/Shearwater/West Australia/2576/1979 HA. In specific embodiments, provided herein is provided herein is a chimeric HA comprising: (i) an influenza virus HA stem domain of influenza A virus A/Hong Kong/4801/14-like (H3) HA; and (ii) an influenza virus HA globular head domain of the HA globular head domain of influenza A virus A/duck/Czechoslovakia/1956 HA.

[00234] In specific embodiments, provided herein is provided herein is a chimeric HA comprising: (i) an influenza virus HA stem domain of influenza A virus A/Hong Kong/4801/14 (H3)-like HA; and (ii) an influenza virus HA globular head domain of the HA globular head domain of influenza A virus A/Shearwater/West Australia/2576/1979-like HA. In specific embodiments, provided herein is provided herein is a chimeric HA comprising: (i) an influenza virus HA stem domain of influenza A virus A/Hong Kong/4801/14-like (H3) HA; and (ii) an influenza virus HA globular head domain of the HA globular head domain of influenza A virus A/duck/Czechoslovakia/1956-like HA.

[00235] In some embodiments, provided herein is a chimeric HA comprising: (i) an influenza virus HA stem domain of influenza A virus A/Perth/16/2009 (H3) HA; and (ii) an influenza virus HA globular head domain of the HA globular head domain of an Hl, H2, H3, H4, H5, H6, H7, H8, H9, H10, Hl l, H12, H13, H14, H15, H16, H17, or H18 subtype of an influenza A virus HA, wherein the influenza virus HA globular head domain is heterologous to the influenza virus HA stem domain. In some embodiments, the influenza virus HA globular head domain is an Hl, H2, H3, H4, H5, H6, H7, H8, H9, H10, Hl l, H12, H13, H14, Hl 5, Hl 6, Hl 7, or Hl 8 subtype of an avian influenza A virus HA. In some embodiments, the influenza virus HA globular head domain is an H4, H7, H10, H14, or H15 subtype of an influenza A virus HA. In some embodiments, the influenza virus HA globular head domain is an H5 subtype of influenza A virus HA. In some embodiments, the influenza virus HA globular head domain is the HA globular head domain of influenza A virus A/Vietnam/1203/04 (H5) HA. In some embodiments, the influenza virus HA globular head domain of an H4 subtype (e.g., A/duck/Czech/56) of influenza A virus HA, an H10 subtype (e.g., A/mallard/Interior or Alaska/IOBMO 1929/10) of influenza A virus HA, an H14 subtype (e.g., A/mallard/Gurjev/263/82) of influenza A virus HA, or an Hl 5 subtype (e.g., A/wedge tailed shearwater/Western Australia/2576/79) of influenza A virus HA. In some embodiments, the influenza virus HA globular head domain is the HA globular head domain of an H7 subtype (e.g., A/mallard/Alberta/24/01 or A/Anhui/1/13) of an influenza A virus HA. In some embodiments, the influenza virus HA globular head domain is the HA globular head domain of influenza A virus A/Alberta/24/01 (H7) HA. In some embodiments, the influenza virus HA globular head domain is not the HA globular head domain of an Hl subtype of influenza A virus HA. In some embodiments, the influenza virus HA globular head domain is not an H2 subtype of an influenza A virus HA. In some embodiments, the influenza virus HA globular head domain is not an H3 subtype of an influenza A virus HA. In some embodiments, the influenza virus HA globular head domain is not an H5 subtype of an influenza A virus HA.

[00236] In some embodiments, provided herein is a chimeric HA comprising: (i) an influenza virus HA stem domain of influenza A virus A/Brisbane/10/2007-like (H3) HA; and (ii) an influenza virus HA globular head domain of the HA globular head domain of an Hl, H2, H3, H4, H5, H6, H7, H8, H9, H10, Hl l, H12, H13, H14, H15, H16, H17, or H18 subtype of an influenza A virus HA, wherein the influenza virus HA globular head domain is heterologous to the influenza virus HA stem domain. In some embodiments, the influenza virus HA globular head domain is an Hl, H2, H3, H4, H5, H6, H7, H8, H9, H10, Hl l, H12, H13, H14, H15, H16, H17, or H18 subtype of an avian influenza A virus HA. In some embodiments, the influenza virus HA globular head domain is an H4, H7, H10, H14, or H15 subtype of an influenza A virus HA. In some embodiments, the influenza virus HA globular head domain is an H5 subtype of influenza A virus HA. In some embodiments, the influenza virus HA globular head domain is the HA globular head domain of influenza A virus A/Vietnam/1203/04 (H5) HA. In some embodiments, the influenza virus HA globular head domain of an H4 subtype (e.g., A/duck/Czech/56) of influenza A virus HA, an H10 subtype (e.g., A/mallard/Interior or Alaska/IOBMO 1929/10) of influenza A virus HA, an H14 subtype (e.g., A/mallard/Gurjev/263/82) of influenza A virus HA, or an Hl 5 subtype (e.g., A/wedge tailed shearwater/Western Australia/2576/79) of influenza A virus HA. In some embodiments, the influenza virus HA globular head domain is the HA globular head domain of an H7 subtype (e.g., A/mallard/Alberta/24/01 or A/Anhui/1/13) of an influenza A virus HA. In some embodiments, the influenza virus HA globular head domain is the HA globular head domain of influenza A virus A/Alberta/24/01 (H7) HA. In some embodiments, the influenza virus HA globular head domain is not the HA globular head domain of an Hl subtype of influenza A virus HA. In some embodiments, the influenza virus HA globular head domain is not an H2 subtype of an influenza A virus HA. In some embodiments, the influenza virus HA globular head domain is not an H3 subtype of an influenza A virus HA. In some embodiments, the influenza virus HA globular head domain is not an H5 subtype of an influenza A virus HA.

[00237] In some embodiments, provided herein is provided herein is a chimeric HA comprising: (i) an influenza virus HA stem domain of influenza A virus A/Hong Kong/1/1968 (H3) HA; and (ii) an influenza virus HA globular head domain of the HA globular head domain of an Hl, H2, H3, H4, H5, H6, H7, H8, H9, H10, Hl l, H12, H13, H14, H15, H16, Hl 7, or H18 subtype of an influenza A virus HA, wherein the influenza virus HA globular head domain is heterologous to the influenza virus HA stem domain. In some embodiments, the influenza virus HA globular head domain is an Hl, H2, H3, H4, H5, H6, H7, H8, H9, H10, Hl l, H12, H13, H14, H15, H16, H17, or H18 subtype of an avian influenza A virus HA. In some embodiments, the influenza virus HA globular head domain is an H4, H7, H10, H14, or H15 subtype of an influenza A virus HA. In some embodiments, the influenza virus HA globular head domain is an H5 subtype of influenza A virus HA. In some embodiments, the influenza virus HA globular head domain is the HA globular head domain of influenza A virus A/Vietnam/1203/04 (H5) HA. In some embodiments, the influenza virus HA globular head domain of an H4 subtype (e.g., A/duck/Czech/56) of influenza A virus HA, an H10 subtype (e.g., A/mallard/Interior or Alaska/IOBMO 1929/10) of influenza A virus HA, an H14 subtype (e.g, A/mallard/Gurjev/263/82) of influenza A virus HA, or an Hl 5 subtype (e.g, A/wedge tailed shearwater/Westem Australia/2576/79) of influenza A virus HA. In some embodiments, the influenza virus HA globular head domain is the HA globular head domain of an H7 subtype (e.g., A/mallard/Alberta/24/01 or A/Anhui/1/13) of an influenza A virus HA. In some embodiments, the influenza virus HA globular head domain is the HA globular head domain of influenza A virus A/Alberta/24/01 (H7) HA. In some embodiments, the influenza virus HA globular head domain is not the HA globular head domain of an Hl subtype of influenza A virus HA. In some embodiments, the influenza virus HA globular head domain is not an H2 subtype of an influenza A virus HA. In some embodiments, the influenza virus HA globular head domain is not an H3 subtype of an influenza A virus HA. In some embodiments, the influenza virus HA globular head domain is not an H5 subtype of an influenza A virus HA.

[00238] In some embodiments, provided herein is provided herein is a chimeric HA comprising: (i) an influenza virus HA stem domain of influenza A virus A/Victoria/361/2011(H3) HA; and (ii) an influenza virus HA globular head domain of the HA globular head domain of an Hl, H2, H3, H4, H5, H6, H7, H8, H9, H10, Hl 1, H12, H13, Hl 4, H15, Hl 6, Hl 7, or H18 subtype of an influenza A virus HA, wherein the influenza virus HA globular head domain is heterologous to the influenza virus HA stem domain. In some embodiments, the influenza virus HA globular head domain is an Hl, H2, H3, H4, H5, H6, H7, H8, H9, H10, Hl l, H12, H13, H14, H15, H16, H17, or H18 subtype of an avian influenza A virus HA. In some embodiments, the influenza virus HA globular head domain is an H4, H7, H10, H14, or H15 subtype of an influenza A virus HA. In some embodiments, the influenza virus HA globular head domain is an H5 subtype of influenza A virus HA. In some embodiments, the influenza virus HA globular head domain is the HA globular head domain of influenza A virus A/Vietnam/1203/04 (H5) HA. In some embodiments, the influenza virus HA globular head domain of an H4 subtype (e.g., A/duck/Czech/56) of influenza A virus HA, an H10 subtype (e.g., A/mallard/Interior or Alaska/IOBMO 1929/10) of influenza A virus HA, an H14 subtype (e.g., A/mallard/Gurjev/263/82) of influenza A virus HA, or an Hl 5 subtype (e.g., A/wedge tailed shearwater/Westem Australia/2576/79) of influenza A virus HA. In some embodiments, the influenza virus HA globular head domain is the HA globular head domain of an H7 subtype (e.g., A/mallard/Alberta/24/01 or A/Anhui/1/13) of an influenza A virus HA. In some embodiments, the influenza virus HA globular head domain is the HA globular head domain of influenza A virus A/Alberta/24/01 (H7) HA. In some embodiments, the influenza virus HA globular head domain is not the HA globular head domain of an Hl subtype of influenza A virus HA. In some embodiments, the influenza virus HA globular head domain is not an H2 subtype of an influenza A virus HA. In some embodiments, the influenza virus HA globular head domain is not an H3 subtype of an influenza A virus HA. In some embodiments, the influenza virus HA globular head domain is not an H5 subtype of an influenza A virus HA.

[00239] In another specific embodiment, provided herein is a chimeric influenza virus HA polypeptide comprising or consisting of (i) an influenza virus HA stem domain polypeptide from influenza A virus A/harbor/Massachusetts/1/2011 (H3); and (ii) an influenza virus HA globular head domain from an influenza A virus of subtype Hl, H2, H3, H4, H5, H6, H7, H8, H9, H10, Hl l, H12, H13, H14, H15, H16, H17, or H18, wherein said influenza virus HA globular head domain is heterologous to said influenza virus HA stem domain polypeptide. In a specific embodiment, the influenza virus HA globular head domain is from an avian influenza A virus of subtype Hl, H2, H3, H4, H5, H6, H7, H8, H9, H10, Hl l, H12, H13, H14, H15, H16, H17, or H18. In a specific embodiment, the influenza virus HA globular head domain is from an influenza A virus of subtype H4, H7, H 10, Hl 4, or Hl 5. In another specific embodiment, the influenza virus HA globular head domain is from an influenza A virus of subtype H4 (e.g. A/duck/Czech/56), subtype H5 (e.g., A/VietNam/1203/04), subtype H7 (e.g., A/mallard/Alberta/24/01 or A/Anhui/1/13), subtype H10 (e.g., A/mallard/Interior or Alaska/IOBMO 1929/10), subtype H14 (e.g., A/mallard/Gurjev/263/82), or subtype H15 (e.g., A/wedge tailed shearwater/Western Australia/2576/79). In some embodiments, the influenza virus HA globular head domain is not the HA globular head domain of an Hl subtype of influenza A virus HA. In some embodiments, the influenza virus HA globular head domain is not an H2 subtype of an influenza A virus HA. In some embodiments, the influenza virus HA globular head domain is not an H3 subtype of an influenza A virus HA. In some embodiments, the influenza virus HA globular head domain is not an H5 subtype of an influenza A virus HA.

[00240] In another specific embodiment, provided herein is a chimeric influenza virus HA polypeptide comprising or consisting of (i) an influenza virus HA stem domain polypeptide from influenza A virus A/Indiana/10/2011 (H3); and (ii) an influenza virus HA globular head domain from an influenza A virus of subtype Hl, H2, H3, H4, H5, H6, H7, H8, H9, H10, Hl 1, H12, H13, H14, H15, H16, H17, or H18, wherein said influenza virus HA globular head domain is heterologous to said influenza virus HA stem domain polypeptide. In a specific embodiment, the influenza virus HA globular head domain is from an avian influenza A virus of subtype Hl, H2, H3, H4, H5, H6, H7, H8, H9, H10, Hl l, H12, H13, H14, H15, H16, H17, or Hl 8. In a specific embodiment, the influenza virus HA globular head domain is from an influenza A virus of subtype H4, H7, H10, H14, or H15. In another specific embodiment, the influenza virus HA globular head domain is from an influenza A virus of subtype H4 (e.g. A/duck/Czech/56), subtype H5 (e.g., A/Viet Nam/1203/04), subtype H7 (e.g., A/mallard/Alberta/24/01 or A/Anhui/1/13), subtype H10 (e.g., A/mallard/Interior or Alaska/IOBMO 1929/10), subtype H14 (e.g., A/mallard/Gurjev/263/82), or subtype H15 (e.g., A/wedge tailed shearwater/Western Australia/2576/79). In some embodiments, the influenza virus HA globular head domain is not the HA globular head domain of an Hl subtype of influenza A virus HA. In some embodiments, the influenza virus HA globular head domain is not an H2 subtype of an influenza A virus HA. In some embodiments, the influenza virus HA globular head domain is not an H3 subtype of an influenza A virus HA. In some embodiments, the influenza virus HA globular head domain is not an H5 subtype of an influenza A virus HA.

[00241] Table 1. Exemplary cH4/3, cH5/3, cH7/3, cH10/3, cH14/3, cH15/3 chimeric influenza HA.

[00242] In some embodiments, a chimeric HA provided herein comprises: (i) the HA stem domain of a HA of an influenza A virus of the H3 subtype; and (ii) the HA globular head domain of a HA of an influenza A virus of the H5 subtype (sometimes referred to herein as a “cH5/3” chimeric HA). In a specific embodiment, the cH5/3 chimeric HA is a cH5/3 chimeric HA described in Table 1, above.

[00243] In some embodiments, a chimeric HA provided herein comprises :(i) the HA stem domain of a HA of an influenza A virus of the H3 subtype; and (ii) the HA globular head domain of a HA of an influenza A virus of the H7 subtype (sometimes referred to herein as a “cH7/3” chimeric HA). In a specific embodiment, the cH7/3 chimeric HA is a cH7/3 chimeric HA described in Table 1, above.

[00244] In some embodiments, a chimeric HA provided herein comprises: (i) the stem domain of a HA of an influenza A virus of the H3 subtype; and (ii) the HA globular head domain of a HA of an influenza A virus of the H4 subtype (sometimes referred to herein as a “cH4/3” chimeric HA). In a specific embodiment, the cH4/3 chimeric HA is a cH4/3 chimeric influenza HA described in Table 1, above.

[00245] In some embodiments, a chimeric HA provided herein comprises: (i) the HA stem domain of a HA of an influenza A virus of the H3 subtype; and (ii) the HA globular head domain of a HA of an influenza A virus of the H10 subtype (sometimes referred to herein as a “cH10/3” chimeric HA). In a specific embodiment, the cH10/3 chimeric HA is a cH10/3 chimeric HA described in Table 1, above. [00246] In some embodiments, a chimeric HA polypeptide provided herein comprises: (i) the HA stem domain of a HA of an influenza A virus of the H3 subtype; and (ii) the HA globular head domain of a HA of an influenza A virus of the H14 subtype (sometimes referred to herein as a “cH14/3” chimeric HA). In a specific embodiment, the cH14/3 chimeric HA is a cH14/3 chimeric HA described in Table 1, above.

[00247] In some embodiments, a chimeric HA provided herein comprises: (i) the HA stem domain of a HA of an influenza A virus of the H3 subtype; and (ii) the HA globular head domain of a HA of an influenza A virus of the Hl 5 subtype (sometimes referred to herein as a “cH15/3” chimeric HA). In a specific embodiment, the cH15/3 chimeric HA is a cH15/3 chimeric HA described in Table 1, above.

[00248] In a specific embodiment, a chimeric HA is a chimeric HA described in in Table 1, above. In a specific embodiment, a chimeric HA is a chimeric HA described in Section 5.3, below.

[00249] A full-length influenza HA typically comprises an HA1 domain an HA2 domain. The HA stem domain is formed by two segments of the HA1 domain and most of the HA2 domain (e.g., the portion of the HA2 domain that does not include the transmembrane and cytoplasmic domains). The two segments of the HA1 domain are separated, in primary sequence, by the globular head domain see, e.g., the amino acid residues between the residues designated A_P and A_q in FIGS. 11 A-l ID for influenza A viruses). In some embodiments, the chimeric HA described herein maintain such a structure. That is, in some embodiments, the chimeric HA described herein comprise a stable stem structure composed of an HA1 domain and an HA2 domain, and a globular head domain separating the two segments of the HA1 domain (in primary sequence), wherein said globular head domain is heterologous to the stem domain formed by the other segments of the HA1 domain and the HA2 domain.

[00250] In some embodiments, a chimeric HA provided herein comprises an influenza virus HA stem domain and an influenza virus HA globular head domain, wherein the influenza virus HA head domain is heterologous to the influenza virus HA stem domain, and wherein the chimeric HA has a primary structure of, in the following order: an HA1 N- terminal stem segment, an influenza virus HA globular head domain, an HA1 C-terminal stem segment, and an HA2. In some embodiments, a chimeric HA provided herein comprises an influenza virus HA stem domain and an influenza virus HA globular head domain, wherein the influenza virus HA globular head domain is heterologous to the influenza virus HA stem domain polypeptide, and wherein the chimeric HA has a primary structure of, in the following order: an HA1 N-terminal stem segment, an influenza virus HA globular head domain, an HA1 C-terminal stem segment, and a portion of the HA2 domain (e.g., the HA2 domain lacking the transmembrane and cytoplasmic domains). The primary sequence of a chimeric HA provided herein might be formed by a single polypeptide, or it might be formed by multiple polypeptides. Typically, a single polypeptide is expressed by any technique deemed suitable by one of skill in the art.

[00251] In some embodiments, a chimeric HA provided herein is monomeric. In certain embodiments, a chimeric HA provided herein is multimeric. In specific embodiments, a chimeric HA provided herein is trimeric. In some embodiments, a chimeric HA provided herein is in a pre-fusion conformation. In some embodiments, a chimeric HA provided herein is in a post-fusion conformation. In some embodiments, chimeric HAs provided herein are in a mix of pre-fusion and post-fusion conformations.

[00252] In some embodiments, a chimeric HA provided herein comprises a signal peptide. Typically, the signal peptide is cleaved during or after polypeptide expression and translation to yield a mature chimeric HA. In specific embodiments, provided herein are mature chimeric HAs that lack a signal peptide. In some embodiments where a chimeric HA provided herein comprises a signal peptide, the signal peptide might be based on any influenza virus signal peptide known to those of skill in the art. The signal peptide of an influenza virus HA may be determined using software, such as, e.g., signalP 5.0. In some embodiments, the signal peptides are based on influenza A virus HA signal peptides. In some embodiments, the signal peptides are based on the signal peptide of an influenza A HA selected from the group consisting of Hl, H2, H3, H4, H5, H6, H7, H8, H9, H10, Hl 1, H12, H13, H14, H15, H16, H17, and H18. In some embodiments, the signal peptide comprises the amino acid sequence of the signal peptide of the HA of an influenza virus in Table 1. In some embodiments, the signal peptide comprises the amino acid sequence of the signal peptide of the HA of influenza virus A/Hong Kong/4801/14. In some embodiments, the signal peptide comprises the amino acid sequence of the signal peptide of the HA of influenza virus A/Shearwater/West Australia/2576/1979 or influenza virus

A/duck/Czechoslovakia/1956. In some embodiments, the signal peptide might be any signal peptide deemed useful to one of skill in the art. In some embodiments, the signal peptide is selected from any one of SEQ ID NOS: 16 to 31 (see Table 2). In some embodiments, the signal peptide is selected from any one of SEQ ID NOS:48 to 52.

[00253] Table 2. Exemplary signal peptide sequences.

[00254] In some embodiments, a chimeric HA provided herein comprises a transmembrane domain. In specific embodiments, the transmembrane domain is from the same group 2 influenza A virus HA as the HA stem domain. In specific embodiments, the transmembrane domain is from the same group 2 influenza A virus HA as the HA2 stem domain. In some embodiments, the transmembrane domain comprises the amino acid sequence of the transmembrane domain of the HA of an influenza virus in Table 1. In some embodiments, the transmembrane domain comprises the amino acid sequence of the HA of influenza virus A/Hong Kong/4801/14. In some embodiments, the transmembrane domain of a chimeric HA comprises one described in Table 3 (e.g., any one of SEQ ID NO:32 to 37). [00255] Table 3. Exemplary influenza A virus HA transmembrane domain sequences.

[00256] In some embodiments, a chimeric HA provided herein comprises a cytoplasmic domain. In specific embodiments, the cytoplasmic domain is from the same group 2 influenza A virus HA as the HA stem domain. In specific embodiments, the cytoplasmic domain is from the same group 2 influenza A virus HA as the HA2 stem domain. In some embodiments, the cytoplasmic domain comprises the amino acid sequence of the cytoplasmic domain of the HA of an influenza virus in Table 1. In some embodiments, the cytoplasmic domain comprises the amino acid sequence of the cytoplasmic domain of the HA of influenza virus A/Hong Kong/4801/14. In some embodiments, the cytoplasmic domain of a chimeric HA comprises one described in Table 4 (e.g., any one of SEQ ID NO:38 to 43).

[00257] Table 4. Exemplary influenza virus HA cytoplasmic domain sequences.

[00258] In some embodiments, a chimeric HA provided herein comprises an influenza virus HA cytoplasmic domain and an influenza virus HA transmembrane domain. In specific embodiments, the cytoplasmic domain and transmembrane domain are from the same group 2 influenza A virus HA as the HA stem domain. In specific embodiments, the cytoplasmic domain and transmembrane domain are from the same group 2 influenza A virus HA as the HA2 stem domain. In some embodiments, the cytoplasmic domain and transmembrane domain comprise the amino acid sequence of the cytoplasmic domain and transmembrane domain of the HA of an influenza virus in Table 1. In some embodiments, the cytoplasmic domain and transmembrane domain comprise the amino acid sequence of the cytoplasmic domain and transmembrane domain of the HA of influenza virus A/Hong Kong/4801/14. [00259] In some embodiments, a chimeric HA provided herein comprises an HA globular head domain, an HA stem domain, an HA transmembrane domain, and an HA cytoplasmic domain. In some embodiments, a chimeric HA provided herein comprises an HA globular head domain, an HA stem domain, an HA transmembrane domain, and an HA cytoplasmic domain, wherein the HA stem domain comprises an HA1 N-terminal stem segment and an HA1 C-terminal stem segment. In some embodiments, a chimeric HA provided herein comprises an HA globular head domain, an HA stem domain, an HA transmembrane domain, and an HA cytoplasmic domain, wherein the HA stem domain comprises an HA1 N-terminal stem segment, an HA1 C-terminal stem segment, and HA2 stem domain, wherein the HA1 N-terminal stem segment comprises the amino acid sequence of SEQ ID NO: 11, wherein the HA1 C-terminal stem segment comprises the amino acid sequence of SEQ ID NO: 12, and wherein the HA2 stem domain comprise the amino acid sequence of SEQ ID NO: 14. [00260] In specific embodiments, a chimeric HA provided herein comprises an HA globular head domain, an HA stem domain, an HA transmembrane domain, and an HA cytoplasmic domain, wherein the HA stem domain comprises an HA1 N-terminal stem segment, an HA1 C-terminal stem segment, and HA2 stem domain, wherein the HA1 N- terminal stem segment comprises the amino acid sequence of SEQ ID NO: 11, and wherein the HA1 C-terminal stem segment and HA2 stem domain comprise the amino acid sequence of SEQ ID NO: 13.

[00261] In specific embodiments, a chimeric HA provided herein comprises an HA globular head domain, an HA stem domain, an HA transmembrane domain, and an HA cytoplasmic domain, wherein the HA stem domain comprises an HA1 N-terminal stem segment, an HA1 C-terminal stem segment, wherein the HA1 N-terminal stem segment comprises the amino acid sequence of SEQ ID NO: 11, and wherein the HA1 C-terminal stem segment, HA transmembrane domain, and HA cytoplasmic domain comprises the amino acid sequence of SEQ ID NO: 15.

[00262] In specific embodiments, provided herein is provided herein is a chimeric HA comprising: (i) an influenza virus HA stem domain of influenza A virus A/Hong Kong/4801/14 (H3) HA; (ii) an influenza virus HA globular head domain of the HA globular head domain of influenza A virus A/Shearwater/West Australia/2576/1979 HA; (iii) the transmembrane domain of influenza A virus A/Hong Kong/4801/14 (H3) HA; and (iv) the cytoplasmic domain of influenza A virus A/Hong Kong/4801/14 (H3) HA. In specific embodiments, provided herein is provided herein is a chimeric HA comprising: (i) an influenza virus HA stem domain of influenza A virus A/Hong Kong/4801/14 (H3) HA; (ii) an influenza virus HA globular head domain of the HA globular head domain of influenza A virus A/duck/Czechoslovakia/1956 HA; (iii) the transmembrane domain of influenza A virus A/Hong Kong/4801/14 (H3) HA; and (iv) the cytoplasmic domain of influenza A virus A/Hong Kong/4801/14 (H3) HA.

[00263] In specific embodiments, provided herein is provided herein is a chimeric HA comprising: (i) an influenza virus HA stem domain of influenza A virus A/Hong Kong/4801/14 (H3)-like HA; (ii) an influenza virus HA globular head domain of the HA globular head domain of influenza A virus A/Shearwater/West Australia/2576/1979 HA; (iii) the transmembrane domain of influenza A virus A/Hong Kong/4801/14-like (H3) HA; and (iv) the cytoplasmic domain of influenza A virus A/Hong Kong/4801/14-like (H3) HA. In specific embodiments, provided herein is provided herein is a chimeric HA comprising: (i) an influenza virus HA stem domain of influenza A virus A/Hong Kong/4801/14-like (H3) HA;

(ii) an influenza virus HA globular head domain of the HA globular head domain of influenza A virus A/duck/Czechoslovakia/1956 HA; (iii) the transmembrane domain of influenza A virus A/Hong Kong/4801/14-like (H3) HA; and (iv) the cytoplasmic domain of influenza A virus A/Hong Kong/4801/14-like (H3) HA.

[00264] In specific embodiments, provided herein is provided herein is a chimeric HA comprising: (i) an influenza virus HA stem domain of influenza A virus A/Hong Kong/4801/14 (H3)-like HA; (ii) an influenza virus HA globular head domain of the HA globular head domain of influenza A virus A/Shearwater/West Australia/2576/1979-like HA;

(iii) the transmembrane domain of influenza A virus A/Hong Kong/4801/14-like (H3) HA; and (iv) the cytoplasmic domain of influenza A virus A/Hong Kong/4801/14-like (H3) HA. In specific embodiments, provided herein is provided herein is a chimeric HA comprising: (i) an influenza virus HA stem domain of influenza A virus A/Hong Kong/4801/14-like (H3) HA; (ii) an influenza virus HA globular head domain of the HA globular head domain of influenza A virus A/duck/Czechoslovakia/1956-like HA; (iii) the transmembrane domain of influenza A virus A/Hong Kong/4801/14-like (H3) HA; and (iv) the cytoplasmic domain of influenza A virus A/Hong Kong/4801/14-like (H3) HA. [00265] In some embodiments, provided herein is provided herein is a chimeric HA comprising: (i) an influenza virus HA stem domain of influenza A virus A/Hong Kong/4801/14 (H3) HA; (ii) an influenza virus HA globular head domain of the HA globular head domain of influenza A virus A/mallard/Sweden/24/2002 H8N4 HA; (iii) the transmembrane domain of an influenza A virus A/Hong Kong/4801/14 (H3) HA; and (iv) the cytoplasmic domain of an influenza A virus A/Hong Kong/4801/14 (H3) HA. In some embodiments, provided herein is provided herein is a chimeric HA comprising: (i) an influenza virus HA stem domain of influenza A virus A/Hong Kong/4801/14 (H3) HA; (ii) an influenza virus HA globular head domain of the HA globular head domain of influenza A virus A/Vietnam/1203/2004 H5N1 HA; (iii) the transmembrane domain of an influenza A virus A/Hong Kong/4801/14 (H3) HA; and (iv) the cytoplasmic domain of an influenza A virus A/Hong Kong/4801/14 (H3) HA.

[00266] In some embodiments, provided herein is provided herein is a chimeric HA comprising: (i) an influenza virus HA stem domain of influenza A virus A/Hong Kong/4801/14 (H3) HA; (ii) an influenza virus HA globular head domain comprising the amino acid sequence of SEQ ID NO:46; (iii) the transmembrane domain of an influenza A virus A/Hong Kong/4801/14 (H3) HA; and (iv) the cytoplasmic domain of an influenza A virus A/Hong Kong/4801/14 (H3) HA. In some embodiments, provided herein is provided herein is a chimeric HA comprising: (i) an influenza virus HA stem domain of influenza A virus A/Hong Kong/4801/14 (H3) HA; (ii) an influenza virus HA globular head domain comprising the amino acid sequence of SEQ ID NO:47; (iii) the transmembrane domain of an influenza A virus A/Hong Kong/4801/14 (H3) HA; and (iv) the cytoplasmic domain of an influenza A virus A/Hong Kong/4801/14 (H3) HA.

[00267] In some embodiments, a chimeric HA comprises an amino acid sequence that is at least 90%, at least 95%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:5. In some embodiments, a chimeric HA comprises an amino acid sequence that is at least 90%, at least 95%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:6. In some embodiments, a chimeric HA comprises an amino acid sequence that is at least 90%, at least 95%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:7. In some embodiments, a chimeric HA comprises an amino acid sequence that is at least 90%, at least 95%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 8.

[00268] In a specific embodiment, a chimeric HA comprises the amino acid sequence of SEQ ID NO:5. In a specific embodiment, a chimeric HA comprises the amino acid sequence

I l l of SEQ ID NO:6. In a specific embodiment, a chimeric HA comprises the amino acid sequence of SEQ ID NO:7. In a specific embodiment, a chimeric HA comprises the amino acid sequence of SEQ ID NO: 8.

[00269] In specific embodiments, the chimeric HAs provided herein are capable of forming a three dimensional structure that is similar to the three dimensional structure of a native influenza HA. Structural similarity might be evaluated based on any technique deemed suitable by those of skill in the art. For instance, reaction, e.g.. under non-denaturing conditions, of a chimeric HA with a neutralizing antibody or antiserum that recognizes a native influenza HA might indicate structural similarity. Useful neutralizing antibodies or antisera are described in, e.g., Sui, et al., 2009, Nat. Struct. Mol. Biol. 16(3):265-273, Ekiert et al., February 26, 2009, Science [DOI: 10.1126/science.1171491], and Kashyap etal., 2008, Proc. Natl. Acad. Sci. USA 105(16):5986-5991, the contents of which are hereby incorporated by reference in their entireties. In some embodiments, the antibody or antiserum is an antibody or antiserum that reacts with a non-contiguous epitope (i.e., not contiguous in primary sequence) that is formed by the tertiary or quaternary structure of a HA.

[00270] In specific embodiments, a chimeric HA described herein retains one, two, or more, or all of the functions of a wild-type influenza virus HA. Non-limiting examples of functions of a wild-type influenza virus HA include fusogenic activity, receptor binding activity, budding, and particle formation. In a specific embodiment, a chimeric HA described herein has fusogenic activity. Assays known to one skilled in the art can be utilized the assess the fusogenic activity of a chimeric HA described herein, such as, for example, immunofluorescence assays and pseudotyped virus-like-particle assays.

[00271] It will be understood by those of skill in the art that the chimeric HA provided herein can be prepared according to any technique known by and deemed suitable to those of skill in the art, including the techniques described herein.

5.3.1 HA Globular Head Domain

[00272] In some embodiments, an influenza virus HA globular head domain comprises a known (e.g., wild-type) HA globular head domain. In some embodiments, an influenza virus HA globular head domain comprises a derivative, e.g., an engineered derivative, of a known (e.g., wild-type) HA globular head domain. For example, the HA globular head domain may contain one or more mutations (e.g., one or more amino acid substitutions) relative to the HA globular head domain of a known (e.g., wild-type) influenza virus HA. In some embodiments, an influenza virus HA globular head domain provided herein comprises an amino acid sequence having at least 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 98%, or 99% identity to the amino acid sequence of an influenza virus HA globular head domain known to those of skill in the art. In some embodiments, an influenza virus HA globular head domain provided herein comprises an amino acid sequence having at least 85%, at least 90%, or least 95% identity to the amino acid sequence of an influenza virus HA globular head domain known to those of skill in the art. In some embodiments, an influenza virus HA globular head domain provided herein comprises an amino acid sequence having at least 96%, at least 97%, at least 98%, or least 99% identity to the amino acid sequence of an influenza virus HA globular head domain known to those of skill in the art. In some embodiment, the influenza virus HA globular head domain known to those of skill in the art is one described herein.

[00273] Those of skill in the art will recognize that an influenza A virus HA globular head domain typically comprises the amino acid residues intervening the cysteine (Cys) that corresponds to amino acid position 52 of an influenza A virus hemagglutinin HA1 domain according to H3 numbering and the cysteine (Cys) that corresponds to amino acid position 277 of an influenza A virus hemagglutinin HA1 domain according to H3 numbering, e.g., A_P and A_q of FIGS. 11 A-l ID, respectively. The amino acid sequence of an HA globular head domain of an influenza A virus HA of interest may be identified by aligning the amino acid sequence of an influenza A virus HA for which the HA globular head domain has been identified with the amino acid sequence of the influenza A virus HA of interest. In some embodiments, the three-dimensional structure of HA may also be considered in determining the HA globular head domain of the influenza A virus of interest.

[00274] An influenza HA globular head domain provided herein might be based on (e.g., might have sequence identity to) the HA globular head domain of any influenza HA known to those of skill or later discovered. In some embodiments, an influenza HA globular head domain is based on the head domain of an influenza A virus HA (e.g., the HA globular head domain of the HA of an influenza A virus described herein). In some embodiments, an influenza virus HA globular head domain is based on the globular head domain of an influenza A virus HA selected from the group consisting of Hl, H2, H3, H4, H5, H6, H7, H8, H9, H10, Hl l, H12, H13, H14, H15, H16, H17, and H18 subtype. In some embodiments, an influenza HA globular head domain is based on the HA globular head domain of an influenza A HA selected from an H5, H6, or H9 subtype. In some embodiments, an influenza HA globular head domain is based on the HA globular head domain of an influenza A HA selected from an H4 or Hl 5 subtype.

[00275] In some embodiments, an influenza virus HA globular head domain comprises the HA globular head domain of an influenza virus strain that does not circulate in humans. In some embodiments, an influenza virus HA globular head domain comprises the HA globular head domain of an influenza virus subtype that does not circulate in humans. In some embodiments, an influenza virus HA globular head domain comprises the HA globular head domain of an avian influenza virus strain or subtype that does not circulate in humans. In some embodiments, an influenza virus HA globular head domain comprises the HA globular head domain of a group 1 influenza A virus HA. In some embodiments, an influenza virus HA globular head domain comprises the HA globular head domain of an H2, H5, H6, H8, H9, Hl l, H12, H13, H16, H17, or H18 subtype. In some embodiments, an influenza virus HA globular head domain comprises the HA globular head domain of an H4, H7, H10, H14, or Hl 5 subtype. In some embodiments, an influenza virus HA globular head domain comprises the HA globular head domain of influenza A virus A/wedge-tailed shearwater/Western Australia/2576/1979 HA or A/wedge-tailed shearwater/We stern Australia/2576/1979-like HA. In some embodiments, an influenza virus HA globular head domain comprises the HA globular head domain of influenza A virus /Duck/Czechoslovakia/1956 HA or A/Duck/Czechoslovakia/1956-like HA. In some embodiments, an influenza virus HA globular head domain comprises the HA globular head domain of the influenza virus HA provided in Table 1. In some embodiments, an HA globular head domain comprises an amino acid sequences that is at least 90%, at least 95%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:9. In some embodiments, an HA globular head domain comprises an amino acid sequences that is at least 90%, at least 95%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 10. In a specific embodiment, an HA globular head domain comprises the amino acid sequence of SEQ ID NO:9. In a specific embodiment, an HA globular head domain comprises the amino acid sequence of SEQ ID NO: 10.

5.3.2 HA Stem Domains

[00276] In some embodiments, an influenza virus HA stem domain comprises an HA stem domain of a group 2 influenza A virus HA known to those of skill in the art. In some embodiments, an influenza virus HA stem domain comprises a derivative, e.g., an engineered derivative, of an HA stem domain of a known (e.g., wild-type) group 2 influenza A virus HA. For example, the HA stem domain may contain one or more mutations e.g., one or more amino acid substitutions) relative to the HA stem domain of a known (e.g., wild-type) influenza virus HA. In some embodiments, an influenza virus HA stem domain provided herein comprises an amino acid sequence having at least 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 98%, or 99% identity to the amino acid sequence of an HA stem domain of a group 2 influenza A virus HA known to those of skill in the art. In some embodiments, an influenza virus HA stem domain provided herein comprises an amino acid sequence having at least 85%, at least 90%, or at least 95% identity to the amino acid sequence of an HA stem domain of a group 2 influenza A virus HA known to those of skill in the art. In some embodiments, an influenza virus HA stem domain provided herein comprises an amino acid sequence having at least 96%, at least 97%, at least 98%, or least 99% identity to the amino acid sequence of an HA stem domain of a group 2 influenza A virus HA known to those of skill in the art. In some embodiments, the group 2 influenza A virus HA is an H3. In some embodiments, the group 2 influenza A virus HA is influenza A virus A/Hong Kong/4801/2014, NYMC X-263 HA or A/Hong Kong/4801/2014-like HA.

[00277] In some embodiments, an influenza virus HA stem domain provided herein comprises the amino acid sequence of the HA stem domain of an H3, H4, H7, H10, H14, and Hl 5 subtype. In some embodiments, an influenza virus HA stem domain provided herein comprises the amino acid sequence of the HA stem domain of H3 subtype. In some embodiments, an influenza virus HA stem domain provided herein comprises the amino acid sequence of the HA stem domain of influenza A virus A/Hong Kong/4801/2014 H3N2, NYMC X-263 HA. In some embodiments, an influenza virus HA stem domain provided herein comprises the amino acid sequence of the HA stem domain of influenza A virus A/Hong Kong/4801/2014-like HA. In some embodiments, an influenza virus HA stem domain provided herein comprises the HA stem domain of an influenza A virus provided in Table 1.

[00278] Typically, an HA stem domain comprises an N-terminal HA1 stem segment, a C- terminal HA1 stem segment, and a portion of an HA2 domain (i.e., a portion of an HA2 domain that does not include the transmembrane and cytoplasmic domains; sometimes referred to as an 'HA2 stem domain"). One skilled in the art will understand that the exact location of the C-terminus of the HA stem domain is determined according to the hydrophobicity of the HA2 domain of the particular influenza A virus HA strain and can be identified using programs such as, e.g., the TMHMM server (www.cbs.dtu.dk/services/TMHMM/; see, e.g., Cuthbertson et al., 2005, Protein Eng Des Sei, 18(6):295-308) hydrophobicity prediction, or uniprot. In specific embodiments, the HA2 stem domain is from the same influenza virus strain or subtype as the portion of the HA stem domain of the HA1 subunit.

[00279] Typically, an influenza A virus HA1 N-terminal stem segment corresponds to a polypeptide consisting of the N-terminal amino acid of a mature HA1 (z.e., an HA1 lacking a signal peptide) through the cysteine residue located in sequence at approximately the 52^nd residue of the HA1 according to H3 numbering. This cysteine residue, termed A_P herein, is generally capable of forming a disulfide bridge with a cysteine residue in the C-terminal stem segment of HA1. Sequences of SEQ ID NOs: 53-69, which are representative influenza A virus HAs, are presented in FIGS. 11 A-l ID, and residue A_P is identified in each. ee also SEQ ID NOS: 70-74 in the sequence table below (Table 5) for the residue Ap identified.

[00280] In specific embodiments, the HA1 N-terminal stem segment comprises the amino acid sequence of SEQ ID NO: 11.

[00281] In some embodiments, the HA1 N-terminal stem segment does not end exactly at A_P (e.g., Cys52 of an HA1 subunit from an H3 HA (z.e., according to H3 numbering)), but at a residue in sequence and structural vicinity to A_P. For example, in some embodiments, the HA1 N-terminal stem segment ends at A_P-i, A_P-2, A_P-3, A_P-4, A_P-s, A_P-6, A_P-7, A_P-s, A_P-9, or A_P. IO. In some embodiments, the HA1 N-terminal stem segment of the chimeric HA described herein ends in the range of A_P+i, A_P2i, A_P+3, A_P+4, A_P+s, A_P+6, A_P+7, A_P+s, A_P+9, or A_P+io. The end of an HA1 N-terminal stem segment should be selected in conjunction with the end of the HA1 C-terminal stem segment and the HA globular head domain so that the resulting HA is capable of forming a three-dimensional structure similar to an HA of a wild-type influenza virus. In such embodiments, an influenza virus HA globular head domain of a chimeric HA is located, in primary sequence, between the N-terminal and C-terminal segments of the HA stem domain.

[00282] Typically, an influenza A virus HA1 C-terminal stem segment corresponds to a polypeptide consisting of the cysteine residue located in the amino acid sequence at approximately the 277^th residue of a mature HA1 (z.e., an HA1 lacking a signal peptide) according to H3 numbering through the C-terminal amino acid of the HA1. This cysteine residue, termed A_q herein, is generally capable of forming a disulfide bridge with cysteine residue A_P in the N-terminal stem segment of HA1. Sequences of SEQ ID NOs: 53-69, which are representative influenza A HAs, are presented in FIGS. 11 A-l ID, and residue A_q is identified in each. See also SEQ ID NOS: 70-74 in the sequence table below (Table 5) for the residue Aq identified. [00283] In specific embodiments, the HA1 C-terminal stem segment comprises the amino acid sequence of SEQ ID NO: 12.

[00284] In some embodiments, the HA1 C-terminal stem segment does not start at A_q (e.g., Cys277 of an HA1 subunit from an H3 HA (z.e., according to H3 numbering)), but at a residue in sequence and structural vicinity to Aq. For example, in some embodiments, the HA1 C-terminal stem segment starts at about Aq-i, Aq-2, Aq-3, Aq-4, Aq-s, Aq-6, Aq-7, Aq-s, Aq-9, or Aq-io. In some embodiments, the HA1 C-terminal stem segment starts at Aq+i, A_q+2, A_q+3, Aq+4, Aq+s, Aq+6, Aq+7, Aq+s, Aq+9, or Aq+io. The end of an HA1 N-terminal stem segment should be selected in conjunction with the start of the HA1 C-terminal stem segment and the globular head domain so that the resulting chimeric HA is capable of forming a three- dimensional structure similar to a wild-type influenza virus HA. In some embodiments, the influenza virus HA stem domain of the chimeric HA described herein maintains the cysteine residues identified in influenza HA polypeptides as A_P and A_q in FIGS. 11 A-l ID, z.e., the cysteine residues identified in influenza HA polypeptides as A_P and A_q in FIGS. 11 A-l ID are maintained in the chimeric HA described herein. See also SEQ ID NOS: 70-74 in the sequence table below (Table 5) for residues Ap and Aq identified.

[00285] In some embodiments, an HA stem domain provided herein comprise little or no HA globular head domain of a group 2 influenza A virus HA. In some embodiments, an HA stem domain provided herein comprise only 1-15, 1-10, 1-5, 5-10, 5-15, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 amino acid residues of the HA globular head domain of a group 2 influenza virus HA. In specific embodiments, an influenza virus HA stem domain comprises the amino acid sequence of the HA1 N-terminal stem segment of SEQ ID NO: 11, the amino acid sequence of the HA1 C-terminal stem segment of SEQ ID NO: 12, and the amino acid sequence of the HA2 stem domain. In specific embodiments, an influenza virus HA stem domain comprises the amino acid sequence of the HA1 N-terminal stem segment of SEQ ID NO: 11, and the amino acid sequence of the HA1 C-terminal stem segment of SEQ ID NO: 12. [00286] In some embodiments, an influenza virus HA stem domain described herein maintains the cysteine residues identified in influenza A virus HAs as A_P and A_q in FIGS.

11 A-l ID. See also SEQ ID NOS: 70-74 in the sequence table below (Table 5) for residues Ap and Aq identified.

[00287] In specific embodiments, influenza virus HA stem domains described herein undergo conformational changes from the pre-fusion to the fusion conformation at a pH lower than the pH of the HA of wild-type influenza A viruses. In some embodiments, influenza virus HA stem domains described herein comprise one or more amino acid substitutions, such as HA1 H17Y (H3 numbering) that increases the stability of the polypeptides at a low pH (e.g., a pH of between 4.9 to 5.2, 3.5 to 4.5, 2.5 to 3.5, 1.5 to 2.5, 0.5 to 1.5). The stability of influenza HA stem domain polypeptides can be assessed using techniques known in the art, such as sensitivity of the HA molecules to trypsin digestion, as described in, e.g., Thoennes et al., 2008, Virology 370: 403-414.

[00288] In some embodiments, influenza virus HA stem domain is capable of forming a three dimensional structure that is similar to the three dimensional structure of the HA stem domain of a native influenza virus HA. Structural similarity might be evaluated based on any technique deemed suitable by those of skill in the art. For instance, reaction, e.g., under nondenaturing conditions, of an influenza virus HA stem domain with a neutralizing antibody or antiserum that recognizes a native influenza virus HA might indicate structural similarity. Useful neutralizing antibodies or antisera are described in, e.g., Sui, et al., 2009, Nat. Struct. Mol. Biol. 16(3):265-273, Ekiert et al., February 26, 2009, Science [DOI:

10.1126/science.1171491], and Kashyap et al., 2008, Proc. Natl. Acad. Sci. USA 105(16):5986-5991, the contents of which are hereby incorporated by reference in their entireties. In some embodiments, the antibody or antiserum is an antibody or antiserum that reacts with a non-contiguous epitope (i.e., not contiguous in primary sequence) that is formed by the tertiary or quaternary structure of a HA.

[00289] In some embodiments, structural similarity might be assessed by spectroscopic techniques such as circular dichroism, Raman spectroscopy, NMR, 3D NMR and X-ray crystallography. Known influenza HA structures determined by X-ray crystallography are described in structural coordinates in Protein Data Bank files including but not limited to 1HGJ (an HA H3N2 strain) and 1RUZ (an HA H1N1 strain).

[00290] In some embodiments, structural similarity is evaluated by RMS deviation between corresponding superimposed portions of two structures. In order to create a meaningful superimposition, in some embodiments, the coordinates of at least 20 corresponding atoms, 25 corresponding atoms, 30 corresponding atoms, 40 corresponding atoms, 50 corresponding atoms, 60 corresponding atoms, 70 corresponding atoms, 80 corresponding atoms, 90 corresponding atoms, 100 corresponding atoms, 120 corresponding atoms, 150 corresponding atoms, 200 corresponding atoms, or 250 corresponding atoms are used to calculate an RMS deviation.

[00291] In some embodiments, the coordinates of all corresponding atoms in amino acid backbones are used to calculate an RMS deviation. In some embodiments, the coordinates of all corresponding alpha carbon-atoms in the amino acid backbones are used to calculate an RMS deviation. In some embodiments, the coordinates of all corresponding identical residues, including side chains, are used to calculate an RMS deviation.

[00292] In some embodiments, coordinates of all or a portion of the corresponding atoms in a HA1 N-terminal segment are used to calculate an RMS deviation. In some embodiments, coordinates of all or a portion of the corresponding atoms in a HA1 C-terminal segment are used to calculate an RMS deviation. In some embodiments, coordinates of all or a portion of the corresponding atoms in both a HA1 N-terminal segment and a C-terminal segment are used to calculate an RMS deviation. In some embodiments, coordinates of all or a portion of corresponding atoms in HA2 domains are used to calculate an RMS deviation.

[00293] In some embodiments, the RMS deviation between the structures of a influenza HA stem domain polypeptide and corresponding portions of a group 2 known influenza A virus HA stem domain (e.g., from 1HGJ or 1RUZ) is 5 A or less, 4 A or less, 3 A or less, 2.5 A or less, 2 A or less, 1.5 A or less, 1 A or less, 0.75 A or less, 0.5 A or less, 0.3 A or less, 0.2 A or less, or 0.1 A or less. Commercially available or open source software might be used to perform the structural superimpositions and/or RMS deviation calculations. Useful examples include but are not limited to Pymol (Delano Scientific LLC), Insightll and Quanta (both from Accelrys), MIDAS (University of California, San Francisco), SwissPDB viewer (Swiss Institute of Bioinformatics), TOPOFIT (Northeastern University), CBSU LOOPP (Cornell University), and SuperPose (University of Alberta, Edmonton).

5.4 Nucleic Acids Encoding Chimeric HA & Methods for Producing Influenza Virus

[00294] Provided herein are nucleic acid molecules that encode a chimeric HA described herein. Due to the degeneracy of the genetic code, any nucleic acid sequence that encodes a chimeric HA described herein is encompassed herein. In some embodiments, nucleic acid sequences corresponding to naturally occurring influenza A virus HA nucleic acid sequences encoding an HA1 N-terminal stem segment, an HA1 C-terminal stem segment, HA2 domain, HA stem domain, HA transmembrane domain, and/or HA cytoplasmic domain are used to produce a chimeric HA. In some embodiments, the nucleic acid molecule comprises a nucleotide sequence encoding an influenza virus HA signal peptide. In specific embodiments, the nucleic acid molecule comprises nucleotide sequences encoding a chimeric HA and preferably comprises the 5' non-coding region and 3' non-coding region from the HA of the same influenza A virus as the influenza A virus engineered to express the chimeric HA. In specific embodiments, the nucleic acid molecule comprises nucleotide sequences encoding a chimeric HA, and the 5' non-coding region, 3' non-coding region, and a nucleotide sequence encoding the signal peptide from the HA of the same influenza A virus as the influenza A virus engineered to express the chimeric HA.

[00295] In some embodiments, provided herein is a nucleic acid molecule comprising a nucleotide sequence that is at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% identical to the nucleotide sequence of SEQ ID NO:44. In specific embodiments, provided herein is a nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO: 44. In some embodiments, provided herein is a nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:44, and the 5' non-coding region and 3' non-coding region from the HA of the same influenza A virus as the influenza A virus engineered to express the chimeric HA. In some embodiments, provided herein is a nucleic acid molecule comprising a nucleotide sequence that is at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% identical to the nucleotide sequence of SEQ ID NO: 45. In specific embodiments, provided herein is a nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:45. In some embodiments, provided herein is a nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:45, and the 5' noncoding region and 3' non-coding region from the HA of the same influenza A virus as the influenza A virus engineered to express the chimeric HA.

[00296] In some embodiments, a nucleic acid molecule encoding a chimeric HA is isolated. In some embodiments, an "isolated" nucleic acid sequence refers to a nucleic acid molecule which is separated from other nucleic acid molecules which are present in the natural source of the nucleic acid. In other words, the isolated nucleic acid molecule can comprise heterologous nucleic acids that are not associated with it in nature. In some embodiments, an "isolated" nucleic acid molecule, such as a cDNA molecule, can be substantially free of other cellular material, or culture medium when produced by recombinant techniques, or substantially free of chemical precursors or other chemicals when chemically synthesized. The term "substantially free of cellular material" includes preparations of nucleic acids in which the nucleic acid molecule is separated from cellular components of the cells from which it is isolated or recombinantly produced. Thus, a nucleic acid molecule that is substantially free of cellular material includes preparations of a nucleic acid having less than about 30%, 20%, 10%, or 5% (by dry weight) of other nucleic acids. The term "substantially free of culture medium" includes preparations of nucleic acid in which the culture medium represents less than about 50%, 20%, 10%, or 5% of the volume of the preparation. The term "substantially free of chemical precursors or other chemicals" includes preparations in which the nucleic acid molecule is separated from chemical precursors or other chemicals which are involved in the synthesis of the nucleic acid molecule. In specific embodiments, such preparations of the nucleic acid molecule have less than about 50%, 30%, 20%), 10%), 5% (by dry weight) of chemical precursors or compounds other than the nucleic acid molecule of interest.

[00297] Provided herein are vectors, including expression vectors, containing a nucleic acid encoding a chimeric HA described herein. In a specific embodiment, the vector is an expression vector that is capable of directing the expression of a nucleic acid encoding a chimeric HA. Non-limiting examples of expression vectors include, but are not limited to, plasmids and viral vectors. In a specific embodiment, the expression vector is an influenza virus (e.g., an influenza A virus).

[00298] An expression vector comprises a nucleic acid molecule encoding a chimeric HA described herein and is in a form suitable for expression of the nucleic acid molecule in a host cell. In a specific embodiment, an expression vector includes one or more regulatory sequences, selected on the basis of the host cells to be used for expression, which is operably linked to the nucleic acid molecule to be expressed. Within an expression vector, "operably linked" is intended to mean that a nucleic acid of interest is linked to the regulatory sequence(s) in a manner which allows for expression of the nucleic acid (e.g., in an in vitro transcription/translation system or in a host cell when the vector is introduced into the host cell). Regulatory sequences include promoters, enhancers and other expression control elements (e.g., polyadenylation signals). Regulatory sequences include those which direct constitutive expression of a nucleic acid molecule in many types of host cells, those which direct expression of the nucleic acid only in certain host cells (e.g., tissue-specific regulatory sequences), and those which direct the expression of the nucleic acid upon stimulation with a particular agent (e.g., inducible regulatory sequences). It will be appreciated by those skilled in the art that the design of the expression vector can depend on such factors as the choice of the host cell to be transformed, the level of expression of protein desired, etc. The term "host cell" is intended to include a particular subject cell transformed or transfected with a nucleic acid molecule and the progeny or potential progeny of such a cell. Progeny of such a cell may not be identical to the parent cell transformed or transfected with the nucleic acid molecule due to mutations or environmental influences that may occur in succeeding generations or integration of the nucleic acid sequence into the host cell genome. In specific embodiments, the host cell is a cell line.

[00299] Expression vectors can be designed for expression of a chimeric HA polypeptide described herein using prokaryotic (e.g., E. coli) or eukaryotic cells (e.g., insect cells (using baculovirus expression vectors, see, e.g., Treanor et al., 2007, JAMA, 297(14): 1577-1582 incorporated by reference herein in its entirety), yeast cells, plant cells, algae, avian, or mammalian cells). Examples of yeast host cells include, but are not limited to S. pombe and S. cerevisiae and examples, infra. An example of avian cells includes, but is not limited to EB66 cells. Examples of mammalian host cells include, but are not limited to, Crucell Per.C6 cells, Vero cells, CHO cells, VERO cells, BHK cells, HeLa cells, COS cells, MDCK cells, 293 cells, 3T3 cells or WI38 cells. In some embodiments, the hosts cells are myeloma cells, e.g., NSO cells, 45.6 TGI.7 cells, AF-2 clone 9B5 cells, AF-2 clone 9B5 cells, J558L cells, MOPC 315 cells, MPC-11 cells, NCI-H929 cells, NP cells, NSO/1 cells, P3 NS1 Ag4 cells, P3/NSl/l-Ag4-l cells, P3U1 cells, P3X63Ag8 cells, P3X63Ag8.653 cells, P3X63Ag8U.1 cells, RPMI 8226 cells, Sp20-Agl4 cells, U266B1 cells, X63AG8.653 cells, Y3.Ag.l.2.3 cells, and YO cells. Non-limiting examples of insect cells include 5f9, Sf21, Trichoplusia ni, Spodoptera frugiperda, and Bombyx mori. In some embodiments, a mammalian cell culture system (e.g., Chinese hamster ovary or baby hamster kidney cells) is used for expression of a chimeric HA. In some embodiments, a plant cell culture system is used for expression of a chimeric HA. See, e.g., U.S. Patent Nos. 7,504,560; 6,770,799; 6,551,820; 6,136,320; 6,034,298; 5,914,935; 5,612,487; and 5,484,719, and U.S. patent application publication Nos. 2009/0208477, 2009/0082548, 2009/0053762, 2008/0038232, 2007/0275014 and 2006/0204487 for plant cells and methods for the production of proteins utilizing plant cell culture systems. In specific embodiments, plant cell culture systems are not used for expression of a chimeric HA. The host cells comprising a nucleic acid molecule that encodes the chimeric HA described herein can be isolated, i.e., the cells are outside of the body of a subject. In some embodiments, the cells are engineered to express a chimeric HAs described herein. In specific embodiments, the host cells are cells from a cell line.

[00300] In some embodiments, provided herein are host cells comprising a nucleic acid molecule comprising a nucleotide sequence encoding a chimeric HA described herein. In a specific embodiment, provided herein are host cells engineered to express a chimeric HA described herein. In a specific embodiment, provided herein are host cells comprising an expression vector comprising nucleic acid molecule encoding a chimeric HA described herein. Host cells are known to one of skill in the art and examples are provided herein. In specific embodiments, the host cells are cells from a cell line.

[00301] An expression vector can be introduced into host cells via conventional transformation, transfection, or infection techniques. Such techniques include, but are not limited to, calcium phosphate or calcium chloride co-precipitation, DEAE-dextran-mediated transfection, lipofection, and electroporation. Suitable methods for transforming or transfecting host cells can be found in Sambrook et al., 1989, Molecular Cloning - A Laboratory Manual, 2nd Edition, Cold Spring Harbor Press, New York, and other laboratory manuals. In some embodiments, a host cell is transiently transfected with an expression vector containing a nucleic acid molecule encoding a chimeric HA. In some embodiments, a host cell is stably transfected with an expression vector containing a nucleic acid molecule encoding a chimeric HA.

[00302] For stable transfection of mammalian cells, it is known that, depending upon the expression vector and transfection technique used, only a small fraction of cells may integrate the foreign DNA into their genome. In order to identify and select these integrants, a nucleic acid that encodes a selectable marker (e.g., for resistance to antibiotics) is generally introduced into the host cells along with the nucleic acid of interest. Examples of selectable markers include those which confer resistance to drugs, such as G418, hygromycin and methotrexate. Cells stably transfected with the introduced nucleic acid sequence can be identified by drug selection (e.g., cells that have incorporated the selectable marker gene will survive, while the other cells die).

[00303] As an alternative to recombinant expression of a chimeric HA using a host cell, an expression vector containing a nucleic acid encoding a chimeric HA can be transcribed and translated in vitro using, e.g., T7 promoter regulatory sequences and T7 polymerase. In a specific embodiment, a coupled transcription/translation system, such as Promega TNT®, or a cell lysate or cell extract comprising the components necessary for transcription and translation may be used to produce a chimeric HA.

[00304] Once a chimeric HA has been produced, it may be isolated or purified by any method known in the art for isolation or purification of a protein, for example, by chromatography (e.g., ion exchange, affinity, particularly by affinity for the specific antigen, by Protein A, and sizing column chromatography), centrifugation, differential solubility, or by any other standard technique for the isolation or purification of proteins.

[00305] Accordingly, provided herein are methods for producing a chimeric HA. In some embodiments, the method comprises culturing a host cell containing a nucleic acid molecule encoding a chimeric HA in a suitable medium such that the chimeric HA is produced. In a specific embodiment, the method comprises culturing a host cell containing a nucleic acid molecule comprising a nucleotide sequence encoding a chimeric HA, or a host cell containing an expression vector containing a nucleic acid molecule comprising a nucleotide sequence encoding a chimeric HA in a suitable medium such that the chimeric HA is produced. In some embodiments, the method further comprises isolating the chimeric HA from the medium or the host cell.

[00306] Also provided herein are methods for producing an influenza virus (e.g., an influenza A virus) comprising a chimeric HA described herein, comprising propagating the virus in any substrate that allows the virus to grow to titers that permit their use in accordance with the methods described herein. In some embodiments, the substrate allows the virus to grow to titers comparable to those determined for the corresponding wild-type virus. In some embodiments, the virus is propagated in embryonated eggs (e.g., chicken eggs). In a specific embodiment, the virus is propagated in 8 day old, 9-day old, 8-10 day old, 10 day old, 11-day old, 10-12 day old, or 12-day old embryonated eggs (e.g., chicken eggs). In some embodiments, the virus is propagated in MDCK cells, Vero cells, 293T cells, or other cell lines known in the art. In some embodiments, the virus is propagated in cells derived from embryonated eggs.

[00307] In one aspect, provided herein are influenza viruses (e.g, influenza A viruses) containing a chimeric HA described herein. In a specific embodiment, the chimeric HA is incorporated into the virions of the influenza virus.

[00308] Influenza viruses (e.g, influenza A viruses) containing a chimeric HA may be produced by supplying in trans the chimeric HA during production of virions using techniques known to one skilled in the art, such as reverse genetics and helper-free plasmid rescue. Alternatively, the replication of an influenza virus comprising a genome engineered to express a chimeric HA in cells susceptible to infection with the virus, wherein hemagglutinin function is provided in trans will produce progeny influenza viruses containing the chimeric HA.

[00309] In another aspect, provided herein are influenza viruses comprising a genome engineered to express a chimeric HA. In a specific embodiment, the genome of a parental influenza virus is engineered to encode a chimeric HA, which is expressed by progeny influenza virus. In specific embodiments, the genome of a parental influenza virus (e.g., influenza A virus) is engineered to encode a chimeric HA, which is expressed and incorporated into the virions of progeny influenza virus. Thus, the progeny influenza virus resulting from the replication of the parental influenza virus contain a chimeric HA. The virions of the parental influenza virus may have incorporated into them a chimeric HA that contains an HA stem domain or a globular head domain from the same or a different group, subtype, or strain of influenza virus. [00310] In some embodiments, the genome of the influenza virus (e.g., influenza A virus) comprises genes encoding non- structural proteins and matrix protein of influenza A virus A/Puerto Rico/8/1934. In some embodiments, the genome of the influenza virus (e.g., influenza A virus) comprises a gene encoding influenza A virus neuraminidase, wherein the strain of the influenza A virus neuraminidase is the same influenza A virus strain as the strain of the HA globular head domain or HA stem domain of the chimeric HA.

[00311] In some embodiments, the virions of the parental influenza virus (e.g., influenza A virus) have incorporated into them an influenza virus (e.g., influenza A virus) neuraminidase, wherein the strain of the influenza A virus neuraminidase is not the same strain as the strain of the HA globular head domain or HA stem domain of the chimeric HA. In some embodiments, the influenza A virus neuraminidase corresponds to the influenza A virus neuraminidase of the HA stem domain of the chimeric HA. In some embodiments, the influenza A virus neuraminidase corresponds to the influenza A virus neuraminidase of the HA globular head domain of the chimeric HA.

[00312] Since the genome of influenza A virus consists of eight (8) single- stranded, negative sense segments, the genome of a parental influenza virus may be engineered to express a chimeric HA using a recombinant segment and techniques known to one skilled in the art, such a reverse genetics and helper-free plasmid rescue. In some embodiment, the recombinant segment comprises a nucleic acid encoding the chimeric HA as well as the 3' and 5' incorporation signals which are required for proper replication, transcription and packaging of the vRNAs (Fujii et al., 2003, Proc. Natl. Acad. Sci. USA 100:2002-2007; Zheng, et al., 1996, Virology 217:242-251, International Publication No. WO 2011/014645, all of which are incorporated by reference herein in their entireties). In a specific embodiment, the recombinant segment uses the 3' and 5' noncoding and/or non-translated sequences of segments of influenza viruses that are from a different or the same group, subtype, or strain as the parental influenza virus (e.g., influenza A virus). In some embodiments, the recombinant segment comprises the 3' noncoding region of an influenza A virus HA, the untranslated regions of an influenza A virus HA, and the 5' non-coding region of an influenza A virus HA. In specific embodiments, the recombinant segment comprises the 3' and 5' noncoding and/or non-translated sequences of the HA segment of an influenza A virus that is the same group, subtype, or strain as the influenza A virus group, subtype, or strain as the HA stem domain of a chimeric HA. In some embodiments, the recombinant segment comprises the 3' and 5' noncoding and/or non-translated sequences of the HA segment of an influenza A virus that is the same group, subtype, or strain as the influenza A virus group, subtype, or strain as the HA globular head domain of a chimeric HA. In specific embodiments, the recombinant segment comprises packaging signals, such as the 5' and 3' non-coding regions and signal peptide of the HA segment of an influenza A virus, from the same group, subtype, or strain as the influenza A virus backbone. For example, if the chimeric HA is engineered to be expressed from an influenza A virus, then the nucleotide sequence encoding chimeric HA comprises the 5' and 3' non-coding regions and the nucleotide sequence encoding the signal peptide of the HA segment of the influenza A virus. In specific embodiments, the recombinant segment encoding the chimeric HA replaces the HA segment of a parental influenza A virus.

[00313] In some embodiments, a chimeric hemagglutinin gene segment encodes a chimeric HA. In specific embodiments, the chimeric hemagglutinin gene segment and at least one other influenza virus gene segment comprise packaging signals that enable the chimeric hemagglutinin gene segment and the at least one other gene segment to segregate together during replication of a recombinant influenza virus (see, Gao & Palese 2009, PNAS 106: 15891-15896; U.S. Patent No. 8,828,406; and International Application Publication No. WO 11/014645).

[00314] In some embodiments, the genome of a parental influenza virus (e.g., influenza A virus) may be engineered to express a chimeric HA using a recombinant segment that is bicistronic. Bicistronic techniques allow the engineering of coding sequences of multiple proteins into a single mRNA through the use of internal ribosome entry site (IRES) sequences. IRES sequences direct the internal recruitment of ribosomes to the RNA molecule and allow downstream translation in a cap independent manner. Briefly, a coding region of one protein is inserted into the open reading frame (ORF) of a second protein. The insertion is flanked by an IRES and any untranslated signal sequences necessary for proper expression and/or function. The insertion must not disrupt the ORF, polyadenylation or transcriptional promoters of the second protein (see, e.g., Garcia-Sastre et al., 1994, J. Virol. 68:6254-6261 and Garcia-Sastre et al., 1994 Dev. Biol. Stand. 82:237-246, each of which is hereby incorporated by reference in its entirety). See also, e.g., U.S. Patent No. 6,887,699, U.S. Patent No. 6,001,634, U.S. Patent No. 5,854,037 and U.S. Patent No. 5,820,871, each of which is incorporated herein by reference in its entirety. Any IRES known in the art or described herein may be used in accordance with the invention (e.g., the IRES of BiP gene, nucleotides 372 to 592 of GenBank database entry HUMGRP78; or the IRES of encephalomyocarditis virus (EMCV), nucleotides 1430-2115 of GenBank database entry CQ867238.). Thus, in some embodiments, a parental influenza virus (e.g., influenza A virus) is engineered to contain a bicistronic RNA segment that expresses the chimeric HA and another polypeptide, such as a gene expressed by the parental influenza virus. In some embodiments, the parental influenza virus gene is the HA gene.

[00315] Techniques known to one skilled in the art may be used to produce an influenza virus (e.g., influenza A virus) containing a chimeric HA and an influenza virus (e.g., influenza A virus) comprising a genome engineered to express a chimeric HA. For example, reverse genetics techniques may be used to generate such an influenza virus (e.g., influenza A virus). Briefly, reverse genetics techniques generally involve the preparation of synthetic recombinant viral RNAs that contain the non-coding regions of the negative- strand, viral RNA which are essential for the recognition by viral polymerases and for packaging signals necessary to generate a mature virion. The recombinant RNAs are synthesized from a recombinant DNA template and reconstituted in vitro with purified viral polymerase complex to form recombinant ribonucleoproteins (RNPs) which can be used to transfect cells. A more efficient transfection is achieved if the viral polymerase proteins are present during transcription of the synthetic RNAs either in vitro or in vivo. The synthetic recombinant RNPs can be rescued into infectious virus particles. The foregoing techniques are described in U.S. Patent No. 5,166,057 issued November 24, 1992; in U.S. Patent No. 5,854,037 issued December 29, 1998; in European Patent Publication EP 0702085A1, published February 20, 1996; in U.S. Patent Application Serial No. 09/152,845; in International Patent Application Publication No. WO 97/12032 published April 3, 1997; Application Publication No. WO 96/34625 published November 7, 1996; in European Patent Publication No. EP A780475; WO 99/02657 published January 21, 1999; Application Publication No. WO 98/53078 published November 26, 1998; Application Publication No. WO 98/02530 published January 22, 1998; Application Publication No. WO 99/15672 published April 1, 1999; Application Publication No. WO 98/13501 published April 2, 1998; Application Publication No. WO 97/06270 published February 20, 1997; and European Patent Application Publication No. 780 475 Al published June 25, 1997, each of which is incorporated by reference herein in its entirety.

[00316] Alternatively, helper-free plasmid technology may be used to produce an influenza virus (e.g. , influenza A virus) containing a chimeric HA and an influenza virus (e.g., influenza A virus) comprising a genome engineered to express a chimeric HA. Briefly, full length cDNAs of viral segments are amplified using PCR with primers that include unique restriction sites, which allow the insertion of the PCR product into the plasmid vector (Flandorfer et al., 2003, J. Virol. 77:9116-9123; Nakaya et al., 2001, J. Virol. 75: 11868- 11873; both of which are incorporated herein by reference in their entireties). The plasmid vector is designed so that an exact negative (vRNA sense) transcript is expressed. For example, the plasmid vector may be designed to position the PCR product between a truncated human RNA polymerase I promoter and a hepatitis delta virus ribozyme sequence such that an exact negative (vRNA sense) transcript is produced from the polymerase I promoter. Separate plasmid vectors comprising each viral segment as well as expression vectors comprising necessary viral proteins may be transfected into cells leading to production of recombinant viral particles. In another example, plasmid vectors from which both the viral genomic RNA and mRNA encoding the necessary viral proteins are expressed may be used. For a detailed description of helper-free plasmid technology see, e.g., International Patent Application Publication No. WO 01/04333; U.S. Patent Nos. 6,951,754, 7,384,774, 6,649,372, and 7,312,064; Fodor et al., 1999, J. Virol. 73:9679-9682; Quinlivan et al., 2005, J. Virol. 79:8431-8439; Hoffmann et al., 2000, Proc. Natl. Acad. Sci. USA 97:6108-6113; and Neumann et al., 1999, Proc. Natl. Acad. Sci. USA 96:9345-9350, each of which is incorporated herein by reference in its entirety.

[00317] The influenza viruses (e.g., influenza A viruses) described herein may be propagated in any substrate that allows the virus to grow to titers that permit their use in accordance with the methods described herein. Thus, in some embodiments, provided herein is a method for producing an influenza virus (e.g., influenza A virus) described herein comprising propagating the virus in a substrate. In some embodiments, the substrate allows the viruses to grow to titers comparable to those determined for the corresponding wild-type viruses. In some embodiments, the substrate is one which is biologically relevant to the influenza virus (e.g., influenza A virus) or to the virus from which the HA function is derived. In a specific embodiment, an attenuated influenza virus by virtue of, e.g., a mutation in the NS1 gene, may be propagated in an IFN-deficient substrate. For example, a suitable IFN-deficient substrate may be one that is defective in its ability to produce or respond to interferon, or is one which an IFN-deficient substrate may be used for the growth of any number of viruses which may require interferon-deficient growth environment. See, for example, U.S. Patent Nos. 6,573,079, issued June 3, 2003, 6,852,522, issued February 8, 2005, and 7,494,808, issued February 24, 2009, the entire contents of each of which is incorporated herein by reference in its entirety. In some embodiments, the virus is propagated in embryonated eggs (e.g., chicken eggs). In a specific embodiment, the virus is propagated in 8 day old, 9-day old, 8-10 day old, 10 day old, 11-day old, 10-12 day old, or 12-day old embryonated eggs (e.g., chicken eggs). In some embodiments, the virus is propagated in a cell line susceptible to influenza virus infection. In some embodiments, the virus is propagated in MDCK cells, Vero cells, 293 T cells, or other cell lines known in the art. In some embodiments, the virus is propagated in cells derived from embryonated eggs.

[00318] The influenza viruses (e.g., influenza A viruses) described herein may be isolated and purified by any method known to those of skill in the art. In some embodiments, the virus is removed from cell culture and separated from cellular components, typically by well- known clarification procedures, e.g., such as gradient centrifugation and column chromatography, and may be further purified as desired using procedures well known to those skilled in the art, e.g., plaque assays.

[00319] In specific embodiments, the influenza viruses, or influenza virus polypeptides, genes or genome segments for use as described herein are obtained or derived from an influenza A virus. In some embodiments, the influenza viruses, or influenza virus polypeptides, genes or genome segments for use as described herein are obtained or derived from two or more influenza A virus subtypes or strains. In a specific embodiment, the influenza A virus is an influenza A virus of the Hl, H2, H3, H4, H5, H6, H7, H8, H9, H10, Hl l, H12, H13, H14, H15, H16, H17, or H18 subtype. In a specific embodiment, the influenza A virus is an influenza A virus of the H2, H4, H5, H6, H7, H8, H9, H10, Hl l, H12, H13, H14, H15, H16, H17, or H18 subtype. In a specific embodiment, the influenza A virus is an influenza A virus of the H5, H8, Hl l, H12, or H13 subtype. In a specific embodiment, the influenza A virus is an influenza A virus of the H5 subtype. In a specific embodiment, the influenza A virus is an influenza A virus of the H8 subtype. In a specific embodiment, the influenza A virus is an influenza A virus of the Hl 1 subtype. In a specific embodiment, the influenza A virus is an influenza A virus of the H12 subtype. In a specific embodiment, the influenza A virus is an influenza A virus of the Hl 3 subtype. In a specific embodiment, the influenza A virus is an avian influenza virus.

[00320] Non-limiting examples of influenza A viruses include subtype H10N4, subtype H10N5, subtype H10N7, subtype H10N8, subtype H10N9, subtype Hl INI, subtype Hl 1N13, subtype Hl 1N2, subtype Hl 1N4, subtype Hl 1N6, subtype Hl 1N8, subtype H11N9, subtype H12N1, subtype H12N4, subtype Hl 2N5, subtype H12N8, subtype H13N2, subtype H13N3, subtype H13N6, subtype H13N7, subtype H14N5, subtype H14N6, subtype H15N8, subtype H15N9, subtype H16N3, subtype H1N1, subtype H1N2, subtype H1N3, subtype H1N6, subtype H1N9, subtype H2N1, subtype H2N2, subtype H2N3, subtype H2N5, subtype H2N7, subtype H2N8, subtype H2N9, subtype H3N1, subtype H3N2, subtype H3N3, subtype H3N4, subtype, H3N5, subtype H3N6, subtype H3N8, subtype H3N9, subtype H4N1, subtype H4N2, subtype H4N3, subtype H4N4, subtype H4N5, subtype H4N6, subtype H4N8, subtype H4N9, subtype H5N1, subtype H5N2, subtype H5N3, subtype H5N4, subtype H5N6, subtype H5N7, subtype H5N8, subtype H5N9, subtype H6N1, subtype H6N2, subtype H6N3, subtype H6N4, subtype H6N5, subtype H6N6, subtype H6N7, subtype H6N8, subtype H6N9, subtype H7N1, subtype H7N2, subtype H7N3, subtype H7N4, subtype H7N5, subtype H7N7, subtype H7N8, subtype H7N9, subtype H8N4, subtype H8N5, subtype H9N1, subtype H9N2, subtype H9N3, subtype H9N5, subtype H9N6, subtype H9N7, subtype H9N8, and subtype H9N9.

[00321] Specific examples of strains of influenza A virus include, but are not limited to: A/Victoria/361/2011 (H3N2); A/California/4/2009 (H1N1); A/California/7/2009 (H1N1); A/Perth/16/2009 (H3N2); A/Brisbane/59/2007 (H1N1); A/Brisbane/10/2007 ((H3N2); A/sw/Iowa/15/30 (H1N1); A/WSN/33 (H1N1); A/eq/Prague/1/56 (H7N7); A/PR/8/34; A/mallard/Potsdam/178-4/83 (H2N2); A/herring gull/DE/712/88 (H16N3); A/sw/Hong Kong/168/1993 (H1N1); A/mallard/Alberta/211/98 (H1N1); A/shorebird/Delaware/168/06 (H16N3); A/sw/Netherlands/25/80 (H1N1); A/sw/Germany/2/81 (H1N1);

A/sw/Hannover/1/81 (H1N1); A/sw/Potsdam/1/81 (H1N1); A/sw/Potsdam/15/81 (H1N1); A/sw/Potsdam/268/81 (H1N1); A/sw/Finistere/2899/82 (H1N1); A/sw/Potsdam/35/82 (H3N2); A/sw/Cote d'Armor/3633/84 (H3N2); A/sw/Gent/1/84 (H3N2);

A/sw/Netherlands/12/85 (H1N1); A/sw/Karrenzien/2/87 (H3N2); A/sw/Schwerin/103/89 (H1N1); A/turkey/Germany/3/91 (H1N1); A/sw/Germany/8533/91 (H1N1);

A/sw/Belgium/220/92 (H3N2); A/sw/Gent/V230/92 (H1N1); A/sw/Leipzig/145/92 (H3N2); A/sw/Re220/92hp (H3N2); A/sw/Bakum/909/93 (H3N2); A/sw/Schleswig-Holstein/1/93 (H1N1); A/sw/Scotland/419440/94 (H1N2); A/sw/Bakum/5/95 (H1N1); A/sw/Best/5C/96 (H1N1); A/sw/England/17394/96 (H1N2); A/sw/Jena/5/96 (H3N2); A/sw/Oedenrode/7C/96 (H3N2); A/sw/Lohne/1/97 (H3N2); A/sw/Cote d'Armor/790/97 (H1N2);

A/sw/Bakum/1362/98 (H3N2); A/sw/Italy/1521/98 (H1N2); A/sw/Italy/1553-2/98 (H3N2); A/sw/Italy/1566/98 (H1N1); A/sw/Italy/ 1589/98 (H1N1); A/sw/Bakum/8602/99 (H3N2); A/sw/Cotes d'Armor/604/99 (H1N2); A/sw/Cote d'Armor/1482/99 (H1N1);

A/sw/Gent/7625/99 (H1N2); A/Hong Kong/1774/99 (H3N2); A/sw/Hong Kong/5190/99 (H3N2); A/sw/Hong Kong/5200/99 (H3N2); A/sw/Hong Kong/5212/99 (H3N2); A/sw/Ille et Villaine/1455/99 (H1N1); A/sw/Italy/1654- 1/99 (H1N2); A/sw/Italy/2034/99 (H1N1);

A/sw/Italy/2064/99 (H1N2); A/sw/Berlin/1578/00 (H3N2);

A/sw/Bakum/1832/00 (H1N2); A/sw/Bakum/1833/00 (H1N2); A/sw/Cote d'Armor/800/00 (H1N2); A/sw/Hong Kong/7982/00 (H3N2); A/sw/Italy/1081/00 (H1N2); A/sw/Belzig/2/01 (H1N1); A/sw/Belzig/54/01 (H3N2); A/sw/Hong Kong/9296/01 (H3N2); A/sw/Hong Kong/9745/01 (H3N2); A/sw/Spain/33601/01 (H3N2); A/sw/Hong Kong/ 1144/02 (H3N2); A/sw/Hong Kong/1197/02 (H3N2); A/sw/Spain/39139/02 (H3N2); A/sw/Spain/42386/02 (H3N2); A/Switzerland/8808/2002 (H1N1); A/sw/Bakum/ 1769/03 (H3N2);

A/sw/Bissendorf/IDTl 864/03 (H3N2); A/sw/Ehren/IDT2570/03 (H1N2); A/sw/Gescher/IDT2702/03 (H1N2); A/sw/Haselunne/2617/03 hp (H1N1); A/sw/Loningen/IDT2530/03 (H1N2); A/sw/IVD/IDT2674/03 (H1N2); A/sw/Nordkirchen/IDT 1993/03 (H3N2); A/sw/Nordwalde/IDT2197/03 (H1N2); A/sw/Norden/IDT2308/03 (H1N2); A/sw/Spain/50047/03 (H1N1); A/sw/Spain/51915/03 (H1N1); A/sw/Vechta/2623/03 (H1N1); A/sw/Visbek/IDT2869/03 (H1N2);

A/sw/Waltersdorf/IDT2527/03 (H1N2); A/sw/Damme/IDT2890/04 (H3N2); A/sw/Geldem/IDT2888/04 (H1N1); A/sw/Granstedt/IDT3475/04 (H1N2); A/sw/Greven/IDT2889/04 (H1N1); A/sw/Gudensberg/IDT2930/04 (H1N2); A/sw/Gudensberg/IDT2931/04 (H1N2); A/sw/Lohne/IDT3357/04 (H3N2); A/sw/Nortrup/IDT3685/04 (H1N2); A/sw/Seesen/IDT3055/04 (H3N2); A/sw/Spain/53207/04 (H1N1); A/sw/Spain/54008/04 (H3N2); A/sw/Stolzenau/IDT3296/04 (H1N2); A/sw/Wedel/IDT2965/04 (H1N1); A/sw/Bad Griesbach/IDT4191/05 (H3N2);

A/sw/Cloppenburg/IDT4777/05 (H1N2); A/sw/Dotlingen/IDT3780/05 (H1N2); A/sw/Dotlingen/IDT4735/05 (H1N2); A/sw/Egglham/IDT5250/05 (H3N2); A/sw/Harkenblek/IDT4097/05 (H3N2); A/sw/Hertzen/IDT4317/05 (H3N2); A/sw/Krogel/IDT4192/05 (H1N1); A/sw/Laer/IDT3893/05 (H1N1); A/sw/Laer/IDT4126/05 (H3N2); A/sw/Merzen/IDT4114/05 (H3N2); A/sw/Muesleringen-S./IDT4263/05 (H3N2); A/sw/Osterhofen/IDT4004/05 (H3N2); A/sw/Sprenge/IDT3805/05 (H1N2);

A/sw/Stadtlohn/IDT3853/05 (H1N2); A/sw/Voglarn/IDT4096/05 (H1N1);

A/sw/Wohlerst/IDT4093/05 (H1N1); A/sw/Bad Griesbach/IDT5604/06 (H1N1);

A/sw/Herzlake/IDT5335/06 (H3N2); A/sw/Herzlake/IDT5336/06 (H3N2);

A/sw/Herzlake/IDT5337/06 (H3N2); and A/wild boar/Germany/Rl 69/2006 (H3N2).

[00322] Other specific examples of strains of influenza A virus include, but are not limited to: A/Toronto/3141/2009 (H1N1); A/Regensburg/D6/2009 (H1N1); A/Bayern/62/2009 (H1N1); A/Bayem/62/2009 (H1N1); A/Bradenburg/ 19/2009 (H1N1); A/Bradenburg/20/2009 (H1N1); A/Distrito Federal/2611/2009 (H1N1); A/Mato Grosso/2329/2009 (H1N1); A/Sao Paul o/l 454/2009 (H1N1); A/Sao Paulo/2233/2009 (H1N1); A/Stockholm/37/2009 (H1N1); A/Stockholm/41/2009 (H1N1); A/Stockholm/45/2009 (H1N1); A/swine/Alberta/OTH-33- 1/2009 (H1N1); A/swine/Alberta/OTH-33- 14/2009 (H1N1); A/swine/Alberta/OTH-33- 2/2009 (H1N1); A/swine/Alberta/OTH-33-21/2009 (H1N1); A/swine/Alberta/OTH-33- 22/2009 (H1N1); A/swine/Alberta/OTH-33 -23/2009 (H1N1); A/swine/Alberta/OTH-33- 24/2009 (H1N1); A/swine/Alberta/OTH-33 -25/2009 (H1N1); A/swine/Alberta/OTH-33- 3/2009 (H1N1); A/swine/Alberta/OTH-33 -7/2009 (H1N1); A/Beijing/502/2009 (H1N1); A/Firenze/ 10/2009 (H1N1); A/Hong Kong/2369/2009 (H1N1); A/Italy/85/2009 (H1N1); A/Santo Domingo/572N/2009 (H1N1); A/Catalonia/385/2009 (H1N1);

A/Catalonia/386/2009 (H1N1); A/Catalonia/387/2009 (H1N1); A/Catalonia/390/2009 (H1N1); A/Catalonia/394/2009 (HlNl);A/Catalonia/397/2009 (H1N1);

A/Catalonia/398/2009 (H1N1); A/Catalonia/399/2009 (H1N1); A/Sao Paulo/2303/2009 (H1N1); A/Akita/1/2009 (H1N1); A/Castro/JXP/2009 (H1N1); A/Fukushima/1/2009 (H1N1); A/Israel/276/2009 (H1N1); A/Israel/277/2009 (H1N1);

A/Israel/70/2009 (H1N1); A/Iwate/ 1/2009 (H1N1); A/Iwate/2/2009 (H1N1);

A/Kagoshima/1/2009 (H1N1); A/Osaka/180/2009 (H1N1); A/Puerto Montt/Bio87/2009 (Hl Nl); A/Sao Paulo/2303/2009 (H1N1); A/Sapporo/1/2009 (H1N1); A/Stockholm/30/2009 (H1N1); A/Stockholm/31/2009 (H1N1); A/Stockholm/32/2009 (H1N1);

A/Stockholm/33/2009 (H1N1); A/Stockholm/34/2009 (H1N1); A/Stockholm/35/2009 (H1N1); A/Stockholm/36/2009 (H1N1); A/Stockholm/38/2009 (H1N1);

A/Stockholm/39/2009 (H1N1); A/Stockholm/40/2009 (H1N1;) A/Stockholm/42/2009 (H1N1); A/Stockholm/43/2009 (H1N1); A/Stockholm/44/2009 (H1N1);

A/Utsunomiya/2/2009 (H1N1); A/WRAIR/0573N/2009 (H1N1); and A/Zhejiang/DTID- ZJU01/2009 (H1N1).

[00323] Other examples of influenza A viruses may be found elsewhere in the application, such as in, e.g., Section 5.3 above and Section 6 below.

[00324] In some embodiments, the influenza viruses provided herein have an attenuated phenotype. In specific embodiments, the attenuated influenza virus is based on influenza A virus. In some embodiments, the attenuated influenza virus may comprise genes or genome segments from one or more strains or subtypes of influenza A virus. In specific embodiments, the attenuated influenza virus comprises, encodes, or both, a chimeric HA and has a backbone of an influenza A virus.

[00325] In specific embodiments, attenuation of influenza A virus is desired such that the virus remains, at least partially, infectious and can replicate in vivo, but only generate low titers resulting in subclinical levels of infection that are non-pathogenic. Such attenuated viruses are especially suited for embodiments described herein wherein the virus or an immunogenic composition thereof is administered to a subject to induce an immune response. Attenuation of the influenza A virus can be accomplished according to any method known in the art, such as, e.g., selecting viral mutants generated by chemical mutagenesis, mutation of the genome by genetic engineering, selecting reassortant viruses that contain segments with attenuated function (e.g., truncated NS1 protein (see, e.g., Hai et al., 2008, Journal of Virology 82(21): 10580-10590, which is incorporated by reference herein in its entirety) or NS1 deletion (see, e.g., Wressnigg et al, 2009, Vaccine 27:2851-2857, which is incorporated by reference herein in its entirety)), or selecting for conditional virus mutants (e.g., cold- adapted viruses, see, e.g., Alexandrova et al., 1990, Vaccine, 8:61-64, which is incorporated by reference herein in its entirety). Alternatively, naturally occurring attenuated influenza A viruses may be used as influenza A virus backbones for the influenza A virus vectors.

[00326] In some embodiments, an influenza virus (e.g., influenza A virus) that contains a chimeric HA is propagated in embryonated chicken eggs. In some embodiments, an influenza virus (e.g., influenza A virus) that contains a chimeric HA is not propagated in embryonated chicken eggs. In some embodiments, an influenza virus (e.g., influenza A virus) that contains a chimeric HA is propagated in embryonated chicken egg cells. In some embodiments, an influenza virus (e.g., influenza A virus) that contains a chimeric HA polypeptide is propagated in mammalian cells, e.g., immortalized human cells (see, e.g., International Application No. PCT/EP2006/067566 published as International Publication No. WO 07/045674 which is herein incorporated by reference in its entirety) or canine kidney cells such as MDCK cells (see, e.g., International Application No. PCT/IB2007/003536 published as International Publication No. WO 08/032219 which is herein incorporated by reference in its entirety).

[00327] In some embodiments, an influenza virus (e.g., influenza A virus) comprising a chimeric HA described herein has one, two, or more of the functions of an influenza virus (e.g., influenza A virus) comprising a wild-type influenza virus (e.g., influenza A virus) HA. Non-limiting examples of functions of a wild-type influenza virus HA include fusogenic activity, receptor binding activity, budding, and particle formation. In a specific embodiment, an influenza virus comprising a chimeric influenza HA polypeptide described herein has fusogenic activity. Assays known to one skilled in the art can be utilized to assess the fusogenic activity of an influenza virus comprising a chimeric influenza HA polypeptide described herein, such as, for example, immunofluorescence assays and pseudotyped virus- like-particle assays. In a specific embodiment, an influenza virus (e.g., influenza A virus) comprising a chimeric influenza HA described herein has replication activity. Assays known to one skilled in the art can be utilized the assess the replication activity of an influenza virus (e.g., influenza A virus) comprising a chimeric influenza HA described herein, such as, for example, plaque assay and western blot analyses.

[00328] Techniques known to one of skill in the art may be used to inactivate viruses containing a chimeric HA. Common methods use formalin, heat, or detergent for inactivation. See, e.g., U.S. Patent No. 6,635,246, which is herein incorporated by reference in its entirety. Other methods include those described in U.S. Patent Nos. 5,891,705; 5,106,619, 4,693,981, 7,238,349, and 7,316,813, U.S. Patent Application Publication Nos. 2008/0181911 and 2009/0263422, and International Patent Application Publication Nos. WO 2001/022992, WO 2006/100109, WO 2002/097072, and WO 2008/009309, each which are incorporated herein by reference in their entireties. In specific embodiments, an inactivated influenza A virus is produced using methods described in Section 6, infra.

[00329] In some embodiments, inactivated influenza virus (e.g., inactivated influenza A virus) that contains a chimeric HA was propagated in embryonated chicken eggs before its inactivation and subsequent use in an immunogenic composition described herein. In some embodiments, the inactivated influenza virus (e.g., inactivated influenza A virus) that contains a chimeric HA was not propagated in embryonated chicken eggs before its inactivation and subsequent use in an immunogenic composition described herein. In some embodiments, the inactivated influenza virus (e.g., inactivated influenza A virus) that contains a chimeric HA was propagated in embryonated chicken egg cells before its inactivation and subsequent use in an immunogenic composition described herein. In some embodiments, the inactivated influenza virus (e.g., inactivated influenza A virus) that contains a chimeric HA polypeptide was propagated in mammalian cells, e.g., immortalized human cells (see, e.g., International Application No. PCT/EP2006/067566 published as International Publication No. WO 07/045674 which is herein incorporated by reference in its entirety) or canine kidney cells such as MDCK cells (see, e.g., International Application No. PCT/IB2007/003536 published as International Publication No. WO 08/032219 which is herein incorporated by reference in its entirety) before its inactivation and subsequent use in an immunogenic composition described herein.

[00330] Techniques for producing split virus vaccines are known to those skilled in the art. By way of non-limiting example, an influenza virus split vaccine may be prepared using inactivated particles disrupted with detergents. One example of a split virus vaccine that can be adapted for use in accordance with the methods described herein is the fluzone®, Influenza Virus Vaccine (Zonal Purified, Subvirion) for intramuscular use, which is formulated as a sterile suspension prepared from influenza viruses propagated in embryonated chicken eggs. The virus-containing fluids are harvested and inactivated with formaldehyde. Influenza virus is concentrated and purified in a linear sucrose density gradient solution using a continuous flow centrifuge. The virus is then chemically disrupted using a nonionic surfactant, octoxinol-9, (Triton® X- 100 - A registered trademark of Union Carbide, Co.) producing a "split virus." The split virus is then further purified by chemical means and suspended in sodium phosphate-buffered isotonic sodium chloride solution. In specific embodiments, an inactivated split influenza A virus is produced using methods described in Section 6, infra.

[00331] In some embodiments, the inactivated split influenza virus (e.g., influenza A virus) is prepared using influenza virus that was propagated in embryonated chicken eggs. In some embodiments, the inactivated split influenza virus (e.g., influenza A virus) is prepared using influenza virus that was not propagated in embryonated chicken eggs. In some embodiments, the inactivated split influenza virus (e.g., influenza A virus) is prepared using influenza virus that was propagated in embryonated chicken egg cells. In some embodiments, the inactivated split influenza virus (e.g., influenza A virus) is prepared using influenza virus that was propagated in mammalian cells, e.g., immortalized human cells (see, e.g., PCT/EP2006/067566 published as WO 07/045674 which is herein incorporated by reference in its entirety) or canine kidney cells such as MDCK cells (see, e.g., PCT/IB2007/003536 published as WO 08/032219 which is herein incorporated by reference in its entirety). Other methods for preparing the split virus vaccine are known in the art, such as, e.g., those described in U.S. Patent Nos. 7,238,349 and 7,316,813, U.S. Patent Application Publication Nos. 2008/0181911 and 2009/0263422, and International Patent Application Publication Nos. WO 2001/022992, WO 2006/100109, WO 2002/097072, and WO 2008/009309, each which are incorporated herein by reference in their entireties.

5.5 Prophylactic Uses

[00332] In one aspect, provided herein are methods of preventing influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus) in a subject, methods of immunizing a subject against influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus), and methods of inducing an immune response to influenza A viruses (e.g., a cross-reactive immune response to plurality of influenza A virus strains or subtypes (e.g. , group 2 influenza A viruses)) using an immunogenic composition described herein. In some embodiments, provided herein are methods of inducing a cross-reactive immune response to plurality of influenza A virus strains or subtypes (e.g., group 2 influenza A viruses) using an immunogenic composition described herein.

[00333] In some embodiments, provided herein is a method of preventing influenza virus disease (e.g., influenza virus disease caused by an influenza A virus, such as, e.g., influenza virus disease caused by a group 2 influenza A virus) in a subject, comprising administering to the subject an immunogenic composition described herein. In some embodiments, provided herein is a method of immunizing a subject against influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus), comprising administering to the subject an immunogenic composition described herein. In some embodiments, provided herein is a method of inducing immune response to influenza A viruses in a subject, comprising administering to the subject an immunogenic composition described herein. In some embodiments, provided herein is a method of inducing a cross- reactive immune response to two or more group 2 influenza A viruses in a subject, comprising administering to the subject an immunogenic composition described herein. In some embodiments, the immunogenic composition is administered intramuscularly to the subject. In some embodiments, the inactivated influenza A virus or inactivated split influenza A virus in an immunogenic composition is administered to the subject at a dose provided herein. In some embodiments, the CpG oligonucleotide adjuvant in an immunogenic composition is administered to the subject at a dose provided herein.

[00334] While not intending to be bound by any particular theory of operation, it is believed that sequential immunization with chimeric HAs that express the same HA stem domain and distinct HA globular head domains are useful for presenting one or more relatively conserved antigenic regions to a subject’s immune system in order to generate an immune response that is capable of cross-reacting with a plurality of influenza A virus strains and subtypes. Accordingly, in some embodiments, provided herein are methods of inducing an immune response in a subject (e.g., human subject) that is capable of cross-reacting with a plurality of influenza A virus strains and subtypes, comprising sequentially administering to the subject two or more immunogenic compositions described herein, wherein each immunogenic composition comprises a chimeric HA and a CpG oligonucleotide adjuvant described herein, wherein each chimeric HA comprises an HA globular head domain and an HA stem domain of a group 2 influenza A virus HA, wherein the HA globular head domain of the chimeric HA is immunologically distinct from the HA globular head domain of the group 2 influenza A virus HA, wherein the chimeric HA of the two or more immunogenic compositions each comprise the same HA stem domain, and wherein the HA globular head domain of each chimeric HA comprises the amino acid sequence of the HA globular head domain of a different strain, subtype, or group from each other. In some embodiments, provided herein are methods of inducing an immune response in a subject (e.g., human subject) that is capable of cross-reacting with a plurality of influenza A virus strains and subtypes, comprising sequentially administering to the subject two or more immunogenic compositions described herein, wherein each immunogenic composition comprises an inactivated influenza A virus and a CpG oligonucleotide adjuvant described herein, wherein each inactivated influenza A virus comprises a chimeric HA, wherein each chimeric HA comprises an HA globular head domain and an HA stem domain of a group 2 influenza A virus HA, wherein the HA globular head domain of the chimeric HA is immunologically distinct from the HA globular head domain of the group 2 influenza A virus HA, wherein the chimeric HA of the two or more immunogenic compositions each comprise the same HA stem domain, and wherein the HA globular head domain of each chimeric HA comprises the amino acid sequence of the HA globular head domain of a different strain, subtype, or group from each other. In some embodiments, provided herein are methods of inducing an immune response in a subject (e.g., human subject) that is capable of cross-reacting with a plurality of influenza A virus strains and subtypes, comprising sequentially administering to the subject two or more immunogenic compositions described herein, wherein each immunogenic composition comprises an inactivated split influenza A virus and a CpG oligonucleotide adjuvant described herein, wherein each inactivated split influenza A virus comprises a chimeric HA, wherein each chimeric HA comprises an HA globular head domain and an HA stem domain of a group 2 influenza A virus HA, wherein the HA globular head domain of the chimeric HA is immunologically distinct from the HA globular head domain of the group 2 influenza A virus HA, wherein the chimeric HA of the two or more immunogenic compositions each comprise the same HA stem domain, and wherein the HA globular head domain of each chimeric HA comprises the amino acid sequence of the HA globular head domain of a different strain, subtype, or group from each other. In some embodiments, each immunogenic composition comprises an aluminum salt. In some embodiments, each immunogenic composition does not comprise an aluminum salt. In some embodiments, an aluminum salt is administered to the subject concurrently or about 1 hour (or about 45 minutes, about 30 minutes, or about 15 minutes) before or after the administration of the first immunogenic composition. In some embodiments, an aluminum salt is administered to the subject concurrently or about 1 hour (or about 45 minutes, about 30 minutes, or about 15 minutes) before or after the administration of the second immunogenic composition. In some embodiments, each immunogenic composition is administered to the subject from about 2 months to about 9 months apart from another immunogenic composition. In some embodiments, each immunogenic composition is administered to the subject from about 3 months to about 9 months or about 3 months to about 6 months apart from another immunogenic composition. In some embodiments, each immunogenic composition is administered to the subject from about 21 days to about 60 days apart from another immunogenic composition. In some embodiments, each immunogenic composition is administered to the subject from about 60 to about 120 days apart from another immunogenic composition. In some embodiments, each immunogenic composition is administered to the subject from about 21 days to about 120 days apart from another immunogenic composition. In some embodiments, each immunogenic composition is administered to the subject from about 21 days to about 6 months apart from another immunogenic composition. In some embodiments, each immunogenic composition is administered to the subject intramuscularly or intranasally.

[00335] In some embodiments, provided herein is a method of inducing an immune response to influenza A viruses (e.g., a cross-reactive immune response to group 2 influenza A viruses) in a subject e.g., human subject), comprising: (a) administering to the subject a first immunogenic composition comprising a chimeric HA and a CpG oligonucleotide adjuvant described herein, wherein the first chimeric HA comprises a first influenza virus HA globular head domain and a first influenza virus HA stalk domain, wherein the first HA stalk domain comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA; and (b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second chimeric HA and a CpG oligonucleotide adjuvant described herein, wherein the second chimeric HA comprises a second influenza virus HA globular head domain and a second influenza virus HA stalk domain, wherein the second HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA, and wherein the second HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the second HA globular head domain. In some embodiments, the first and second immunogenic compositions each comprise an aluminum salt. The aluminum salt in the first and second immunogenic compositions may or may not be the same. In some embodiments, the first and second immunogenic compositions do not comprise an aluminum salt. In some embodiments, an aluminum salt is administered to the subject concurrently or about 1 hour (or about 45 minutes, about 30 minutes, or about 15 minutes) before or after the administration of the first immunogenic composition. In some embodiments, an aluminum salt is administered to the subject concurrently or about 1 hour (or about 45 minutes, about 30 minutes, or about 15 minutes) before or after the administration of the second immunogenic composition. In some embodiments, the first and second immunogenic compositions are administered to the subject from about 2 months to about 9 months apart from each other. In some embodiments, the first and second immunogenic compositions are administered to the subject from about 3 months to about 9 months or about 3 months to about 6 months apart from each other. In some embodiments, each immunogenic composition is administered to the subject from about 21 days to about 60 days apart from another immunogenic composition. In some embodiments, each immunogenic composition is administered to the subject from about 21 days to about 120 days apart from another immunogenic composition. In some embodiments, each immunogenic composition is administered to the subject from about 21 days to about 6 months apart from another immunogenic composition. In some embodiments, the method further comprises administering to the subject a third immunogenic composition a certain time after the administration of the second immunogenic composition to the subject, wherein the third immunogenic composition comprises a third chimeric HA and a CpG oligonucleotide adjuvant described herein, wherein the third chimeric HA comprises a third influenza virus HA globular head domain and a third influenza virus HA stalk domain, wherein the third HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA, wherein the third HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA, and the third HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the first HA globular head domain and the second HA globular head domain. In some embodiments, each immunogenic composition is administered to the subject intramuscularly or intranasally. In some embodiments, the chimeric HA in an immunogenic composition is administered to the subject at a dose provided herein. In some embodiments, the CpG oligonucleotide adjuvant in an immunogenic composition is administered to the subject at a dose provided herein.

[00336] In some embodiments, provided herein is a method of inducing an immune response to influenza A viruses (e.g., a cross-reactive immune response to group 2 influenza A viruses) in a subject (e.g., a human subject), comprising: (a) administering to the subject a first immunogenic composition comprising a first inactivated influenza virus and a CpG oligonucleotide adjuvant described herein, wherein the first inactivated influenza virus comprises a first chimeric HA, wherein the first chimeric HA comprises a first influenza virus HA globular head domain and a first influenza virus HA stalk domain, wherein the first HA stalk domain comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the second HA globular head domain; and (b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second inactivated influenza A virus and a CpG oligonucleotide adjuvant described herein, wherein the second inactivated influenza A virus comprises a second chimeric HA, and wherein the second chimeric HA comprises a second influenza virus HA globular head domain and a second influenza virus HA stalk domain, wherein the second HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA, wherein the second HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the second HA globular head domain. In some embodiments, the first and second immunogenic compositions each comprise an aluminum salt. The aluminum salt in the first and second immunogenic compositions may or may not be the same. In some embodiments, the first and second immunogenic compositions do not comprise an aluminum salt. In some embodiments, an aluminum salt is administered to the subject concurrently or about 1 hour (or about 45 minutes, about 30 minutes, or about 15 minutes) before or after the administration of the first immunogenic composition. In some embodiments, an aluminum salt is administered to the subject concurrently or about 1 hour (or about 45 minutes, about 30 minutes, or about 15 minutes) before or after the administration of the second immunogenic composition. In some embodiments, the first and second immunogenic compositions are administered to the subject from about 2 months to about 9 months apart from each other. In some embodiments, the first and second immunogenic compositions are administered to the subject from about 3 months to about 9 months or about 3 months to about 6 months apart from each other. In some embodiments, the first and second immunogenic compositions are administered to the subject from about 60 to about 120 days apart from each other. In some embodiments, each immunogenic composition is administered to the subject from about 21 days to about 60 days apart from another immunogenic composition. In some embodiments, each immunogenic composition is administered to the subject from about 21 days to about 120 days apart from another immunogenic composition. In some embodiments, each immunogenic composition is administered to the subject from about 21 days to about 6 months apart from another immunogenic composition. In some embodiments, the method further comprises administering to the subject a third immunogenic composition a certain time after the administration of the second immunogenic composition to the subject, wherein the third immunogenic composition comprises a third inactivated influenza virus and a CpG oligonucleotide adjuvant described herein, wherein the third inactivated influenza virus comprises a third chimeric HA, and wherein the third chimeric HA comprises a third influenza virus HA globular head domain and a third influenza virus HA stalk domain, wherein the third HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA, wherein the third HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA, and the third HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the first HA globular head domain and the second HA globular head domain. In some embodiments, each immunogenic composition is administered to the subject intramuscularly or intranasally. In some embodiments, the chimeric HA in an immunogenic composition is administered to the subject at a dose provided herein. In some embodiments, the CpG oligonucleotide adjuvant in an immunogenic composition is administered to the subject at a dose provided herein.

[00337] In some embodiments, provided herein is a method of inducing an immune response to influenza A viruses (e.g., a cross-reactive immune response to group 2 influenza A viruses) in a subject (e.g., a human subject), comprising: (a) administering to the subject a first immunogenic composition comprising a first inactivated split influenza virus and a CpG oligonucleotide adjuvant described herein, wherein the first inactivated split influenza virus comprises a first chimeric HA, wherein the first chimeric HA comprises a first influenza virus HA globular head domain and a first influenza virus HA stalk domain, wherein the first HA stalk domain comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the second HA globular head domain; and (b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second inactivated split influenza A virus and a CpG oligonucleotide adjuvant described herein, wherein the second inactivated influenza A virus comprises a second chimeric HA, and wherein the second chimeric HA comprises a second influenza virus HA globular head domain and a second influenza virus HA stalk domain, wherein the second HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA, wherein the second HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the second HA globular head domain. In some embodiments, the first and second immunogenic compositions each comprise an aluminum salt. The aluminum salt in the first and second immunogenic compositions may or may not be the same. In some embodiments, the first and second immunogenic compositions do not comprise an aluminum salt. In some embodiments, an aluminum salt is administered to the subject concurrently or about 1 hour (or about 45 minutes, about 30 minutes, or about 15 minutes) before or after the administration of the first immunogenic composition. In some embodiments, an aluminum salt is administered to the subject concurrently or about 1 hour (or about 45 minutes, about 30 minutes, or about 15 minutes) before or after the administration of the second immunogenic composition. In some embodiments, the first and second immunogenic compositions are administered to the subject from about 2 months to about 9 months apart from each other. In some embodiments, the first and second immunogenic compositions are administered to the subject from about 3 months to about 9 months or about 3 months to about 6 months apart from each other. In some embodiments, the first and second immunogenic compositions are administered to the subject from about 60 to about 120 days apart from each other. In some embodiments, each immunogenic composition is administered to the subject from about 21 days to about 60 days apart from another immunogenic composition. In some embodiments, each immunogenic composition is administered to the subject from about 21 days to about 120 days apart from another immunogenic composition. In some embodiments, each immunogenic composition is administered to the subject from about 21 days to about 6 months apart from another immunogenic composition. In some embodiments, the method further comprises administering to the subject a third immunogenic composition a certain time after the administration of the second immunogenic composition to the subject, wherein the third immunogenic composition comprises a third inactivated split influenza virus and a CpG oligonucleotide adjuvant described herein, wherein the third inactivated split influenza virus comprises a third chimeric HA, and wherein the third chimeric HA comprises a third influenza virus HA globular head domain and a third influenza virus HA stalk domain, wherein the third HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA, wherein the third HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA, and the third HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the first HA globular head domain and the second HA globular head domain. In some embodiments, each immunogenic composition is administered to the subject intramuscularly or intranasally. In some embodiments, the chimeric HA in an immunogenic composition is administered to the subject at a dose provided herein. In some embodiments, the CpG oligonucleotide adjuvant in an immunogenic composition is administered to the subject at a dose provided herein.

[00338] In some embodiments, provided herein are methods preventing influenza virus disease (e.g., influenza virus disease caused by an influenza A virus, such as, e.g., influenza virus disease caused by a group 2 influenza A virus) in a subject (e.g., human subject), comprising sequentially administering to the subject two or more immunogenic compositions described herein, wherein each immunogenic composition comprises a chimeric HA and a CpG oligonucleotide adjuvant described herein, wherein each chimeric HA comprises an HA globular head domain and an HA stem domain of a group 2 influenza A virus HA, wherein the HA globular head domain of the chimeric HA is immunologically distinct from the HA globular head domain of the group 2 influenza A virus HA, wherein the chimeric HA of the two or more immunogenic compositions each comprise the same HA stem domain, and wherein the HA globular head domain of each chimeric HA comprises the amino acid sequence of the HA globular head domain of a different strain, subtype, or group from each other. In some embodiments, provided herein are methods preventing influenza virus disease (e.g., influenza virus disease caused by an influenza A virus, such as, e.g., influenza virus disease caused by a group 2 influenza A virus) in a subject (e.g., a human subject), comprising sequentially administering to the subject two or more immunogenic compositions described herein, wherein each immunogenic composition comprises an inactivated influenza virus and a CpG oligonucleotide adjuvant described herein, wherein each inactivated influenza virus comprises a chimeric HA, wherein each chimeric HA comprises an HA globular head domain and an HA stem domain of a group 2 influenza A virus HA, wherein the HA globular head domain of the chimeric HA is immunologically distinct from the HA globular head domain of the group 2 influenza A virus HA, wherein the chimeric HA of the two or more immunogenic compositions each comprise the same HA stem domain, and wherein the HA globular head domain of each chimeric HA comprises the amino acid sequence of the HA globular head domain of a different strain, subtype, or group from each other. In some embodiments, provided herein are methods preventing influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus) in a subject (e.g., a human subject), comprising sequentially administering to the subject two or more immunogenic compositions described herein, wherein each immunogenic composition comprises an inactivated split influenza virus and a CpG oligonucleotide adjuvant described herein, wherein each inactivated split influenza virus comprises a chimeric HA, wherein each chimeric HA comprises an HA globular head domain and an HA stem domain of a group 2 influenza A virus HA, wherein the HA globular head domain of the chimeric HA is immunologically distinct from the HA globular head domain of the group 2 influenza A virus HA, wherein the chimeric HA of the two or more immunogenic compositions each comprise the same HA stem domain, and wherein the HA globular head domain of each chimeric HA comprises the amino acid sequence of the HA globular head domain of a different strain, subtype, or group from each other. In some embodiments, each immunogenic composition comprises an aluminum salt. In some embodiments, each immunogenic composition does not comprise an aluminum salt. In some embodiments, an aluminum salt is administered to the subject concurrently or about 1 hour (or about 45 minutes, about 30 minutes, or about 15 minutes) before or after the administration of the first immunogenic composition. In some embodiments, an aluminum salt is administered to the subject concurrently or about 1 hour (or about 45 minutes, about 30 minutes, or about 15 minutes) before or after the administration of the second immunogenic composition. In some embodiments, each immunogenic composition is administered to the subject from about 2 months to about 9 months apart from another immunogenic composition. In some embodiments, each immunogenic composition is administered to the subject from about 3 months to about 9 months or about 3 months to about 6 months apart from another immunogenic composition. In some embodiments, each immunogenic composition is administered to the subject from about 21 days to about 60 days apart from another immunogenic composition. In some embodiments, each immunogenic composition is administered to the subject from about 21 days to about 120 days apart from another immunogenic composition. In some embodiments, each immunogenic composition is administered to the subject from about 21 days to about 6 months apart from another immunogenic composition. In some embodiments, each immunogenic composition is administered to the subject from about 60 days to about 120 days apart from another immunogenic composition. In some embodiments, each immunogenic composition is administered to the subject intramuscularly or intranasally. In some embodiments, the chimeric HA in an immunogenic composition is administered to the subject at a dose provided herein. In some embodiments, the CpG oligonucleotide adjuvant in an immunogenic composition is administered to the subject at a dose provided herein.

[00339] In some embodiments, provided herein is a method of preventing influenza virus disease (e.g., influenza virus disease caused by influenza A virus) in a subject (e.g., a human subject), comprising: (a) administering to the subject a first immunogenic composition comprising a chimeric HA and a CpG oligonucleotide adjuvant described herein, wherein the first chimeric HA comprises a first influenza virus HA globular head domain and a first influenza virus HA stalk domain, wherein the first HA stalk domain comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA; and (b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second chimeric HA and a CpG oligonucleotide adjuvant described herein, wherein the second chimeric HA comprises a second influenza virus HA globular head domain and a second influenza virus HA stalk domain, wherein the second HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA, and wherein the second HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the second HA globular head domain. In some embodiments, the first and second immunogenic compositions each comprise an aluminum salt. The aluminum salt in the first and second immunogenic compositions may or may not be the same. In some embodiments, the first and second immunogenic compositions do not comprise an aluminum salt. In some embodiments, an aluminum salt is administered to the subject concurrently or about 1 hour (or about 45 minutes, about 30 minutes, or about 15 minutes) before or after the administration of the first immunogenic composition. In some embodiments, an aluminum salt is administered to the subject concurrently or about 1 hour (or about 45 minutes, about 30 minutes, or about 15 minutes) before or after the administration of the second immunogenic composition. In some embodiments, the first and second immunogenic compositions are administered to the subject from about 2 months to about 9 months apart from each other. In some embodiments, the first and second immunogenic compositions are administered to the subject from about 3 months to about 9 months or about 3 months to about 6 months apart from each other. In some embodiments, each immunogenic composition is administered to the subject from about 21 days to about 60 days apart from another immunogenic composition. In some embodiments, each immunogenic composition is administered to the subject from about 21 days to about 120 days apart from another immunogenic composition. In some embodiments, each immunogenic composition is administered to the subject from about 21 days to about 6 months apart from another immunogenic composition. In some embodiments, the method further comprises administering to the subject a third immunogenic composition a certain time after the administration of the second immunogenic composition to the subject, wherein the third immunogenic composition comprises a third chimeric HA and a CpG oligonucleotide adjuvant described herein, wherein the third chimeric HA comprises a third influenza virus HA globular head domain and a third influenza virus HA stalk domain, wherein the third HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA, wherein the third HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA, and the third HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the first HA globular head domain and the second HA globular head domain. In some embodiments, each immunogenic composition is administered to the subject intramuscularly or intranasally. In some embodiments, the chimeric HA in an immunogenic composition is administered to the subject at a dose provided herein. In some embodiments, the CpG oligonucleotide adjuvant in an immunogenic composition is administered to the subject at a dose provided herein.

[00340] In some embodiments, provided herein is a method of preventing influenza virus disease (e.g., influenza virus disease caused by influenza A virus) in a subject (e.g., a human subject), comprising: (a) administering to the subject a first immunogenic composition comprising a first inactivated influenza virus and a CpG oligonucleotide adjuvant described herein, wherein the first inactivated influenza virus comprises a first chimeric HA, and wherein the first chimeric HA comprises a first influenza virus HA globular head domain and a first influenza virus HA stalk domain, wherein the first HA stalk domain comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA; and (b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second inactivated influenza virus and a CpG oligonucleotide adjuvant described herein, wherein the second inactivated influenza virus comprises a second chimeric HA, and wherein the second chimeric HA comprises a second influenza virus HA globular head domain and a second influenza virus HA stalk domain, wherein the second HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA, and wherein the second HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the second HA globular head domain. In some embodiments, the first and second immunogenic compositions each comprise an aluminum salt. The aluminum salt in the first and second immunogenic compositions may or may not be the same. In some embodiments, the first and second immunogenic compositions do not comprise an aluminum salt. In some embodiments, an aluminum salt is administered to the subject concurrently or about 1 hour (or about 45 minutes, about 30 minutes, or about 15 minutes) before or after the administration of the first immunogenic composition. In some embodiments, an aluminum salt is administered to the subject concurrently or about 1 hour (or about 45 minutes, about 30 minutes, or about 15 minutes) before or after the administration of the second immunogenic composition. In some embodiments, the first and second immunogenic compositions are administered to the subject from about 2 months to about 9 months apart from each other. In some embodiments, the first and second immunogenic compositions are administered to the subject from about 3 months to about 9 months or about 3 months to about 6 months apart from each other. In some embodiments, the first and second immunogenic compositions are administered to the subject from about 21 days to about 60 days apart from each other. In some embodiments, the first and second immunogenic compositions are administered to the subject from about 21 days to about 120 days apart from each other. In some embodiments, the first and second immunogenic compositions are administered to the subject from about 60 days to about 120 days apart from each other. In some embodiments, the method further comprises administering to the subject a third immunogenic composition a certain time after the administration of the second immunogenic composition to the subject, wherein the third immunogenic composition comprises a third inactivated influenza virus and a CpG oligonucleotide adjuvant described herein, wherein the third inactivated influenza virus comprises a third chimeric HA, and wherein the third chimeric HA comprises a third influenza virus HA globular head domain and a third influenza virus HA stalk domain, wherein the third HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA, wherein the third HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA, and wherein the third HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the first HA globular head domain and the second HA globular head domain. In some embodiments, each immunogenic composition is administered to the subject intramuscularly or intranasally. In some embodiments, the chimeric HA in an immunogenic composition is administered to the subject at a dose provided herein. In some embodiments, the CpG oligonucleotide adjuvant in an immunogenic composition is administered to the subject at a dose provided herein.

[00341] In some embodiments, provided herein is a method of preventing influenza virus disease (e.g., influenza virus disease caused by influenza A virus) in a subject (e.g., a human subject), comprising: (a) administering to the subject a first immunogenic composition comprising a first inactivated split influenza virus and a CpG oligonucleotide adjuvant described herein, wherein the first inactivated split influenza virus comprises a first chimeric HA, and wherein the first chimeric HA comprises a first influenza virus HA globular head domain and a first influenza virus HA stalk domain, wherein the first HA stalk domain comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA; and (b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second inactivated split influenza virus and a CpG oligonucleotide adjuvant described herein, wherein the second inactivated split influenza virus comprises a second chimeric HA, and wherein the second chimeric HA comprises a second influenza virus HA globular head domain and a second influenza virus HA stalk domain, wherein the second HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA, and wherein the second HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the second HA globular head domain. In some embodiments, the first and second immunogenic compositions each comprise an aluminum salt. The aluminum salt in the first and second immunogenic compositions may or may not be the same. In some embodiments, the first and second immunogenic compositions do not comprise an aluminum salt. In some embodiments, an aluminum salt is administered to the subject concurrently or about 1 hour (or about 45 minutes, about 30 minutes, or about 15 minutes) before or after the administration of the first immunogenic composition. In some embodiments, an aluminum salt is administered to the subject concurrently or about 1 hour (or about 45 minutes, about 30 minutes, or about 15 minutes) before or after the administration of the second immunogenic composition. In some embodiments, the first and second immunogenic compositions are administered to the subject from about 2 months to about 9 months apart from each other. In some embodiments, the first and second immunogenic compositions are administered to the subject from about 3 months to about 9 months or about 3 months to about 6 months apart from each other. In some embodiments, the first and second immunogenic compositions are administered to the subject from about 21 days to about 60 days apart from each other. In some embodiments, the first and second immunogenic compositions are administered to the subject from about 21 days to about 120 days apart from each other. In some embodiments, the first and second immunogenic compositions are administered to the subject from about 60 days to about 120 days apart from each other. In some embodiments, each immunogenic composition is administered to the subject from about 21 days to about 60 days apart from another immunogenic composition. In some embodiments, each immunogenic composition is administered to the subject from about 21 days to about 120 days apart from another immunogenic composition. In some embodiments, each immunogenic composition is administered to the subject from about 21 days to about 6 months apart from another immunogenic composition. In some embodiments, the method further comprises administering to the subject a third immunogenic composition a certain time after the administration of the second immunogenic composition to the subject, wherein the third immunogenic composition comprises a third inactivated split influenza virus and a CpG oligonucleotide adjuvant described herein, wherein the third inactivated split influenza virus comprises a third chimeric HA, and wherein the third chimeric HA comprises a third influenza virus HA globular head domain and a third influenza virus HA stalk domain, wherein the third HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA, wherein the third HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA, and wherein the third HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the first HA globular head domain and the second HA globular head domain. In some embodiments, each immunogenic composition is administered to the subject intramuscularly or intranasally. In some embodiments, the chimeric HA in an immunogenic composition is administered to the subject at a dose provided herein. In some embodiments, the CpG oligonucleotide adjuvant in an immunogenic composition is administered to the subject at a dose provided herein.

[00342] In some embodiments, provided herein are methods of immunizing a subject (e.g., a human subject) against influenza virus disease (e.g., influenza virus disease caused by an influenza A virus, such as, e.g., influenza virus disease caused by a group 2 influenza A virus), comprising sequentially administering to the subject two or more immunogenic compositions described herein, wherein each immunogenic composition comprises a chimeric HA and a CpG oligonucleotide adjuvant described herein, wherein each chimeric HA comprises an HA globular head domain and an HA stem domain of a group 2 influenza A virus HA, wherein the HA globular head domain of the chimeric HA is immunologically distinct from the HA globular head domain of the group 2 influenza A virus HA, wherein the chimeric HA of the two or more immunogenic compositions each comprise the same HA stem domain, and wherein the HA globular head domain of each chimeric HA comprises the amino acid sequence of the HA globular head domain of a different strain, subtype, or group from each other. In some embodiments, provided herein are methods of immunizing a subject (e.g., a human subject) against influenza virus disease (e.g., influenza virus disease caused by an influenza A virus, such as, e.g., influenza virus disease caused by a group 2 influenza A virus), comprising sequentially administering to the subject two or more immunogenic compositions described herein, wherein each immunogenic composition comprises an inactivated influenza virus and a CpG oligonucleotide adjuvant described herein, wherein each inactivated influenza virus comprises a chimeric HA, wherein each chimeric HA comprises an HA globular head domain and an HA stem domain of a group 2 influenza A virus HA, wherein the HA globular head domain of the chimeric HA is immunologically distinct from the HA globular head domain of the group 2 influenza A virus HA, wherein the chimeric HA of the two or more immunogenic compositions each comprise the same HA stem domain, and wherein the HA globular head domain of each chimeric HA comprises the amino acid sequence of the HA globular head domain of a different strain, subtype, or group from each other. In some embodiments, provided herein are methods of immunizing a subject (e.g, a human subject) against influenza virus disease (e.g, influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus), comprising sequentially administering to the subject two or more immunogenic compositions described herein, wherein each immunogenic composition comprises an inactivated split influenza virus and a CpG oligonucleotide adjuvant described herein, wherein each inactivated split influenza virus comprises a chimeric HA, wherein each chimeric HA comprises an HA globular head domain and an HA stem domain of a group 2 influenza A virus HA, wherein the HA globular head domain of the chimeric HA is immunologically distinct from the HA globular head domain of the group 2 influenza A virus HA, wherein the chimeric HA of the two or more immunogenic compositions each comprise the same HA stem domain, and wherein the HA globular head domain of each chimeric HA comprises the amino acid sequence of the HA globular head domain of a different strain, subtype, or group from each other. In some embodiments, each immunogenic composition comprises an aluminum salt. In some embodiments, each immunogenic composition does not comprise an aluminum salt. In some embodiments, an aluminum salt is administered to the subject concurrently or about 1 hour (or about 45 minutes, about 30 minutes, or about 15 minutes) before or after the administration of the first immunogenic composition. In some embodiments, an aluminum salt is administered to the subject concurrently or about 1 hour (or about 45 minutes, about 30 minutes, or about 15 minutes) before or after the administration of the second immunogenic composition. In some embodiments, each immunogenic composition is administered to the subject from about 2 months to about 9 months apart from another immunogenic composition. In some embodiments, each immunogenic composition is administered to the subject from about 3 months to about 9 months or about 3 months to about 6 months apart from another immunogenic composition. In some embodiments, each immunogenic composition is administered to the subject from about 21 days to about 60 days apart from another immunogenic composition. In some embodiments, each immunogenic composition is administered to the subject to the subject from about 21 days to about 120 days apart from another immunogenic composition. In some embodiments, each immunogenic composition is administered to the subject from about 60 days to about 120 days apart from another immunogenic composition. In some embodiments, each immunogenic composition is administered to the subject intramuscularly or intranasally. In some embodiments, the chimeric HA in an immunogenic composition is administered to the subject at a dose provided herein. In some embodiments, the CpG oligonucleotide adjuvant in an immunogenic composition is administered to the subject at a dose provided herein.

[00343] In some embodiments, provided herein is a method of immunizing a subject (e.g., a human subject) against influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus), comprising: (a) administering to the subject a first immunogenic composition comprises a chimeric HA and a CpG oligonucleotide adjuvant described herein, wherein the first chimeric HA comprises a first influenza virus HA globular head domain and a first influenza virus HA stalk domain, wherein the first HA stalk domain comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA; and (b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second chimeric HA and a CpG oligonucleotide adjuvant described herein, wherein the second chimeric HA comprises a second influenza virus HA globular head domain and a second influenza virus HA stalk domain, wherein the second HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA, and wherein the second HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the second HA globular head domain. In some embodiments, the first and second immunogenic compositions each comprise an aluminum salt. The aluminum salt in the first and second immunogenic compositions may or may not be the same. In some embodiments, the first and second immunogenic compositions do not comprise an aluminum salt. In some embodiments, an aluminum salt is administered to the subject concurrently or about 1 hour (or about 45 minutes, about 30 minutes, or about 15 minutes) before or after the administration of the first immunogenic composition. In some embodiments, an aluminum salt is administered to the subject concurrently or about 1 hour (or about 45 minutes, about 30 minutes, or about 15 minutes) before or after the administration of the second immunogenic composition. In some embodiments, the first and second immunogenic compositions are administered to the subject from about 2 months to about 9 months apart from each other. In some embodiments, the first and second immunogenic compositions are administered to the subject from about 3 months to about 9 months or about 3 months to about 6 months apart from each other. In some embodiments, each immunogenic composition is administered to the subject from about 21 days to about 60 days apart from another immunogenic composition. In some embodiments, each immunogenic composition is administered to the subject from about 21 days to about 120 days apart from another immunogenic composition. In some embodiments, each immunogenic composition is administered to the subject from about 21 days to about 6 months apart from another immunogenic composition. In some embodiments, the method further comprises administering to the subject a third immunogenic composition a certain time after the administration of the second immunogenic composition to the subject, wherein the third immunogenic composition comprises a third chimeric HA and a CpG oligonucleotide adjuvant described herein, wherein the third chimeric HA comprises a third influenza virus HA globular head domain and a third influenza virus HA stalk domain, wherein the third HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA, wherein the third HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA, and the third HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the first HA globular head domain and the second HA globular head domain. In some embodiments, each immunogenic composition is administered to the subject intramuscularly or intranasally. In some embodiments, the inactivated influenza A virus in an immunogenic composition is administered to the subject at a dose provided herein. In some embodiments, the CpG oligonucleotide adjuvant in an immunogenic composition is administered to the subject at a dose provided herein.

[00344] In some embodiments, provided herein is a method of immunizing a subject (e.g., a human subject) against influenza virus disease (e.g., influenza virus disease caused by an influenza A virus, such as, e.g., influenza virus disease caused by a group 2 influenza A virus), comprising: (a) administering to the subject a first immunogenic composition comprising a first inactivated influenza virus and a CpG oligonucleotide adjuvant described herein, wherein the first inactivated influenza virus comprises a first chimeric HA, and wherein the first chimeric HA comprises a first influenza virus HA globular head domain and a first influenza virus HA stalk domain, wherein the first HA stalk domain comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA; and (b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second inactivated influenza virus and a CpG oligonucleotide adjuvant described herein, wherein the second inactivated influenza virus comprises a second chimeric HA, and wherein the second chimeric HA comprises a second influenza virus HA globular head domain and a second influenza virus HA stalk domain, wherein the second HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA, wherein the second HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the second HA globular head domain. In some embodiments, the first and second immunogenic compositions each comprise an aluminum salt. The aluminum salt in the first and second immunogenic compositions may or may not be the same. In some embodiments, the first and second immunogenic compositions do not comprise an aluminum salt. In some embodiments, an aluminum salt is administered to the subject concurrently or about 1 hour (or about 45 minutes, about 30 minutes, or about 15 minutes) before or after the administration of the first immunogenic composition. In some embodiments, an aluminum salt is administered to the subject concurrently or about 1 hour (or about 45 minutes, about 30 minutes, or about 15 minutes) before or after the administration of the second immunogenic composition. In some embodiments, the first and second immunogenic compositions are administered to the subject from about 2 months to about 9 months apart from each other. In some embodiments, the first and second immunogenic compositions are administered to the subject from about 3 months to about 9 months or about 3 months to about 6 months apart from each other. In some embodiments, the first and second immunogenic compositions are administered to the subject from about 21 days to about 60 days apart from each other. In some embodiments, the first and second immunogenic compositions are administered to the subject from about 21 days to about 120 days apart from each other. In some embodiments, the first and second immunogenic compositions are administered to the subject from about 60 days to about 120 days apart from each other. In some embodiments, the method further comprises administering to the subject a third immunogenic composition a certain time after the administration of the second immunogenic composition to the subject, wherein the third immunogenic composition comprises a third inactivated influenza virus and a CpG oligonucleotide adjuvant described herein, wherein the third inactivated influenza virus comprises a third chimeric HA, and wherein the third chimeric HA comprises a third influenza virus HA globular head domain and a third influenza virus HA stalk domain, wherein the third HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA, wherein the third HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA, and wherein the third HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the first HA globular head domain and the second HA globular head domain. In some embodiments, each immunogenic composition is administered to the subject intramuscularly or intranasally. In some embodiments, the chimeric HA in an immunogenic composition is administered to the subject at a dose provided herein. In some embodiments, the CpG oligonucleotide adjuvant in an immunogenic composition is administered to the subject at a dose provided herein.

[00345] In some embodiments, provided herein is a method of immunizing a subject (e.g., a human subject) against influenza virus disease (e.g., influenza virus disease caused by an influenza A virus, such as, e.g., influenza virus disease caused by a group 2 influenza A virus), comprising: (a) administering to the subject a first immunogenic composition comprising a first inactivated split influenza virus and a CpG oligonucleotide adjuvant described herein, wherein the first inactivated split influenza virus comprises a first chimeric HA, and wherein the first chimeric HA comprises a first influenza virus HA globular head domain and a first influenza virus HA stalk domain, wherein the first HA stalk domain comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA; and (b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second inactivated split influenza virus and a CpG oligonucleotide adjuvant described herein, wherein the second inactivated split influenza virus comprises a second chimeric HA, and wherein the second chimeric HA comprises a second influenza virus HA globular head domain and a second influenza virus HA stalk domain, wherein the second HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA, wherein the second HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the second HA globular head domain. In some embodiments, the first and second immunogenic compositions each comprise an aluminum salt. The aluminum salt in the first and second immunogenic compositions may or may not be the same. In some embodiments, the first and second immunogenic compositions do not comprise an aluminum salt. In some embodiments, an aluminum salt is administered to the subject concurrently or about 1 hour (or about 45 minutes, about 30 minutes, or about 15 minutes) before or after the administration of the first immunogenic composition. In some embodiments, an aluminum salt is administered to the subject concurrently or about 1 hour (or about 45 minutes, about 30 minutes, or about 15 minutes) before or after the administration of the second immunogenic composition. In some embodiments, the first and second immunogenic compositions are administered to the subject from about 2 months to about 9 months apart from each other. In some embodiments, the first and second immunogenic compositions are administered to the subject from about 3 months to about 9 months or about 3 months to about 6 months apart from each other. In some embodiments, the first and second immunogenic compositions are administered to the subject from about 21 days to about 60 days apart from each other. In some embodiments, the first and second immunogenic compositions are administered to the subject from about 21 days to about 120 days apart from each other. In some embodiments, the first and second immunogenic compositions are administered to the subject from about 60 days to about 120 days apart from each other. In some embodiments, the method further comprises administering to the subject a third immunogenic composition a certain time after the administration of the second immunogenic composition to the subject, wherein the third immunogenic composition comprises a third inactivated split influenza virus and a CpG oligonucleotide adjuvant described herein, wherein the third inactivated split influenza virus comprises a third chimeric HA, and wherein the third chimeric HA comprises a third influenza virus HA globular head domain and a third influenza virus HA stalk domain, wherein the third HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA, wherein the third HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA, and wherein the third HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the first HA globular head domain and the second HA globular head domain. In some embodiments, each immunogenic composition is administered to the subject intramuscularly or intranasally. In some embodiments, the chimeric HA in an immunogenic composition is administered to the subject at a dose provided herein. In some embodiments, the CpG oligonucleotide adjuvant in an immunogenic composition is administered to the subject at a dose provided herein.

[00346] In some embodiments, provided herein is a method of inducing an immune response to influenza A viruses (e.g., a cross-reactive immune response to group 2 influenza A viruses) in a subject (e.g., a human subject), comprising: (a) administering to the subject a first immunogenic composition comprising a live attenuated influenza A virus and a CpG oligonucleotide adjuvant described herein, wherein the live attenuated influenza A virus comprises a first chimeric HA, and wherein the first chimeric HA comprises a first influenza virus HA globular head domain and a first influenza virus HA stalk domain, wherein the first HA stalk domain comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA; and (b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising an inactivated influenza virus and a CpG oligonucleotide adjuvant described herein, wherein the inactivated influenza virus comprises a second chimeric HA, and wherein the second chimeric HA comprises a second influenza virus HA globular head domain and a second influenza virus HA stalk domain, wherein the second HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA, and wherein the second HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the second HA globular head domain. In some embodiments, the second immunogenic composition comprises an aluminum salt. In some embodiments, the second immunogenic composition does not comprise an aluminum salt. In some embodiments, an aluminum salt is administered to the subject concurrently or about 1 hour (or about 45 minutes, about 30 minutes, or about 15 minutes) before or after the administration of the second immunogenic composition. In some embodiments, the first and second immunogenic compositions are administered to the subject from about 2 months to about 9 months apart from each other. In some embodiments, the first and second immunogenic compositions are administered to the subject from about 3 months to about 9 months or about 3 months to about 6 months apart from each other. In some embodiments, the first and second immunogenic compositions are administered to the subject from about 21 days to about 60 days apart from each other. In some embodiments, the first and second immunogenic compositions are administered to the subject from about 21 days to about 120 days apart from each other. In some embodiments, the first and second immunogenic compositions are administered to the subject from about 60 days to about 120 days apart from each other. In some embodiments, each immunogenic composition is administered to the subject from about 21 days to about 6 months apart from another immunogenic composition. In some embodiments, the method further comprises administering to the subject a third immunogenic composition a certain time after the administration of the second immunogenic composition to the subject, wherein the third immunogenic composition comprises a second inactivated influenza virus and a CpG oligonucleotide adjuvant described herein, wherein the second inactivated influenza virus comprises a third chimeric HA, and wherein the third chimeric HA comprises a third influenza virus HA globular head domain and a third influenza virus HA stalk domain, wherein the third HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA, wherein the third HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA, and wherein the third HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the first HA globular head domain and the second HA globular head domain. In some embodiments, each immunogenic composition is administered to the subject intramuscularly or intranasally. In some embodiments, the live attenuated influenza A virus in an immunogenic composition is administered to the subject at a dose provided herein. In some embodiments, the chimeric HA in an immunogenic composition is administered to the subject at a dose provided herein. In some embodiments, the CpG oligonucleotide adjuvant in an immunogenic composition is administered to the subject at a dose provided herein.

[00347] In some embodiments, provided herein is a method of inducing an immune response to influenza A viruses (e.g., a cross-reactive immune response to group 2 influenza A viruses) in a subject (e.g., a human subject), comprising: (a) administering to the subject a first immunogenic composition comprising a live attenuated influenza A virus and a CpG oligonucleotide adjuvant described herein, wherein the live attenuated influenza A virus comprises a first chimeric HA, and wherein the first chimeric HA comprises a first influenza virus HA globular head domain and a first influenza virus HA stalk domain, wherein the first HA stalk domain comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA; and (b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising an inactivated split influenza virus and a CpG oligonucleotide adjuvant described herein, wherein the inactivated split influenza virus comprises a second chimeric HA, and wherein the second chimeric HA comprises a second influenza virus HA globular head domain and a second influenza virus HA stalk domain, wherein the second HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA, and wherein the second HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the second HA globular head domain. In some embodiments, the second immunogenic composition comprises an aluminum salt. In some embodiments, the second immunogenic composition does not comprise an aluminum salt. In some embodiments, an aluminum salt is administered to the subject concurrently or about 1 hour (or about 45 minutes, about 30 minutes, or about 15 minutes) before or after the administration of the second immunogenic composition. In some embodiments, the first and second immunogenic compositions are administered to the subject from about 2 months to about 9 months apart from each other. In some embodiments, the first and second immunogenic compositions are administered to the subject from about 3 months to about 9 months or about 3 months to about 6 months apart from each other. In some embodiments, the first and second immunogenic compositions are administered to the subject from about 21 days to about 60 days apart from each other. In some embodiments, the first and second immunogenic compositions are administered to the subject from about 21 days to about 120 days apart from each other. In some embodiments, the first and second immunogenic compositions are administered to the subject from about 60 days to about 120 days apart from each other. In some embodiments, each immunogenic composition is administered to the subject from about 21 days to about 60 days apart from another immunogenic composition. In some embodiments, each immunogenic composition is administered to the subject from about 21 days to about 120 days apart from another immunogenic composition. In some embodiments, each immunogenic composition is administered to the subject from about 21 days to about 6 months apart from another immunogenic composition. In some embodiments, the method further comprises administering to the subject a third immunogenic composition a certain time after the administration of the second immunogenic composition to the subject, wherein the third immunogenic composition comprises a second inactivated split influenza virus and a CpG oligonucleotide adjuvant described herein, wherein the second inactivated split influenza virus comprises a third chimeric HA, and wherein the third chimeric HA comprises a third influenza virus HA globular head domain and a third influenza virus HA stalk domain, wherein the third HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA, wherein the third HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA, and wherein the third HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the first HA globular head domain and the second HA globular head domain. In some embodiments, each immunogenic composition is administered to the subject intramuscularly or intranasally. In some embodiments, the live attenuated influenza A virus in an immunogenic composition is administered to the subject at a dose provided herein. In some embodiments, the chimeric HA in an immunogenic composition is administered to the subject at a dose provided herein. In some embodiments, the CpG oligonucleotide adjuvant in an immunogenic composition is administered to the subject at a dose provided herein.

[00348] In some embodiments, provided herein is a method of preventing influenza virus disease (e.g., influenza virus disease caused by an influenza A virus, such as, e.g., influenza virus disease caused by a group 2 influenza A virus) in a subject (e.g., a human subject), comprising: (a) administering to the subject a first immunogenic composition comprising a live attenuated influenza A virus and a CpG oligonucleotide adjuvant described herein, wherein the live attenuated influenza A virus comprises a first chimeric HA, and wherein the first chimeric HA comprises a first influenza virus HA globular head domain and a first influenza virus HA stalk domain, wherein the first HA stalk domain comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA; and (b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising an inactivated influenza virus and a CpG oligonucleotide adjuvant described herein, wherein the inactivated influenza virus comprises a second chimeric HA, and wherein the second chimeric HA comprises a second influenza virus HA globular head domain and a second influenza virus HA stalk domain, wherein the second HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA, and wherein the second HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the second HA globular head domain. In some embodiments, the second immunogenic composition comprises an aluminum salt. In some embodiments, the second immunogenic composition does not comprise an aluminum salt. In some embodiments, an aluminum salt is administered to the subject concurrently or about 1 hour (or about 45 minutes, about 30 minutes, or about 15 minutes) before or after the administration of the second immunogenic composition. In some embodiments, the first and second immunogenic compositions are administered to the subject from about 2 months to about 9 months apart from each other. In some embodiments, the first and second immunogenic compositions are administered to the subject from about 3 months to about 9 months or about 3 months to about 6 months apart from each other. In some embodiments, the first and second immunogenic compositions are administered to the subject from about 21 days to about 60 days apart from each other. In some embodiments, the first and second immunogenic compositions are administered to the subject from about 21 days to about 120 days apart from each other. In some embodiments, the first and second immunogenic compositions are administered to the subject from about 60 days to about 120 days apart from each other. In some embodiments, each immunogenic composition is administered to the subject from about 21 days to about 6 months apart from another immunogenic composition. In some embodiments, the method further comprises administering to the subject a third immunogenic composition a certain time after the administration of the second immunogenic composition to the subject, wherein the third immunogenic composition comprises a second inactivated influenza virus and a CpG oligonucleotide adjuvant described herein, wherein the second inactivated influenza virus comprises a third chimeric HA, and wherein the third chimeric HA comprises a third influenza virus HA globular head domain and a third influenza virus HA stalk domain, wherein the third HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA, wherein the third HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA, and wherein the third HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the first HA globular head domain and the second HA globular head domain. In some embodiments, each immunogenic composition is administered to the subject intramuscularly or intranasally. In some embodiments, the live attenuated influenza A virus in an immunogenic composition is administered to the subject at a dose provided herein. In some embodiments, the chimeric HA in an immunogenic composition is administered to the subject at a dose provided herein. In some embodiments, the CpG oligonucleotide adjuvant in an immunogenic composition is administered to the subject at a dose provided herein. [00349] In some embodiments, provided herein is a method of preventing influenza virus disease (e.g., influenza virus disease caused by an influenza A virus, such as, e.g., influenza virus disease caused by a group 2 influenza A virus) in a subject (e.g., a human subject), comprising: (a) administering to the subject a first immunogenic composition comprising a live attenuated influenza A virus and a CpG oligonucleotide adjuvant described herein, wherein the live attenuated influenza A virus comprises a first chimeric HA, and wherein the first chimeric HA comprises a first influenza virus HA globular head domain and a first influenza virus HA stalk domain, wherein the first HA stalk domain comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA; and (b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising an inactivated split influenza virus and a CpG oligonucleotide adjuvant described herein, wherein the inactivated split influenza virus comprises a second chimeric HA, and wherein the second chimeric HA comprises a second influenza virus HA globular head domain and a second influenza virus HA stalk domain, wherein the second HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA, and wherein the second HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the second HA globular head domain. In some embodiments, the second immunogenic composition comprises an aluminum salt. In some embodiments, the second immunogenic composition does not comprise an aluminum salt. In some embodiments, an aluminum salt is administered to the subject concurrently or about 1 hour (or about 45 minutes, about 30 minutes, or about 15 minutes) before or after the administration of the second immunogenic composition. In some embodiments, the first and second immunogenic compositions are administered to the subject from about 2 months to about 9 months apart from each other. In some embodiments, the first and second immunogenic compositions are administered to the subject from about 3 months to about 9 months or about 3 months to about 6 months apart from each other. In some embodiments, the first and second immunogenic compositions are administered to the subject from about 21 days to about 60 days apart from each other. In some embodiments, the first and second immunogenic compositions are administered to the subject from about 21 days to about 120 days apart from each other. In some embodiments, the first and second immunogenic compositions are administered to the subject from about 60 days to about 120 days apart from each other. In some embodiments, each immunogenic composition is administered to the subject from about 21 days to about 6 months apart from another immunogenic composition. In some embodiments, the method further comprises administering to the subject a third immunogenic composition a certain time after the administration of the second immunogenic composition to the subject, wherein the third immunogenic composition comprises a second inactivated split influenza virus and a CpG oligonucleotide adjuvant described herein, wherein the second inactivated split influenza virus comprises a third chimeric HA, and wherein the third chimeric HA comprises a third influenza virus HA globular head domain and a third influenza virus HA stalk domain, wherein the third HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA, wherein the third HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA, and wherein the third HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the first HA globular head domain and the second HA globular head domain. In some embodiments, each immunogenic composition is administered to the subject intramuscularly or intranasally. In some embodiments, the live attenuated influenza A virus in an immunogenic composition is administered to the subject at a dose provided herein. In some embodiments, the chimeric HA in an immunogenic composition is administered to the subject at a dose provided herein. In some embodiments, the CpG oligonucleotide adjuvant in an immunogenic composition is administered to the subject at a dose provided herein.

[00350] In some embodiments, provided herein is a method of immunizing a subject (e.g., a human subject) against influenza virus disease (e.g., influenza virus disease caused by an influenza A virus, such as, e.g., influenza virus disease caused by a group 2 influenza A virus), comprising: (a) administering to the subject a first immunogenic composition comprising a live attenuated influenza A virus and a CpG oligonucleotide adjuvant described herein, wherein the live attenuated influenza A virus comprises a first chimeric HA, and wherein the first chimeric HA comprises a first influenza virus HA globular head domain and a first influenza virus HA stalk domain, wherein the first HA stalk domain comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA; and (b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising an inactivated influenza virus and a CpG oligonucleotide adjuvant described herein, wherein the inactivated influenza virus comprises a second chimeric HA, and wherein the second chimeric HA comprises a second influenza virus HA globular head domain and a second influenza virus HA stalk domain, wherein the second HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA, and wherein the second HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the second HA globular head domain. In some embodiments, the second immunogenic composition comprises an aluminum salt. In some embodiments, the second immunogenic composition does not comprise an aluminum salt. In some embodiments, an aluminum salt is administered to the subject concurrently or about 1 hour (or about 45 minutes, about 30 minutes, or about 15 minutes) before or after the administration of the second immunogenic composition. In some embodiments, the first and second immunogenic compositions are administered to the subject from about 2 months to about 9 months apart from each other. In some embodiments, the first and second immunogenic compositions are administered to the subject from about 3 months to about 9 months or about 3 months to about 6 months apart from each other. In some embodiments, the first and second immunogenic compositions are administered to the subject from about 21 days to about 60 days apart from each other. In some embodiments, the first and second immunogenic compositions are administered to the subject from about 21 days to about 120 days apart from each other. In some embodiments, the first and second immunogenic compositions are administered to the subject from about 60 days to about 120 days apart from each other. In some embodiments, each immunogenic composition is administered to the subject from about 21 days to about 6 months apart from another immunogenic composition. In some embodiments, the method further comprises administering to the subject a third immunogenic composition a certain time after the administration of the second immunogenic composition to the subject, wherein the third immunogenic composition comprises a second inactivated influenza virus and a CpG oligonucleotide adjuvant described herein, wherein the second inactivated influenza virus comprises a third chimeric HA, and wherein the third chimeric HA comprises a third influenza virus HA globular head domain and a third influenza virus HA stalk domain, wherein the third HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA, wherein the third HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA, and wherein the third HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the first HA globular head domain and the second HA globular head domain. In some embodiments, each immunogenic composition is administered to the subject intramuscularly or intranasally. In some embodiments, the live attenuated influenza A virus in an immunogenic composition is administered to the subject at a dose provided herein. In some embodiments, the chimeric HA in an immunogenic composition is administered to the subject at a dose provided herein. In some embodiments, the CpG oligonucleotide adjuvant in an immunogenic composition is administered to the subject at a dose provided herein. [00351] In some embodiments, provided herein is a method of immunizing a subject (e.g., a human subject) against influenza virus disease (e.g., influenza virus disease caused by an influenza A virus, such as, e.g., influenza virus disease caused by a group 2 influenza A virus), comprising: (a) administering to the subject a first immunogenic composition comprising a live attenuated influenza A virus and a CpG oligonucleotide adjuvant described herein, wherein the live attenuated influenza A virus comprises a first chimeric HA, and wherein the first chimeric HA comprises a first influenza virus HA globular head domain and a first influenza virus HA stalk domain, wherein the first HA stalk domain comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA; and (b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising an inactivated split influenza virus and a CpG oligonucleotide adjuvant described herein, wherein the inactivated split influenza virus comprises a second chimeric HA, and wherein the second chimeric HA comprises a second influenza virus HA globular head domain and a second influenza virus HA stalk domain, wherein the second HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA, and wherein the second HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the second HA globular head domain. In some embodiments, the second immunogenic composition comprises an aluminum salt. In some embodiments, the second immunogenic composition does not comprise an aluminum salt. In some embodiments, an aluminum salt is administered to the subject concurrently or about 1 hour (or about 45 minutes, about 30 minutes, or about 15 minutes) before or after the administration of the second immunogenic composition. In some embodiments, the first and second immunogenic compositions are administered to the subject from about 2 months to about 9 months apart from each other. In some embodiments, the first and second immunogenic compositions are administered to the subject from about 3 months to about 9 months or about 3 months to about 6 months apart from each other. In some embodiments, the first and second immunogenic compositions are administered to the subject from about 21 days to about 60 days apart from each other. In some embodiments, the first and second immunogenic compositions are administered to the subject from about 21 days to about 120 days apart from each other. In some embodiments, the first and second immunogenic compositions are administered to the subject from about 60 days to about 120 days apart from each other. In some embodiments, each immunogenic composition is administered to the subject from about 21 days to about 6 months apart from another immunogenic composition. In some embodiments, the method further comprises administering to the subject a third immunogenic composition a certain time after the administration of the second immunogenic composition to the subject, wherein the third immunogenic composition comprises a second inactivated split influenza virus and a CpG oligonucleotide adjuvant described herein, wherein the second inactivated split influenza virus comprises a third chimeric HA, and wherein the third chimeric HA comprises a third influenza virus HA globular head domain and a third influenza virus HA stalk domain, wherein the third HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA, wherein the third HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA, and wherein the third HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the first HA globular head domain and the second HA globular head domain. In some embodiments, each immunogenic composition is administered to the subject intramuscularly or intranasally. In some embodiments, the live attenuated influenza A virus in an immunogenic composition is administered to the subject at a dose provided herein. In some embodiments, the chimeric HA in an immunogenic composition is administered to the subject at a dose provided herein. In some embodiments, the CpG oligonucleotide adjuvant in an immunogenic composition is administered to the subject at a dose provided herein. [00352] In some embodiments, provided herein is a method of preventing influenza virus disease in a subject (e.g., a human subject), comprising: (a) administering to the subject a first immunogenic composition comprising a first chimeric HA and a CpG oligonucleotide adjuvant described herein, wherein the first chimeric HA comprises the HA globular head domain of influenza virus A/wedge-tailed/shearwater/ Western Australia/2576/1979 HA and the HA stalk domain of influenza virus A/Hong Kong/48012014 (H3N2) NYMC X-263; and (b) administering to the subject a second immunogenic composition comprising a second chimeric HA and a CpG oligonucleotide adjuvant described herein, wherein the second chimeric HA comprises the HA globular head domain of influenza virus A/duck/Czechoslovakia/1956 (H4N6) and the HA stalk domain of influenza virus A/Hong Kong/48012014 (H3N2) NYMC X-263. In some embodiments, provided herein is a method of preventing influenza virus disease in a subject (e.g., a human subject), comprising: (a) administering to the subject a first immunogenic composition comprising a first inactivated influenza virus and a CpG oligonucleotide adjuvant described herein, wherein the first inactivated influenza virus comprises a first chimeric HA, wherein the first chimeric HA comprises the HA globular head domain of influenza virus A/wedge-tailed/shearwater/ Western Australia/2576/1979 HA and the HA stalk domain of influenza virus A/Hong Kong/48012014 (H3N2) NYMC X-263; and (b) administering to the subject a second immunogenic composition comprising a second inactivated influenza virus and a CpG oligonucleotide adjuvant described herein, wherein the second inactivated influenza virus comprises a second chimeric HA, wherein the second chimeric HA comprises the HA globular head domain of influenza virus A/duck/Czechoslovakia/1956 (H4N6) and the HA stalk domain of influenza virus A/Hong Kong/48012014 (H3N2) NYMC X-263. In some embodiments, the first inactivated influenza virus and/or the second inactivated influenza virus comprise the neuraminidase of influenza virus A/Hong Kong/48012014 (H3N2) NYMC X-263. In some embodiments, the first inactivated influenza virus and/or the second inactivated influenza virus comprise proteins (e.g., non- structural proteins and matrix protein) encoded by genes from influenza virus A/Puerto Rico/08/1934 (H1N1). In some embodiments, provided herein is a method of preventing influenza virus disease in a subject (e.g., a human subject), comprising: (a) administering to the subject a first immunogenic composition comprising a first inactivated split influenza virus and a CpG oligonucleotide adjuvant described herein, wherein the first inactivated split influenza virus comprises a first chimeric HA, wherein the first chimeric HA comprises the HA globular head domain of influenza virus A/wedge-tailed/shearwater/ Western Australia/2576/1979 HA and the HA stalk domain of influenza virus A/Hong Kong/48012014 (H3N2) NYMC X-263; and (b) administering to the subject a second immunogenic composition comprising a second inactivated split influenza virus and a CpG oligonucleotide adjuvant described herein, wherein the second inactivated split influenza virus comprises a second chimeric HA, wherein the second chimeric HA comprises the HA globular head domain of influenza virus A/duck/Czechoslovakia/1956 (H4N6) and the HA stalk domain of influenza virus A/Hong Kong/48012014 (H3N2) NYMC X-263. In some embodiments, the first inactivated split influenza virus and/or the second inactivated split influenza virus comprise the neuraminidase of influenza virus A/Hong Kong/48012014 (H3N2) NYMC X-263. In some embodiments, the first inactivated split influenza virus and/or the second inactivated split influenza virus comprise proteins (e.g., non- structural proteins and matrix protein) encoded by genes from influenza virus A/Puerto Rico/08/1934 (H1N1). In some embodiments, the first immunogenic composition and/or the second immunogenic composition comprises an aluminum salt. In some embodiments, the first immunogenic composition and/or the second immunogenic composition does not comprise an aluminum salt. In some embodiments, an aluminum salt is administered to the subject concurrently or about 1 hour (or about 45 minutes, about 30 minutes, or about 15 minutes) before or after the administration of the first immunogenic composition and/or the second immunogenic composition. In some embodiments, the aluminum salt comprises amorphous aluminum hydroxyphosphate sulfate, aluminum hydroxide, aluminum phosphate, and potassium aluminum sulfate. In some embodiments, the first and second immunogenic compositions are administered to the subject from about 2 months to about 9 months apart from each other. In some embodiments, the first and second immunogenic compositions are administered to the subject from about 3 months to about 9 months or about 3 months to about 6 months apart from each other. In some embodiments, the first and second immunogenic compositions are administered to the subject from about 21 days to about 60 days apart from each other. In some embodiments, the first and second immunogenic compositions are administered to the subject from about 21 days to about 120 days apart from each other. In some embodiments, the first and second immunogenic compositions are administered to the subject from about 60 days to about 120 days apart from each other. In some embodiments, each immunogenic composition is administered to the subject intramuscularly or intranasally. In some embodiments, the live attenuated influenza A virus in an immunogenic composition is administered to the subject at a dose provided herein. In some embodiments, the CpG oligonucleotide adjuvant comprises the nucleotide sequence of SEQ ID NO: 3 or 4. In some embodiments, the CpG oligonucleotide adjuvant comprises CpG 1018® adjuvant. In some embodiments, the chimeric HA in an immunogenic composition is administered to the subject at a dose provided herein. In some embodiments, the CpG oligonucleotide adjuvant in an immunogenic composition is administered to the subject at a dose provided herein. In some embodiments, the aluminum salt in an immunogenic composition is administered to the subject at a dose provided herein.

[00353] In some embodiments, provided herein is a method of immunizing a subject (e.g., a human subject) against influenza virus disease (e.g., influenza virus disease caused by an influenza A virus, such as, e.g., influenza virus disease caused by a group 2 influenza A virus), comprising: (a) administering to the subject a first immunogenic composition comprising a first chimeric HA and a CpG oligonucleotide adjuvant described herein, wherein the first chimeric HA comprises the HA globular head domain of influenza virus A/wedge-tailed/shearwater/ Western Australia/2576/1979 HA and the HA stalk domain of influenza virus A/Hong Kong/48012014 (H3N2) NYMC X-263; and (b) administering to the subject a second immunogenic composition comprising a second chimeric HA and a CpG oligonucleotide adjuvant described herein, wherein the second chimeric HA comprises the HA globular head domain of influenza virus A/duck/Czechoslovakia/1956 (H4N6) and the HA stalk domain of influenza virus A/Hong Kong/48012014 (H3N2) NYMC X-263. In some embodiments, provided herein is a method of immunizing a subject (e.g., a human subject) against influenza virus disease (e.g., influenza virus disease caused by an influenza A virus, such as, e.g., influenza virus disease caused by a group 2 influenza A virus), comprising: (a) administering to the subject a first immunogenic composition comprising a first inactivated influenza virus and a CpG oligonucleotide adjuvant described herein, wherein the first inactivated influenza virus comprises a first chimeric HA, wherein the first chimeric HA comprises the HA globular head domain of influenza virus A/wedge- tailed/shearwater/ Western Australia/2576/1979 HA and the HA stalk domain of influenza virus A/Hong Kong/48012014 (H3N2) NYMC X-263; and (b) administering to the subject a second immunogenic composition comprising a second inactivated influenza virus and a CpG oligonucleotide adjuvant described herein, wherein the second inactivated influenza virus comprises a second chimeric HA, wherein the second chimeric HA comprises the HA globular head domain of influenza virus A/duck/Czechoslovakia/1956 (H4N6) and the HA stalk domain of influenza virus A/Hong Kong/48012014 (H3N2) NYMC X-263. In some embodiments, the first inactivated influenza virus and/or the second inactivated influenza virus comprise the neuraminidase of influenza virus A/Hong Kong/48012014 (H3N2) NYMC X-263. In some embodiments, the first inactivated influenza virus and/or the second inactivated influenza virus comprise proteins (e.g., non- structural proteins and matrix protein) encoded by genes from influenza virus A/Puerto Rico/08/1934 (H1N1). In some embodiments, provided herein is a method of immunizing a subject (e.g., a human subject) against influenza virus disease (e.g., influenza virus disease caused by an influenza A virus, such as, e.g., influenza virus disease caused by a group 2 influenza A virus), comprising: (a) administering to the subject a first immunogenic composition comprising a first inactivated split influenza virus and a CpG oligonucleotide adjuvant described herein, wherein the first inactivated split influenza virus comprises a first chimeric HA, wherein the first chimeric HA comprises the HA globular head domain of influenza virus A/wedge-tailed/shearwater/ Western Australia/2576/1979 HA and the HA stalk domain of influenza virus A/Hong Kong/48012014 (H3N2) NYMC X-263; and (b) administering to the subject a second immunogenic composition comprising a second inactivated split influenza virus and a CpG oligonucleotide adjuvant described herein, wherein the second inactivated split influenza virus comprises a second chimeric HA, wherein the second chimeric HA comprises the HA globular head domain of influenza virus A/duck/Czechoslovakia/1956 (H4N6) and the HA stalk domain of influenza virus A/Hong Kong/48012014 (H3N2) NYMC X-263. In some embodiments, the first inactivated split influenza virus and/or the second inactivated split influenza virus comprise the neuraminidase of influenza virus A/Hong Kong/48012014 (H3N2) NYMC X-263. In some embodiments, the first inactivated split influenza virus and/or the second inactivated split influenza virus comprise proteins (e.g., non- structural proteins and matrix protein) encoded by genes from influenza virus A/Puerto Rico/08/1934 (H1N1). In some embodiments, the first immunogenic composition and/or the second immunogenic composition comprises an aluminum salt. In some embodiments, the first immunogenic composition and/or the second immunogenic composition does not comprise an aluminum salt. In some embodiments, an aluminum salt is administered to the subject concurrently or about 1 hour (or about 45 minutes, about 30 minutes, or about 15 minutes) before or after the administration of the first immunogenic composition and/or the second immunogenic composition. In some embodiments, the aluminum salt comprises amorphous aluminum hydroxyphosphate sulfate, aluminum hydroxide, aluminum phosphate, and potassium aluminum sulfate. In some embodiments, the first and second immunogenic compositions are administered to the subject from about 2 months to about 9 months apart from each other. In some embodiments, the first and second immunogenic compositions are administered to the subject from about 3 months to about 9 months or about 3 months to about 6 months apart from each other. In some embodiments, the first and second immunogenic compositions are administered to the subject from about 21 days to about 60 days apart from each other. In some embodiments, the first and second immunogenic compositions are administered to the subject from about 21 days to about 120 days apart from each other. In some embodiments, the first and second immunogenic compositions are administered to the subject from about 60 days to about 120 days apart from each other. In some embodiments, each immunogenic composition is administered to the subject intramuscularly or intranasally. In some embodiments, the live attenuated influenza A virus in an immunogenic composition is administered to the subject at a dose provided herein. In some embodiments, the chimeric HA in an immunogenic composition is administered to the subject at a dose provided herein. In some embodiments, the CpG oligonucleotide adjuvant comprises the nucleotide sequence of SEQ ID NO: 3 or 4. In some embodiments, the CpG oligonucleotide adjuvant comprises CpG 1018® adjuvant. In some embodiments, the CpG oligonucleotide adjuvant in an immunogenic composition is administered to the subject at a dose provided herein. In some embodiments, the aluminum salt in an immunogenic composition is administered to the subject at a dose provided herein.

[00354] In some embodiments, provided herein is a method of inducing an immune response to influenza A viruses (e.g., a cross-reactive immune response to group 2 influenza A viruses) in a subject (e.g., a human subject), comprising: (a) administering to the subject a first immunogenic composition comprising a first chimeric HA and a CpG oligonucleotide adjuvant described herein, wherein the first chimeric HA comprises the HA globular head domain of influenza virus A/wedge-tailed/shearwater/ Western Australia/2576/1979 HA and the HA stalk domain of influenza virus A/Hong Kong/48012014 (H3N2) NYMC X-263; and (b) administering to the subject a second immunogenic composition comprising a second chimeric HA and a CpG oligonucleotide adjuvant described herein, wherein the second chimeric HA comprises the HA globular head domain of influenza virus A/duck/Czechoslovakia/1956 (H4N6) and the HA stalk domain of influenza virus A/Hong Kong/48012014 (H3N2) NYMC X-263. In some embodiments, provided herein is a method of inducing an immune response to influenza A viruses (e.g., a cross-reactive immune response to group 2 influenza A viruses) in a subject (e.g., a human subject), comprising: (a) administering to the subject a first immunogenic composition comprising a first inactivated influenza virus and a CpG oligonucleotide adjuvant described herein, wherein the first inactivated influenza virus comprises a first chimeric HA, wherein the first chimeric HA comprises the HA globular head domain of influenza virus A/wedge-tailed/shearwater/ Western Australia/2576/1979 HA and the HA stalk domain of influenza virus A/Hong Kong/48012014 (H3N2) NYMC X-263; and (b) administering to the subject a second immunogenic composition comprising a second inactivated influenza virus and a CpG oligonucleotide adjuvant described herein, wherein the second inactivated influenza virus comprises a second chimeric HA, wherein the second chimeric HA comprises the HA globular head domain of influenza virus A/duck/Czechoslovakia/1956 (H4N6) and the HA stalk domain of influenza virus A/Hong Kong/48012014 (H3N2) NYMC X-263. In some embodiments, the first inactivated influenza virus and/or the second inactivated influenza virus comprise the neuraminidase of influenza virus A/Hong Kong/48012014 (H3N2) NYMC X-263. In some embodiments, the first inactivated influenza virus and/or the second inactivated influenza virus comprise proteins (e.g., non- structural proteins and matrix protein) encoded by genes from influenza virus A/Puerto Rico/08/1934 (H1N1). In some embodiments, provided herein is a method of inducing an immune response to influenza A viruses (e.g., a cross-reactive immune response to group 2 influenza A viruses) in a subject (e.g., a human subject), comprising: (a) administering to the subject a first immunogenic composition comprising a first inactivated split influenza virus and a CpG oligonucleotide adjuvant described herein, wherein the first inactivated split influenza virus comprises a first chimeric HA, wherein the first chimeric HA comprises the HA globular head domain of influenza virus A/wedge-tailed/shearwater/ Western Australia/2576/1979 HA and the HA stalk domain of influenza virus A/Hong Kong/48012014 (H3N2) NYMC X-263; and (b) administering to the subject a second immunogenic composition comprising a second inactivated split influenza virus and a CpG oligonucleotide adjuvant described herein, wherein the second inactivated split influenza virus comprises a second chimeric HA, wherein the second chimeric HA comprises the HA globular head domain of influenza virus A/duck/Czechoslovakia/1956 (H4N6) and the HA stalk domain of influenza virus A/Hong Kong/48012014 (H3N2) NYMC X-263. In some embodiments, the first inactivated split influenza virus and/or the second inactivated split influenza virus comprise the neuraminidase of influenza virus A/Hong Kong/48012014 (H3N2) NYMC X-263. In some embodiments, the first inactivated split influenza virus and/or the second inactivated split influenza virus comprise proteins (e.g., non- structural proteins and matrix protein) encoded by genes from influenza virus A/Puerto Rico/08/1934 (H1N1). In some embodiments, the first immunogenic composition and/or the second immunogenic composition comprises an aluminum salt. In some embodiments, the first immunogenic composition and/or the second immunogenic composition does not comprise an aluminum salt. In some embodiments, an aluminum salt is administered to the subject concurrently or about 1 hour (or about 45 minutes, about 30 minutes, or about 15 minutes) before or after the administration of the first immunogenic composition and/or the second immunogenic composition. In some embodiments, the aluminum salt comprises amorphous aluminum hydroxyphosphate sulfate, aluminum hydroxide, aluminum phosphate, and potassium aluminum sulfate. In some embodiments, the first and second immunogenic compositions are administered to the subject from about 2 months to about 9 months apart from each other. In some embodiments, the first and second immunogenic compositions are administered to the subject from about 3 months to about 9 months or about 3 months to about 6 months apart from each other. In some embodiments, the first and second immunogenic compositions are administered to the subject from about 21 days to about 60 days apart from each other. In some embodiments, the first and second immunogenic compositions are administered to the subject from about 21 days to about 120 days apart from each other. In some embodiments, the first and second immunogenic compositions are administered to the subject from about 60 days to about 120 days apart from each other. In some embodiments, each immunogenic composition is administered to the subject intramuscularly or intranasally. In some embodiments, the live attenuated influenza A virus in an immunogenic composition is administered to the subject at a dose provided herein. In some embodiments, the chimeric HA in an immunogenic composition is administered to the subject at a dose provided herein. In some embodiments, the CpG oligonucleotide adjuvant comprises the nucleotide sequence of SEQ ID NO: 3 or 4. In some embodiments, the CpG oligonucleotide adjuvant comprises CpG 1018® adjuvant. In some embodiments, the CpG oligonucleotide adjuvant in an immunogenic composition is administered to the subject at a dose provided herein. In some embodiments, the aluminum salt in an immunogenic composition is administered to the subject at a dose provided herein. [00355] In some embodiments, provided herein is a method of preventing influenza virus disease in a subject (e.g., a human subject), comprising: (a) administering to the subject a first immunogenic composition comprising a first chimeric HA and a CpG oligonucleotide adjuvant described herein, wherein the first chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8; and (b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second chimeric HA and a CpG oligonucleotide adjuvant described herein, wherein the second chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8, wherein the second chimeric HA comprises the amino acid sequence of SEQ ID NO:5 or 6, if the first chimeric HA comprises the amino acid sequence of SEQ ID NO:7 or 8, and the second chimeric HA comprises the amino acid sequence of SEQ ID NO:7 or 8, if the first chimeric HA comprises the amino acid sequence of SEQ ID NO:5 or 6. In some embodiments, the method further comprises administering to the subject a third immunogenic composition a certain time after the administration of the second immunogenic composition to the subject, wherein the third immunogenic composition comprises a third chimeric HA and a CpG oligonucleotide adjuvant described herein, and wherein the third chimeric HA comprises a third influenza virus HA globular head domain and a third influenza virus HA stalk domain, wherein the third HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA of SEQ ID NO: 5, 6, 7, or 8, wherein the third HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA, and wherein the third HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the first HA globular head domain of the first chimeric HA and the second HA globular head domain of the second chimeric HA. In some embodiments, each immunogenic composition is administered to the subject intramuscularly or intranasally. In some embodiments, each immunogenic composition is administered to the subject from about 21 days to about 60 days apart from another immunogenic composition. In some embodiments, each immunogenic composition is administered to the subject from about 21 days to about 120 days apart from another immunogenic composition. In some embodiments, each immunogenic composition is administered to the subject from about 21 days to about 6 months apart from another immunogenic composition. In some embodiments, the chimeric HA in an immunogenic composition is administered to the subject at a dose provided herein. In some embodiments, the CpG oligonucleotide adjuvant comprises the nucleotide sequence of SEQ ID NO: 4, or CpG 1018® adjuvant. In some embodiments, the CpG oligonucleotide adjuvant in an immunogenic composition is administered to the subject at a dose provided herein.

[00356] In some embodiments, provided herein is a method of preventing influenza virus disease in a subject (e.g., a human subject), comprising: (a) administering to the subject a first immunogenic composition comprising a first inactivated influenza virus and a CpG oligonucleotide adjuvant described herein, wherein the first inactivated influenza virus comprises a first chimeric HA, and wherein the first chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8; and (b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second inactivated influenza virus and a CpG oligonucleotide adjuvant described herein, wherein the second inactivated influenza virus comprises a second chimeric HA, and wherein the second chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8, wherein the second chimeric HA comprises the amino acid sequence of SEQ ID NO:5 or 6, if the first chimeric HA comprises the amino acid sequence of SEQ ID NO:7 or 8, and the second chimeric HA comprises the amino acid sequence of SEQ ID NO:7 or 8, if the first chimeric HA comprises the amino acid sequence of SEQ ID NO:5 or 6. In some embodiments, the method further comprises administering to the subject a third immunogenic composition a certain time after the administration of the second immunogenic composition to the subject, wherein the third immunogenic composition comprises a third inactivated influenza virus and a CpG oligonucleotide adjuvant described herein, wherein the third inactivated influenza virus comprises a third chimeric HA, and wherein the third chimeric HA comprises a third influenza virus HA globular head domain and a third influenza virus HA stalk domain, wherein the third HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA of SEQ ID NO: 5, 6, 7, or 8, wherein the third HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA, and wherein the third HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the first HA globular head domain of the first chimeric HA and the second HA globular head domain of the second chimeric HA. In some embodiments, each immunogenic composition is administered to the subject intramuscularly or intranasally. In some embodiments, each immunogenic composition is administered to the subject from about 21 days to about 60 days apart from another immunogenic composition. In some embodiments, each immunogenic composition is administered to the subject from about 21 days to about 120 days apart from another immunogenic composition. In some embodiments, each immunogenic composition is administered to the subject from about 21 days to about 6 months apart from another immunogenic composition. In some embodiments, the chimeric HA in an immunogenic composition is administered to the subject at a dose provided herein. In some embodiments, the CpG oligonucleotide adjuvant comprises the nucleotide sequence of SEQ ID NO: 4, or CpG 1018® adjuvant. In some embodiments, the CpG oligonucleotide adjuvant in an immunogenic composition is administered to the subject at a dose provided herein.

[00357] In some embodiments, provided herein is a method of preventing influenza virus disease in a subject (e.g., a human subject), comprising: (a) administering to the subject a first immunogenic composition comprising a first inactivated split influenza virus and a CpG oligonucleotide adjuvant described herein, wherein the first inactivated split influenza virus comprises a first chimeric HA, and wherein the first chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8; and (b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second inactivated split influenza virus and a CpG oligonucleotide adjuvant described herein, wherein the second inactivated split influenza virus comprises a second chimeric HA, and wherein the second chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8, wherein the second chimeric HA comprises the amino acid sequence of SEQ ID NO:5 or 6, if the first chimeric HA comprises the amino acid sequence of SEQ ID NO:7 or 8, and the second chimeric HA comprises the amino acid sequence of SEQ ID NO:7 or 8, if the first chimeric HA comprises the amino acid sequence of SEQ ID NO:5 or 6. In some embodiments, the method further comprises administering to the subject a third immunogenic composition a certain time after the administration of the second immunogenic composition to the subject, wherein the third immunogenic composition comprises a third inactivated split influenza virus and a CpG oligonucleotide adjuvant described herein, wherein the third inactivated split influenza virus comprises a third chimeric HA, and wherein the third chimeric HA comprises a third influenza virus HA globular head domain and a third influenza virus HA stalk domain, wherein the third HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA of SEQ ID NO: 5, 6, 7, or 8, wherein the third HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA, and wherein the third HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the first HA globular head domain of the first chimeric HA and the second HA globular head domain of the second chimeric HA. In some embodiments, each immunogenic composition is administered to the subject intramuscularly or intranasally. In some embodiments, each immunogenic composition is administered to the subject from about 21 days to about 60 days apart from another immunogenic composition. In some embodiments, each immunogenic composition is administered to the subject from about 21 days to about 120 days apart from another immunogenic composition. In some embodiments, each immunogenic composition is administered to the subject from about 21 days to about 6 months apart from another immunogenic composition. In some embodiments, the chimeric HA in an immunogenic composition is administered to the subject at a dose provided herein. In some embodiments, the CpG oligonucleotide adjuvant comprises the nucleotide sequence of SEQ ID NO: 4, or CpG 1018® adjuvant. In some embodiments, the CpG oligonucleotide adjuvant in an immunogenic composition is administered to the subject at a dose provided herein. [00358] In some embodiments, provided herein is a method of immunizing a subject against influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus), comprising: (a) administering to the subject a first immunogenic composition comprising a first chimeric HA and a CpG oligonucleotide adjuvant described herein, wherein the first chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8; and (b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second chimeric HA and a CpG oligonucleotide adjuvant described herein, wherein the second chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8, wherein the second chimeric HA comprises the amino acid sequence of SEQ ID NO:5 or 6, if the first chimeric HA comprises the amino acid sequence of SEQ ID NO:7 or 8, and the second chimeric HA comprises the amino acid sequence of SEQ ID NO:7 or 8, if the first chimeric HA comprises the amino acid sequence of SEQ ID NO:5 or 6. In some embodiments, the method further comprises administering to the subject a third immunogenic composition a certain time after the administration of the second immunogenic composition to the subject, wherein the third immunogenic composition comprises a third chimeric HA and a CpG oligonucleotide adjuvant described herein, and wherein the third chimeric HA comprises a third influenza virus HA globular head domain and a third influenza virus HA stalk domain, wherein the third HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA of SEQ ID NO: 5, 6, 7, or 8, wherein the third HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA, and wherein the third HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the first HA globular head domain of the first chimeric HA and the second HA globular head domain of the second chimeric HA. In some embodiments, each immunogenic composition is administered to the subject intramuscularly or intranasally. In some embodiments, each immunogenic composition is administered to the subject from about 21 days to about 60 days apart from another immunogenic composition. In some embodiments, each immunogenic composition is administered to the subject from about 21 days to about 120 days apart from another immunogenic composition. In some embodiments, each immunogenic composition is administered to the subject from about 21 days to about 6 months apart from another immunogenic composition. In some embodiments, the chimeric HA in an immunogenic composition is administered to the subject at a dose provided herein. In some embodiments, the CpG oligonucleotide adjuvant in an immunogenic composition is administered to the subject at a dose provided herein.

[00359] In some embodiments, provided herein is a method of immunizing a subject against influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus), comprising: (a) administering to the subject a first immunogenic composition comprising a first inactivated influenza virus and a CpG oligonucleotide adjuvant described herein, wherein the first inactivated influenza virus comprises a first chimeric HA, and wherein the first chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8; and (b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second inactivated influenza virus and a CpG oligonucleotide adjuvant described herein, wherein the second inactivated influenza virus comprises a second chimeric HA, and wherein the second chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8, wherein the second chimeric HA comprises the amino acid sequence of SEQ ID NO:5 or 6, if the first chimeric HA comprises the amino acid sequence of SEQ ID NO:7 or 8, and the second chimeric HA comprises the amino acid sequence of SEQ ID NO:7 or 8, if the first chimeric HA comprises the amino acid sequence of SEQ ID NO:5 or 6. In some embodiments, the method further comprises administering to the subject a third immunogenic composition a certain time after the administration of the second immunogenic composition to the subject, wherein the third immunogenic composition comprises a third inactivated influenza virus and a CpG oligonucleotide adjuvant described herein, wherein the third inactivated influenza virus comprises a third chimeric HA, and wherein the third chimeric HA comprises a third influenza virus HA globular head domain and a third influenza virus HA stalk domain, wherein the third HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA of SEQ ID NO: 5, 6, 7, or 8, wherein the third HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA, and wherein the third HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the first HA globular head domain of the first chimeric HA and the second HA globular head domain of the second chimeric HA. In some embodiments, each immunogenic composition is administered to the subject intramuscularly or intranasally. In some embodiments, each immunogenic composition is administered to the subject from about 21 days to about 60 days apart from another immunogenic composition. In some embodiments, each immunogenic composition is administered to the subject from about 21 days to about 120 days apart from another immunogenic composition. In some embodiments, each immunogenic composition is administered to the subject from about 21 days to about 6 months apart from another immunogenic composition. In some embodiments, the chimeric HA in an immunogenic composition is administered to the subject at a dose provided herein. In some embodiments, the CpG oligonucleotide adjuvant in an immunogenic composition is administered to the subject at a dose provided herein.

[00360] In some embodiments, provided herein is a method of immunizing a subject against influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus), comprising: (a) administering to the subject a first immunogenic composition comprising a first inactivated split influenza virus and a CpG oligonucleotide adjuvant described herein, wherein the first inactivated split influenza virus comprises a first chimeric HA, and wherein the first chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8; and (b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second inactivated split influenza virus and a CpG oligonucleotide adjuvant described herein, wherein the second inactivated split influenza virus comprises a second chimeric HA, and wherein the second chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8, wherein the second chimeric HA comprises the amino acid sequence of SEQ ID NO:5 or 6, if the first chimeric HA comprises the amino acid sequence of SEQ ID NO:7 or 8, and the second chimeric HA comprises the amino acid sequence of SEQ ID NO:7 or 8, if the first chimeric HA comprises the amino acid sequence of SEQ ID NO:5 or 6. In some embodiments, the method further comprises administering to the subject a third immunogenic composition a certain time after the administration of the second immunogenic composition to the subject, wherein the third immunogenic composition comprises a third inactivated split influenza virus and a CpG oligonucleotide adjuvant described herein, wherein the third inactivated split influenza virus comprises a third chimeric HA, and wherein the third chimeric HA comprises a third influenza virus HA globular head domain and a third influenza virus HA stalk domain, wherein the third HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA of SEQ ID NO: 5, 6, 7, or 8, wherein the third HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA, and wherein the third HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the first HA globular head domain of the first chimeric HA and the second HA globular head domain of the second chimeric HA. In some embodiments, each immunogenic composition is administered to the subject intramuscularly or intranasally. In some embodiments, each immunogenic composition is administered to the subject from about 21 days to about 60 days apart from another immunogenic composition. In some embodiments, each immunogenic composition is administered to the subject from about 21 days to about 120 days apart from another immunogenic composition. In some embodiments, each immunogenic composition is administered to the subject from about 21 days to about 6 months apart from another immunogenic composition. In some embodiments, the chimeric HA in an immunogenic composition is administered to the subject at a dose provided herein. In some embodiments, the CpG oligonucleotide adjuvant in an immunogenic composition is administered to the subject at a dose provided herein. [00361] In some embodiments, provided herein is a method inducing an immune response to influenza A viruses (e.g., a cross-reactive immune response to group 2 influenza A viruses) in a subject, comprising: (a) administering to the subject a first immunogenic composition comprising a first chimeric HA and a CpG oligonucleotide adjuvant described herein, wherein the first chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8; and (b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second chimeric HA and a CpG oligonucleotide adjuvant described herein, wherein the second chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8, wherein the second chimeric HA comprises the amino acid sequence of SEQ ID NO:5 or 6, if the first chimeric HA comprises the amino acid sequence of SEQ ID NO:7 or 8, and the second chimeric HA comprises the amino acid sequence of SEQ ID NO:7 or 8, if the first chimeric HA comprises the amino acid sequence of SEQ ID NO:5 or 6. In some embodiments, the method further comprises administering to the subject a third immunogenic composition a certain time after the administration of the second immunogenic composition to the subject, wherein the third immunogenic composition comprises a third chimeric HA and a CpG oligonucleotide adjuvant described herein, and wherein the third chimeric HA comprises a third influenza virus HA globular head domain and a third influenza virus HA stalk domain, wherein the third HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA of SEQ ID NO: 5, 6, 7, or 8, wherein the third HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA, and wherein the third HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the first HA globular head domain of the first chimeric HA and the second HA globular head domain of the second chimeric HA. In some embodiments, each immunogenic composition is administered to the subject intramuscularly or intranasally. In some embodiments, each immunogenic composition is administered to the subject from about 21 days to about 60 days apart from another immunogenic composition. In some embodiments, each immunogenic composition is administered to the subject from about 21 days to about 120 days apart from another immunogenic composition. In some embodiments, each immunogenic composition is administered to the subject from about 21 days to about 6 months apart from another immunogenic composition. In some embodiments, the chimeric HA in an immunogenic composition is administered to the subject at a dose provided herein. In some embodiments, the CpG oligonucleotide adjuvant in an immunogenic composition is administered to the subject at a dose provided herein.

[00362] In some embodiments, provided herein is a method inducing an immune response to influenza A viruses (e.g., a cross-reactive immune response to group 2 influenza A viruses) in a subject, comprising: (a) administering to the subject a first immunogenic composition comprising a first inactivated influenza virus and a CpG oligonucleotide adjuvant described herein, wherein the first inactivated influenza virus comprises a first chimeric HA, and wherein the first chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8; and (b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second inactivated influenza virus and a CpG oligonucleotide adjuvant described herein, wherein the second inactivated influenza virus comprises a second chimeric HA, and wherein the second chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8, wherein the second chimeric HA comprises the amino acid sequence of SEQ ID NO:5 or 6, if the first chimeric HA comprises the amino acid sequence of SEQ ID NO:7 or 8, and the second chimeric HA comprises the amino acid sequence of SEQ ID NO:7 or 8, if the first chimeric HA comprises the amino acid sequence of SEQ ID NO:5 or 6. In some embodiments, the method further comprises administering to the subject a third immunogenic composition a certain time after the administration of the second immunogenic composition to the subject, wherein the third immunogenic composition comprises a third inactivated influenza virus and a CpG oligonucleotide adjuvant described herein, wherein the third inactivated influenza virus comprises a third chimeric HA, and wherein the third chimeric HA comprises a third influenza virus HA globular head domain and a third influenza virus HA stalk domain, wherein the third HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA of SEQ ID NO: 5, 6, 7, or 8, wherein the third HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA, and wherein the third HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the first HA globular head domain of the first chimeric HA and the second HA globular head domain of the second chimeric HA. In some embodiments, each immunogenic composition is administered to the subject intramuscularly or intranasally. In some embodiments, each immunogenic composition is administered to the subject from about 21 days to about 60 days apart from another immunogenic composition. In some embodiments, each immunogenic composition is administered to the subject from about 21 days to about 120 days apart from another immunogenic composition. In some embodiments, each immunogenic composition is administered to the subject from about 21 days to about 6 months apart from another immunogenic composition. In some embodiments, the chimeric HA in an immunogenic composition is administered to the subject at a dose provided herein. In some embodiments, the CpG oligonucleotide adjuvant in an immunogenic composition is administered to the subject at a dose provided herein.

[00363] In some embodiments, provided herein is a method inducing an immune response to influenza A viruses (e.g., a cross-reactive immune response to group 2 influenza A viruses) in a subject, comprising: (a) administering to the subject a first immunogenic composition comprising a first inactivated split influenza virus and a CpG oligonucleotide adjuvant described herein, wherein the first inactivated split influenza virus comprises a first chimeric HA, and wherein the first chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8; and (b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second inactivated split influenza virus and a CpG oligonucleotide adjuvant described herein, wherein the second inactivated influenza virus comprises a second chimeric HA, and wherein the second chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8, wherein the second chimeric HA comprises the amino acid sequence of SEQ ID NO:5 or 6, if the first chimeric HA comprises the amino acid sequence of SEQ ID NO:7 or 8, and the second chimeric HA comprises the amino acid sequence of SEQ ID NO:7 or 8, if the first chimeric HA comprises the amino acid sequence of SEQ ID NO:5 or 6. In some embodiments, the method further comprises administering to the subject a third immunogenic composition a certain time after the administration of the second immunogenic composition to the subject, wherein the third immunogenic composition comprises a third inactivated split influenza virus and a CpG oligonucleotide adjuvant described herein, wherein the third inactivated split influenza virus comprises a third chimeric HA, and wherein the third chimeric HA comprises a third influenza virus HA globular head domain and a third influenza virus HA stalk domain, wherein the third HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA of SEQ ID NO: 5, 6, 7, or 8, wherein the third HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA, and wherein the third HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the first HA globular head domain of the first chimeric HA and the second HA globular head domain of the second chimeric HA. In some embodiments, each immunogenic composition is administered to the subject intramuscularly or intranasally. In some embodiments, each immunogenic composition is administered to the subject from about 21 days to about 60 days apart from another immunogenic composition. In some embodiments, each immunogenic composition is administered to the subject from about 21 days to about 120 days apart from another immunogenic composition. In some embodiments, each immunogenic composition is administered to the subject from about 21 days to about 6 months apart from another immunogenic composition. In some embodiments, the chimeric HA in an immunogenic composition is administered to the subject at a dose provided herein. In some embodiments, the CpG oligonucleotide adjuvant in an immunogenic composition is administered to the subject at a dose provided herein.

[00364] In some embodiments, the CpG oligonucleotide adjuvant included in each immunogenic composition is the same. In some embodiments, the same aluminum adjuvant is included in each immunogenic composition. In some embodiments, the same aluminum adjuvant is concurrently or sequentially to the subject.

[00365] In another aspect, provided herein are methods of preventing influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus) in a subject (e.g., a human subject), comprising administering to the subject an immunogenic composition comprising a chimeric HA described herein, and administering to the subject a CpG oligonucleotide adjuvant described herein. In some embodiments, provided herein are methods of preventing influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus) in a subject (e.g., a human subject), comprising administering to the subject an immunogenic composition comprising an inactivated influenza A virus, comprising a chimeric HA described herein, and administering to the subject a CpG oligonucleotide adjuvant described herein. In some embodiments, provided herein are methods of preventing influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus) in a subject (e.g., a human subject), comprising administering to the subject an immunogenic composition comprising an inactivated split influenza A virus, comprising a chimeric HA described herein, and administering to the subject a CpG oligonucleotide adjuvant described herein. In some embodiments, the immunogenic composition and the CpG oligonucleotide adjuvant are administered concurrently. In some embodiments, the immunogenic composition and the CpG oligonucleotide adjuvant are administered concurrently via the same route of administration. In some embodiments, the immunogenic composition and the CpG oligonucleotide adjuvant are administered sequentially via the same route or different routes of administration. In some embodiments, the immunogenic composition and the CpG oligonucleotide adjuvant are administered within about 1 hour of each other via the same route or different routes of administration. In some embodiments, the immunogenic composition and the CpG oligonucleotide adjuvant are administered within about 15 minutes, about 30 minutes, or about 45 minutes of each other via the same route or different routes of administration. In some embodiments, the immunogenic composition and the CpG oligonucleotide adjuvant are administered within about 1 hour of each other intramuscularly or intranasally. In some embodiments, the immunogenic composition and the CpG oligonucleotide adjuvant are administered within about 15 minutes, about 30 minutes, or about 45 minutes of each other intramuscularly or intranasally. In some embodiments, the chimeric HA comprises the amino acid sequence of SEQ ID NO:5, 6, 7, or 8. In some embodiments, the chimeric HA in an immunogenic composition is administered to the subject at a dose provided herein. In some embodiments, the CpG oligonucleotide adjuvant is administered to the subject at a dose provided herein. [00366] In some embodiments, provided herein is a method of preventing an influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus) in a subject (e.g., a human subject), comprising: (a) administering to the subject an immunogenic composition comprising a chimeric HA in an admixture with a pharmaceutically acceptable carrier, wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises an amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA, and wherein the HA globular head domain of the chimeric HA comprises the amino acid sequence of an HA globular head of an influenza A virus of a different strain, subtype, or group than the group 2 influenza A virus HA; and (b) administering to the subject a CpG oligonucleotide adjuvant described herein. In some embodiments, provided herein is a method of preventing an influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus) in a subject (e.g., a human subject), comprising: (a) administering to the subject an immunogenic composition comprising an inactivated influenza virus in an admixture with a pharmaceutically acceptable carrier, wherein the inactivated influenza virus comprises a chimeric HA, wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises an amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA, and wherein the HA globular head domain of the chimeric HA comprises the amino acid sequence of an HA globular head of an influenza A virus of a different strain, subtype, or group than the group 2 influenza A virus HA; and (b) administering to the subject a CpG oligonucleotide adjuvant described herein. In some embodiments, provided herein is a method of preventing an influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus) in a subject (e.g., a human subject), comprising: (a) administering to the subject an immunogenic composition comprising an inactivated split influenza virus in an admixture with a pharmaceutically acceptable carrier, wherein the inactivated split influenza virus comprises a chimeric HA, wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises an amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA, and wherein the HA globular head domain of the chimeric HA comprises the amino acid sequence of an HA globular head of an influenza A virus of a different strain, subtype, or group than the group 2 influenza A virus HA; and (b) administering to the subject a CpG oligonucleotide adjuvant described herein. In some embodiments, the immunogenic composition and the CpG oligonucleotide adjuvant are administered concurrently. In some embodiments, the immunogenic composition and the CpG oligonucleotide adjuvant are administered concurrently via the same route of administration. In some embodiments, the immunogenic composition and the CpG oligonucleotide adjuvant are administered sequentially via the same route or different routes of administration. In some embodiments, the immunogenic composition and the CpG oligonucleotide adjuvant are administered within about 1 hour of each other via the same route or different routes of administration. In some embodiments, the immunogenic composition and the CpG oligonucleotide adjuvant are administered within about 15 minutes, about 30 minutes, or about 45 minutes of each other via the same route or different routes of administration. In some embodiments, the immunogenic composition and the CpG oligonucleotide adjuvant are administered within about 1 hour of each other intramuscularly or intranasally. In some embodiments, the immunogenic composition and the CpG oligonucleotide adjuvant are administered within about 15 minutes, about 30 minutes, or about 45 minutes of each other intramuscularly or intranasally. In some embodiments, the chimeric HA in an immunogenic composition is administered to the subject at a dose provided herein. In some embodiments, the CpG oligonucleotide adjuvant is administered to the subject at a dose provided herein.

[00367] In another aspect, provided herein are methods of immunizing a subject (e.g., a human subject) against influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus), comprising administering to the subject an immunogenic composition comprising a chimeric HA described herein, and administering to the subject a CpG oligonucleotide adjuvant described herein. In some embodiments, provided herein are methods of immunizing a subject (e.g., a human subject) against influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus), comprising administering to the subject an immunogenic composition comprising an inactivated influenza virus, wherein the inactivated influenza virus comprises a chimeric HA described herein, and administering to the subject a CpG oligonucleotide adjuvant described herein. In some embodiments, provided herein are methods of immunizing a subject (e.g., a human subject) against influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus), comprising administering to the subject an immunogenic composition comprising an inactivated split influenza virus, wherein the inactivated influenza virus comprises a chimeric HA described herein, and administering to the subject a CpG oligonucleotide adjuvant described herein. In some embodiments, the immunogenic composition and the CpG oligonucleotide adjuvant are administered concurrently. In some embodiments, the immunogenic composition and the CpG oligonucleotide adjuvant are administered concurrently via the same route of administration. In some embodiments, the immunogenic composition and the CpG oligonucleotide adjuvant are administered sequentially via the same route or different routes of administration. In some embodiments, the immunogenic composition and the CpG oligonucleotide adjuvant are administered within about 1 hour of each other via the same route or different routes of administration. In some embodiments, the immunogenic composition and the CpG oligonucleotide adjuvant are administered within about 15 minutes, about 30 minutes, or about 45 minutes of each other via the same route or different routes of administration. In some embodiments, the immunogenic composition and the CpG oligonucleotide adjuvant are administered within about 1 hour of each other intramuscularly or intranasally. In some embodiments, the immunogenic composition and the CpG oligonucleotide adjuvant are administered within about 15 minutes, about 30 minutes, or about 45 minutes of each other intramuscularly or intranasally. In some embodiments, the chimeric HA comprises the amino acid sequence of SEQ ID NO:5, 6, 7, or 8. In some embodiments, the chimeric HA in an immunogenic composition is administered to the subject at a dose provided herein. In some embodiments, the CpG oligonucleotide adjuvant is administered to the subject at a dose provided herein.

[00368] In some embodiments, provided herein is a method of immunizing a subject (e.g., a human subject) against an influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus), comprising: (a) administering to the subject an immunogenic composition comprising a chimeric HA in an admixture with a pharmaceutically acceptable carrier, wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises an amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA, and wherein the HA globular head domain of the chimeric HA comprises the amino acid sequence of an HA globular head of an influenza A virus of a different strain, subtype, or group than the group 2 influenza A virus HA; and (b) administering to the subject a CpG oligonucleotide adjuvant described herein. In some embodiments, provided herein is a method of immunizing a subject (e.g., a human subject) against an influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus), comprising: (a) administering to the subject an immunogenic composition comprising an inactivated influenza virus in an admixture with a pharmaceutically acceptable carrier, wherein the inactivated influenza virus comprises a chimeric HA, wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises an amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA, and wherein the HA globular head domain of the chimeric HA comprises the amino acid sequence of an HA globular head of an influenza A virus of a different strain, subtype, or group than the group 2 influenza A virus HA; and (b) administering to the subject a CpG oligonucleotide adjuvant described herein. In some embodiments, provided herein is a method of immunizing a subject (e.g., a human subject) against influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus), comprising: (a) administering to the subject an immunogenic composition comprising an inactivated split influenza virus in an admixture with a pharmaceutically acceptable carrier, wherein the inactivated split influenza virus comprises a chimeric HA, wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises an amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA, and wherein the HA globular head domain of the chimeric HA comprises the amino acid sequence of an HA globular head of an influenza A virus of a different strain, subtype, or group than the group 2 influenza A virus HA; and (b) administering to the subject a CpG oligonucleotide adjuvant described herein. In some embodiments, the immunogenic composition and the CpG oligonucleotide adjuvant are administered concurrently. In some embodiments, the immunogenic composition and the CpG oligonucleotide adjuvant are administered concurrently via the same route of administration. In some embodiments, the immunogenic composition and the CpG oligonucleotide adjuvant are administered sequentially via the same route or different routes of administration. In some embodiments, the immunogenic composition and the CpG oligonucleotide adjuvant are administered within about 1 hour of each other via the same route or different routes of administration. In some embodiments, the immunogenic composition and the CpG oligonucleotide adjuvant are administered within about 15 minutes, about 30 minutes, or about 45 minutes of each other via the same route or different routes of administration. In some embodiments, the immunogenic composition and the CpG oligonucleotide adjuvant are administered within about 1 hour of each other intramuscularly or intranasally. In some embodiments, the immunogenic composition and the CpG oligonucleotide adjuvant are administered within about 15 minutes, about 30 minutes, or about 45 minutes of each other intramuscularly or intranasally. In some embodiments, the chimeric HA in an immunogenic composition is administered to the subject at a dose provided herein. In some embodiments, the CpG oligonucleotide adjuvant is administered to the subject at a dose provided herein.

[00369] In another aspect, provided herein are methods of inducing an immune response to influenza A viruses (e.g., a cross-reactive immune response to group 2 influenza A viruses) in a subject (e.g., a human subject), comprising administering to the subject an immunogenic composition comprising a chimeric HA described herein, and administering to the subject a CpG oligonucleotide adjuvant described herein. In some embodiments, provided herein are methods of inducing an immune response to influenza A viruses (e.g., a cross-reactive immune response to group 2 influenza A viruses) in a subject (e.g., a human subject), comprising administering to the subject an immunogenic composition comprising an inactivated influenza virus, wherein the inactivated influenza virus comprises a chimeric HA described herein, and administering to the subject a CpG oligonucleotide adjuvant described herein. In some embodiments, provided herein are methods of inducing an immune response to influenza A viruses (e.g., a cross-reactive immune response to group 2 influenza A viruses) in a subject (e.g., a human subject), comprising administering to the subject an immunogenic composition comprising an inactivated split influenza virus, wherein the inactivated split influenza virus comprises a chimeric HA described herein, and administering to the subject a CpG oligonucleotide adjuvant described herein. In some embodiments, the immunogenic composition and the CpG oligonucleotide adjuvant are administered concurrently. In some embodiments, the immunogenic composition and the CpG oligonucleotide adjuvant are administered concurrently via the same route of administration. In some embodiments, the immunogenic composition and the CpG oligonucleotide adjuvant are administered sequentially via the same route or different routes of administration. In some embodiments, the immunogenic composition and the CpG oligonucleotide adjuvant are administered within about 1 hour of each other via the same route or different routes of administration. In some embodiments, the immunogenic composition and the CpG oligonucleotide adjuvant are administered within about 15 minutes, about 30 minutes, or about 45 minutes of each other via the same route or different routes of administration. In some embodiments, the immunogenic composition and the CpG oligonucleotide adjuvant are administered within about 1 hour of each other intramuscularly or intranasally. In some embodiments, the immunogenic composition and the CpG oligonucleotide adjuvant are administered within about 15 minutes, about 30 minutes, or about 45 minutes of each other intramuscularly or intranasally. In some embodiments, the chimeric HA comprises the amino acid sequence of SEQ ID NO:5, 6, 7, or 8. In some embodiments, the chimeric HA in an immunogenic composition is administered to the subject at a dose provided herein. In some embodiments, the CpG oligonucleotide adjuvant is administered to the subject at a dose provided herein. [00370] In some embodiments, provided herein is a method of inducing an immune response to influenza A viruses (e.g., a cross-reactive immune response to group 2 influenza A viruses) in a subject (e.g., human subject), comprising: (a) administering to the subject an immunogenic composition comprising a chimeric HA in an admixture with a pharmaceutically acceptable carrier, wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises an amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA, and wherein the HA globular head domain of the chimeric HA comprises the amino acid sequence of an HA globular head of an influenza A virus of a different strain, subtype, or group than the group 2 influenza A virus HA; and (b) administering to the subject a CpG oligonucleotide adjuvant described herein. In some embodiments, provided herein is a method of inducing an immune response to influenza A viruses (e.g., a cross-reactive immune response to group 2 influenza A viruses) in a subject (e.g., human subject), comprising: (a) administering to the subject an immunogenic composition comprising an inactivated influenza virus in an admixture with a pharmaceutically acceptable carrier, wherein the inactivated influenza virus comprises a chimeric HA, wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises an amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA, and wherein the HA globular head domain of the chimeric HA comprises the amino acid sequence of an HA globular head of an influenza A virus of a different strain, subtype, or group than the group 2 influenza A virus HA; and (b) administering to the subject a CpG oligonucleotide adjuvant described herein. In some embodiments, provided herein is a method of inducing an immune response to influenza A viruses (e.g., a cross-reactive immune response to group 2 influenza A viruses) in a subject (e.g., human subject), comprising: (a) administering to the subject an immunogenic composition comprising an inactivated split influenza virus in an admixture with a pharmaceutically acceptable carrier, wherein the inactivated split influenza virus comprises a chimeric HA, wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises an amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA, and wherein the HA globular head domain of the chimeric HA comprises the amino acid sequence of an HA globular head of an influenza A virus of a different strain, subtype, or group than the group 2 influenza A virus HA; and (b) administering to the subject a CpG oligonucleotide adjuvant described herein. In some embodiments, the immunogenic composition and the CpG oligonucleotide adjuvant are administered concurrently. In some embodiments, the immunogenic composition and the CpG oligonucleotide adjuvant are administered concurrently via the same route of administration. In some embodiments, the immunogenic composition and the CpG oligonucleotide adjuvant are administered sequentially via the same route or different routes of administration. In some embodiments, the immunogenic composition and the CpG oligonucleotide adjuvant are administered within about 1 hour of each other via the same route or different routes of administration. In some embodiments, the immunogenic composition and the CpG oligonucleotide adjuvant are administered within about 15 minutes, about 30 minutes, or about 45 minutes of each other via the same route or different routes of administration. In some embodiments, the immunogenic composition and the CpG oligonucleotide adjuvant are administered within about 1 hour of each other intramuscularly or intranasally. In some embodiments, the immunogenic composition and the CpG oligonucleotide adjuvant are administered within about 15 minutes, about 30 minutes, or about 45 minutes of each other intramuscularly or intranasally. In some embodiments, the chimeric HA in an immunogenic composition is administered to the subject at a dose provided herein. In some embodiments, the CpG oligonucleotide adjuvant is administered to the subject at a dose provided herein.

[00371] In some embodiments, provided herein are methods of preventing influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus) in a subject, methods of immunizing a subject against influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus), and/or inducing an immune response against influenza virus (e.g., influenza A virus, such as, e.g., group 2 influenza A virus) using a method or regimen described in Section 6, infra.

[00372] In some embodiments, the methods of preventing of influenza virus disease (e.g, influenza virus disease caused by influenza A virus, such as, e.g, group 2 influenza A virus) in a subject and/or methods of immunizing a subject against influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus) induce antibodies (e.g., IgG) cross-reactive with a plurality of influenza A viruses. In some embodiments, the methods of preventing of influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus) in a subject and/or methods of immunizing a subject against influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus) induce antibodies (e.g., IgG) cross-reactive with a plurality of group 2 influenza A viruses. In some embodiments, the methods of preventing of influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus) in a subject and/or methods of immunizing a subject against influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus) induce antibodies (e.g., IgG) cross-reactive with a plurality of heterotypic influenza A viruses. In some embodiments, the methods of preventing of influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus) in a subject and/or methods of immunizing a subject against influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus) induce antibodies (e.g., IgG) cross-reactive with a plurality of heterosubtypic influenza A viruses. In some embodiments, the methods of preventing of influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus) in a subject and/or methods of immunizing a subject against influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus) induce antibodies (e.g., IgG) cross-reactive with a plurality of homosubtypic influenza A viruses.

[00373] In specific embodiments, the methods for preventing an influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus) and/or immunizing a subject against influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus) provided herein induce poly-functional T cells. In specific embodiments, the methods for preventing an influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus) and/or immunizing a subject against influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus) provided herein induce antibodies with activity in an ADCC reporter assay, such as described herein. In specific embodiments, the methods for preventing an influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus) and/or immunizing a subject against influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus) provided herein induce antibodies that inhibit influenza A virus (e.g., group 2 influenza A viruses) from infecting cells as assessed in a microneutralization assay, such as described herein. In some embodiments, methods for preventing an influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus) and/or immunizing a subject against influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus) provided herein induce antibodies targeting the conserved HA globular head trimer interface.

[00374] In specific embodiments, the methods for preventing an influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus) and/or immunizing a subject against influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus) provided herein induce an anti-neuraminidase immune response. In specific embodiments, the methods for preventing an influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus) and/or immunizing a subject against influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus) provided herein induce antibodies against neuraminidase. Techniques known to one of skill in the art or described herein may be used to measure the antineuraminidase immune response induced.

[00375] In specific embodiments, the methods for preventing an influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus) and/or immunizing a subject against influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus) provided herein induce antibodies with one or more of the characteristics of the antibodies described in Section 6, infra.

[00376] In specific embodiments, the methods for preventing an influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus) and/or immunizing a subject against influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus) provided herein induce an immune response such as described in Section 6, infra. In specific embodiments, the methods for preventing an influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus) and/or immunizing a subject against influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus) provided herein induce antibodies that bind to or crossreact with the HA of one, two, or more, or all of the group 2 influenza A viruses described in Section 6, infra. In specific embodiments, the methods for preventing an influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus) and/or immunizing a subject against influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus) provided herein induce antibodies that cross-react with the HA of a group 1 influenza A virus described in Section 6, infra. In specific embodiments, the methods for preventing an influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus) and/or immunizing a subject against influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus) provided herein induce antibodies that cross-react with the HA of a plurality of heterotypic influenza A viruses. In specific embodiments, the methods for preventing an influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus) and/or immunizing a subject against influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus) provided herein induce antibodies that cross-react with the HA of a plurality of heterosubtypic influenza A viruses. In specific embodiments, the methods for preventing an influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g, group 2 influenza A virus) and/or immunizing a subject against influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus) provided herein induce antibodies that cross-react with the HA of a plurality of homotypic influenza A viruses. In specific embodiments, the methods for preventing an influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus) and/or immunizing a subject against influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus) provided herein induce antibodies that cross-react with the HA of a plurality of homosubtypic influenza A viruses.

[00377] In specific embodiments, the methods for preventing an influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus) and/or immunizing a subject against influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus) provided herein induce an immune response that is HA stalk-specific. In specific embodiments, the methods for preventing an influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus) and/or immunizing a subject against influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus) provided herein induce antibodies that are HA stalk-specific. In specific embodiments, the methods for preventing an influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus) and/or immunizing a subject against influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus) provided herein induce an immune response that is NA-specific. In specific embodiments, the methods for preventing an influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus) and/or immunizing a subject against influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus) provided herein induce antibodies that are NA-specific.

[00378] In some embodiments, the methods for preventing an influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus) and/or immunizing a subject against influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus) provided herein result in a reduction in the replication of the influenza virus (e.g., an influenza A virus, such as, e.g., a group 2 influenza A virus) in the subject as measured by in vivo and in vitro assays known to those of skill in the art and described herein. In some embodiments, the replication of the influenza virus (e.g., an influenza A virus, such as, e.g., a group 2 influenza A virus) is reduced by approximately 1 log or more, approximately 2 logs or more, approximately 3 logs or more, approximately 4 logs or more, approximately 5 logs or more, approximately 6 logs or more, approximately 7 logs or more, approximately 8 logs or more, approximately 9 logs or more, approximately 10 logs or more, 1 to 3 logs, 1 to 5 logs, 1 to 8 logs, 1 to 9 logs, 2 to 10 logs, 2 to 5 logs, 2 to 7 logs, 2 logs to 8 logs, 2 to 9 logs, 2 to 10 logs 3 to 5 logs, 3 to 7 logs, 3 to 8 logs, 3 to 9 logs, 4 to 6 logs, 4 to 8 logs, 4 to 9 logs, 5 to 6 logs, 5 to 7 logs, 5 to 8 logs, 5 to 9 logs, 6 to 7 logs, 6 to 8 logs, 6 to 9 logs, 7 to 8 logs, 7 to 9 logs, or 8 to 9 logs. [00379] In specific embodiments, the methods of preventing an influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus) in a subject results in one, two, or more of the following: prevents the onset of one or more symptoms of the disease, reduces the number of symptoms of the disease, reduces the severity of the symptoms of the disease, and/or reduces the length of the disease. Symptoms of influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus) include fever, chills, cough, sore throat, runny or stuffy nose, muscle or body aches, headaches, fatigue (tiredness), vomiting and diarrhea.

[00380] In a specific embodiment, a method of immunizing a subject against influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus) comprises the methodology set forth in Section 6, infra. In another specific embodiment, a method for preventing an influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus) in a subject comprises the methodology set forth in Section 6, infra. In another specific embodiment, a method of immunizing a subject against influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus) comprises an immunization regimen set forth in Section 6, infra, using the same chimeric HA polypeptides or other chimeric HA polypeptides described herein. In another specific embodiment, a method for preventing an influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus) in a subject comprises an immunization regimen set forth in Section 6, infra, using the same chimeric HA polypeptides or other chimeric HA polypeptides described herein. [00381] In some embodiments, the methods for preventing an influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus) and/or immunizing a subject against influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus) provided herein provide at least partial protection against influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus).

[00382] An immunogenic composition may be administered to a subject by a variety of routes of administration. An immunogenic composition and a CpG oligonucleotide adjuvant may be administered via the same route or different routes of administration. A CpG oligonucleotide adjuvant and/or aluminum adjuvant/aluminum adjuvant may be administered via the same route or different routes of administration. The routes of administration may include intranasal, intratracheal, oral, topical, intradermal, intramuscular, intraperitoneal, transdermal, intravenous, conjunctival and subcutaneous routes. In some embodiments, an immunogenic composition is formulated for intramuscular administration.

[00383] In some embodiments, the dose of a live attenuated influenza A virus described herein, which is administered to a subject, may be 10⁴ plaque forming units (PFU) to 10¹⁰ PFU. In some embodiments, the dose of a chimeric HA described herein (e.g., as provided in inactivated influenza virus or inactivated split influenza virus), which is administered to a subject, may range from about 1 pg to about 75 pg of chimeric HA. In some embodiments, the dose of a chimeric HA described herein (e.g., as provided in inactivated influenza virus or inactivated split influenza virus), which is administered to a subject, may range from about 15 pg to about 75 pg of chimeric HA. In some embodiments, the dose of a chimeric HA described herein (e.g., as provided in inactivated influenza virus or inactivated split influenza virus), which is administered to a subject, may range from about 5 pg to about 50 pg of chimeric HA. In some embodiments, the dose of a chimeric HA described herein (e.g., as provided in inactivated influenza virus or inactivated split influenza virus), which is administered to a subject, may range from about 10 pg to about 50 pg of chimeric HA. In some embodiments, the dose of a chimeric HA described herein (e.g., as provided in inactivated influenza virus or inactivated split influenza virus), which is administered to a subject, may range from about 5 pg to about 45 pg of chimeric HA. In some embodiments, the dose of a chimeric HA described herein (e.g., as provided in inactivated influenza virus or inactivated split influenza virus), which is administered to a subject, may range from about 5 pg to about 40 pg of chimeric HA. In some embodiments, the dose of a chimeric HA described herein (e.g., as provided in inactivated influenza virus or inactivated split influenza virus), which is administered to a subject, may range from about 10 pg to about 40 pg of chimeric HA. In some embodiments, the dose of a chimeric HA described herein (e.g., as provided in inactivated influenza virus or inactivated split influenza virus), which is administered to a subject, may range from about 10 pg to about 35 pg of chimeric HA. In some embodiments, the dose of a chimeric HA described herein (e.g., as provided in inactivated influenza virus or inactivated split influenza virus), which is administered to a subject, may range from about 15 pg to about 35 pg of chimeric HA. In some embodiments, the dose of a chimeric HA described herein (e.g., as provided in inactivated influenza virus or inactivated split influenza virus), which is administered to a subject, may range from about 15 pg to about 30 pg of chimeric HA. In some embodiments, the dose of a chimeric HA described herein (e.g., as provided in inactivated influenza virus or inactivated split influenza virus), which is administered to a subject, comprises about 15 pg of chimeric HA. In some embodiments, the dose of a chimeric HA described herein (e.g., as provided in inactivated influenza virus or inactivated split influenza virus), which is administered to a subject, comprises about 20 pg of chimeric HA. In some embodiments, the dose of a chimeric HA described herein (e.g., as provided in inactivated influenza virus or inactivated split influenza virus), which is administered to a subject, comprises about 25 pg of chimeric HA. In some embodiments, the dose of a chimeric HA described herein (e.g., as provided in inactivated influenza virus or inactivated split influenza virus), which is administered to a subject, comprises about 30 pg of chimeric HA. In some embodiments, the dose of a chimeric HA described herein (e.g., as provided in inactivated influenza virus or inactivated split influenza virus), which is administered to a subject, may range from about 25 pg to about 50 pg of chimeric HA. In some embodiments, the dose of a chimeric HA described herein (e.g., as provided in inactivated influenza virus or inactivated split influenza virus), which is administered to a subject, may range from about 1 pg to about 15 pg of chimeric HA. In some embodiments, the dose of a chimeric HA described herein (e.g., as provided in inactivated influenza virus or inactivated split influenza virus), which is administered to a subject, may range from about 1 pg to about 10 pg of chimeric HA. In some embodiments, the dose of a chimeric HA described herein (e.g., as provided in inactivated influenza virus or inactivated split influenza virus), which is administered to a subject, may range from about 0.1 pg to about 5 pg of chimeric HA. In some embodiments, the dose of a chimeric HA described herein (e.g., as provided in inactivated influenza virus or inactivated split influenza virus), which is administered to a subject, may range from about 0.1 pg to about 3 pg of chimeric HA. In some embodiments, the dose of a chimeric HA described herein (e.g., as provided in inactivated influenza virus or inactivated split influenza virus), which is administered to a subject, may range from about 0.1 pg to about 1 pg of chimeric HA. In some embodiments, the dose of a chimeric HA described herein (e.g., as provided in inactivated influenza virus or inactivated split influenza virus), which is administered to a subject, may range from about 5 pg to about 15 pg of chimeric HA. In some embodiments, the dose of a chimeric HA described herein (e.g., as provided in inactivated influenza virus or inactivated split influenza virus), which is administered to a subject, may range from about 1 pg to about 10 pg of chimeric HA. In some embodiments, the dose of a chimeric HA described herein (e.g., as provided in inactivated influenza virus or inactivated split influenza virus), which is administered to a subject, is about 10 pg, about 15 pg, about 16 pg, about 17 pg, or about 18 pg of chimeric HA. In some embodiments, the dose of a chimeric HA described herein (e.g., as provided in inactivated influenza virus or inactivated split influenza virus), which is administered to a subject, is about 10 pg of chimeric HA. In some embodiments, the dose of a chimeric HA described herein (e.g, as provided in inactivated influenza virus or inactivated split influenza virus), which is administered to a subject, is about 15 pg of chimeric HA. In some embodiments the dose of a chimeric HA described herein (e.g., as provided in inactivated influenza virus or inactivated split influenza virus), which is administered to a subject, is about 19 pg, about 20 pg, about 25 pg, about 30 pg, or about 35 pg of chimeric HA. In some embodiments, the dose of a chimeric HA described herein (e.g., as provided in inactivated influenza virus or inactivated split influenza virus), which is administered to a subject, is about 40 pg, about 45 pg, about 50 pg, about 55 pg, or about 60 pg of chimeric HA. In some embodiments, the dose of a chimeric HA described herein (e.g., as provided in inactivated influenza virus or inactivated split influenza virus), which is administered to a subject, is about 15 pg, 30 pg, or 60 pg. In specific embodiments, the dose of a chimeric HA described herein (e.g., as provided in inactivated influenza virus or inactivated split influenza virus), which is administered to a subject, is a dose described in Section 6, infra.

[00384] In some embodiments, the dose of CpG oligonucleotide adjuvant described herein, which is administered to a subject, ranges from about 750 pg to about 6,000 pg. In some embodiments, the dose of CpG oligonucleotide adjuvant described herein, which is administered to a subject, ranges from about 100 pg to about 1,000 pg. In some embodiments, the dose of CpG oligonucleotide adjuvant described herein, which is administered to a subject, ranges from about 1,000 pg to about 4,000 pg. In some embodiments, the dose of CpG oligonucleotide adjuvant described herein, which is administered to a subject, ranges from about 2,000 pg to about 4,000 pg. In some embodiments, the dose of CpG oligonucleotide adjuvant described herein, which is administered to a subject, ranges from about 3,000 pg to about 4,000 pg. In some embodiments, the dose of CpG oligonucleotide adjuvant described herein, which is administered to a subject, ranges from about 3,000 pg to about 6,000 pg. In some embodiments, the dose of CpG oligonucleotide adjuvant described herein, which is administered to a subject, is about 500 pg, about 1,000 pg, about 2,000 pg. In some embodiments, the dose of CpG oligonucleotide adjuvant described herein, which is administered to a subject, is about 3,000 pg, 3,500 pg, or about 4,000 pg. In some embodiments, the dose of CpG oligonucleotide adjuvant described herein, which is administered to a subject, is about 5,000 pg or 6,000 pg. In some embodiments, the dose of CpG oligonucleotide adjuvant described herein, which is administered to a subject, is about 3,000 pg,

[00385] In some embodiments, the dose of CpG oligonucleotide adjuvant described herein, which is administered to a subject, ranges from about 1 pg to about 50 pg. In some embodiments, the dose of CpG oligonucleotide adjuvant described herein, which is administered to a subject, ranges from about 1 pg to about 30 pg. In some embodiments, the dose of CpG oligonucleotide adjuvant described herein, which is administered to a subject, ranges from about 1 pg to about 15 pg. In some embodiments, the dose of CpG oligonucleotide adjuvant described herein, which is administered to a subject, is about 1 pg, about 15 pg, or about 30 pg. In some embodiments, the dose of CpG oligonucleotide adjuvant described herein, which is administered to a subject, is a dose described in Section 6, infra.

[00386] In some embodiments, the dose of an aluminum salt described herein, which is administered to a subject, ranges from 5 pg to about 50 pg. In some embodiments, the dose of an aluminum salt described herein, which is administered to a subject, ranges about 50 pg to about 800 pg of an aluminum salt. In some embodiments, the dose of an aluminum salt described herein, which is administered to a subject, is about 100 pg. In some embodiments, the dose of an aluminum salt described herein, which is administered to a subject, is about 150 pg. In some embodiments, the dose of an aluminum salt described herein, which is administered to a subject, is about 200 pg. In some embodiments, the dose of an aluminum salt described herein, which is administered to a subject, is about 250 pg In some embodiments, the dose of an aluminum salt described herein, which is administered to a subject, is about 300 pg. In some embodiments, the dose of an aluminum salt described herein, which is administered to a subject, is 350 pg. In some embodiments, the dose of an aluminum salt described herein, which is administered to a subject, is about 400 pg. In some embodiments, the dose of an aluminum salt described herein, which is administered to a subject, is about 450 pg. In some embodiments, the dose of an aluminum salt described herein, which is administered to a subject, is about 500 pg. In some embodiments, the dose of an aluminum salt described herein, which is administered to a subject, is about 550 pg. In some embodiments, the dose of an aluminum salt described herein, which is administered to a subject, is about 600 pg. In some embodiments, the dose of an aluminum salt described herein, which is administered to a subject, is about 650 pg. In some embodiments, the dose of an aluminum salt described herein, which is administered to a subject, is about 700 pg In some embodiments, the dose of an aluminum salt described herein, which is administered to a subject, is about 750 pg. In some embodiments, the dose of an aluminum salt described herein, which is administered to a subject, is about 800 pg.

[00387] In some embodiments, the subject is a human. In some embodiments, the subject is a human infant. In some embodiments, the subject is a human child. In some embodiments, the subject is a human adult. In some embodiments, the subject is an elderly human. In some embodiments, the subject is naive. In some embodiments, the subject has not been previously vaccinated for influenza. In some embodiments, the subject has been previously vaccinated for influenza. In some embodiments, the subject has been previously exposed to seasonal influenza virus (e.g., seasonal influenza A virus). Typically, a human adult has been exposed to seasonal influenza virus (e.g., seasonal influenza A virus). In some embodiments, the subject has a condition that makes them more vulnerable to influenza disease (e.g., severe influenza disease).

[00388] In another aspect, provided herein is a method for producing an antibody(ies) to influenza virus, comprising administering to a subject (e.g., a human subject or non-human subject) an immunogenic composition described herein. In some embodiments, provided herein is a methods for producing an antibody(ies) to influenza virus HA, comprising administering to a subject (e.g., a human subject or non-human subject) an immunogenic composition described herein. In some embodiments, provided herein is a method for producing an antibody(ies) to influenza virus, comprising administering to a subject (e.g., a human subject or non-human subject) two or more immunogenic compositions described herein. In some embodiments, provided herein is a methods for producing an antibody(ies) to influenza virus HA, comprising administering to a subject (e.g., a human subject or non- human subject) two or more immunogenic compositions described herein. In some embodiments, provided herein is a method for producing an antibody(ies) to influenza virus, comprising administering to a subject (e.g., a human subject or non-human subject) an immunogenic composition described herein in a regimen described herein. In some embodiments, provided herein is a methods for producing an antibody(ies) to influenza virus HA, comprising administering to a subject (e.g., a human subject or non-human subject) an immunogenic composition described herein in a regimen described herein. In some embodiments, the antibody(ies) is isolated from the subject using a technique(s) known to one of skill in the art. In some embodiments, the antibody(ies) is optimized using a technique(s) known to one of skill in the art. In some embodiments, the antibody(ies) is humanized using a technique(s) known to one of skill in the art. In some embodiments, the antibody(ies) is human because it was induced in a non-human animal capable of producing human antibodies.

[00389] In some embodiments, hybridomas are produced using B cells expressing an antibody produced by a method described herein.

[00390] In another aspect, an antibody(ies) induced by a method described herein. In some embodiments, provided herein is a pharmaceutical composition comprising an antibody described herein. The pharmaceutical composition may comprise a pharmaceutically acceptable carrier. The antibody or a pharmaceutical composition thereof may be used in a method of treating and/or preventing influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus) in a subject (e.g., human subject), and/or in a method for detecting influenza virus or HA, and/or diagnosing influenza virus infection. The antibody may be a monoclonal or polyclonal antibody. The antibody may be a human or humanized antibody.

[00391] In some embodiments, provided herein are method of treating and/or preventing influenza virus disease (e.g, influenza virus disease caused by influenza A virus, such as, e.g, group 2 influenza A virus) in a subject (e.g., a human subject), comprising administering to the subject an antibody(ies) produced by methods described herein, or a pharmaceutical composition comprising the antibody(ies). In some embodiments, provided herein are method of treating and/or preventing influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus) in a subject (e.g., a human subject), comprising administering to the subject an antibody(ies) produced by methods described herein in admixture with a pharmaceutically acceptable carrier. The antibody may be a monoclonal or polyclonal antibody. In some embodiments, the antibody(ies) administered to the subject has been humanized. In some embodiments, the antibody(ies) is administered to the subject are human. In some embodiments, the antibody(ies) administered to the subject have one, two, or more, or all of the characteristics of the antibodies described in Section 6, infra. In some embodiments, the subject is a human. In some embodiments, the subject is a human infant. In some embodiments, the subject is a human child. In some embodiments, the subject is a human adult. In some embodiments, the subject is an elderly human.

[00392] In some embodiments, the antibody(ies) or pharmaceutical composition is administered may be administered to a subject by a variety of routes. For example, the antibody(ies) or pharmaceutical composition may be administered parenterally. In some embodiments, the antibody(ies) or pharmaceutical composition is administered intramuscularly. In some embodiments, the antibody(ies) or pharmaceutical composition is administered subcutaneously. In some embodiments, the antibody(ies) or pharmaceutical composition is administered intravenously.

[00393] In some embodiments, the antibody(ies) or pharmaceutical composition is administered to a subject at a dose of 5 mg/kg to 50 mg/kg. In some embodiments, the average weight of a human adult subject is 60 kg to 80 kg. In some embodiments, the average weight of a human child is 9 kg to 60 kg. In some embodiments, the average weight of a human infant is 3 kg to 10 kg. In some embodiments, the antibody(ies) or pharmaceutical composition is administered to a subject at a dose of 45 mg to 4,000 mg.

[00394] In some embodiments, the methods of treating and/or preventing an influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus) in a subject results in one, two, or more of the following: prevents the onset of one or more symptoms of the disease, reduces the number of symptoms of the disease, reduces the severity of the symptoms of the disease, and/or reduces the length of the disease.

5.6 Biological Assays

[00395] Also provided herein are biological assays that may be used to characterize a chimeric HA, nucleic acid sequence encoding such chimeric HA, and viruses containing, expressing, or both such chimeric HA. See, also, Section 6 below. In specific embodiments, an assay described in Section 6 below is used to characterize a chimeric HA, a nucleic acid molecule encoding such chimeric HA, or virus containing, expressing, or both such chimeric HA. In specific embodiments, the immunogenicity or effectiveness of an immunogenic composition described herein is assessed using one, two, or more assays described in Section 6 below. In some embodiments, the B-cell mediated immune response induced by an immunogenic composition described herein is assessed using techniques known in the art. In some embodiments, the T-cell mediated immune response induced by an immunogenic composition described herein is assessed using techniques known in the art, such as, e.g., in Example 1 below. In some embodiments, a hemagglutinin inhibition assay and/or a microneutralization is used to assess the antibody response induced following administration of an immunogenic composition described herein.

5.6.1 Assays For Testing Activity Of Chimeric HA

[00396] Assays for testing the expression of a chimeric HA in an influenza A virus may be conducted using any assay known in the art. For example, an assay for incorporation into an influenza virus comprises growing the virus, such as described in Section 5.4 or 6, purifying the viral particles by centrifugation through a sucrose cushion, and subsequent analysis for chimeric HA expression by an immunoassay, such as Western blotting, using methods well known in the art. Methods for determining whether a hemagglutinin polypeptide is chimeric are known to those of skill in the art.

[00397] In some embodiments, a chimeric HA disclosed herein is assayed for proper folding and functionality by testing its ability to bind specifically to a neutralizing antibody directed to an influenza virus hemagglutinin polypeptide, such as the HA stalk domain of the chimeric HA, using any assay for antibody-antigen interaction known in the art. Neutralizing antibodies for use in such assays include, for example, the neutralizing antibodies described in Ekiert et al., 2009, Science Express, 26 February 2009; Kashyap et al., 2008, Proc Natl Acad Sci USA 105: 5986-5991; Sui et al. 2009, Nature Structural and Molecular Biology, 16:265-273; Wang et al., 2010, P LOS Pathogens 6(2): 1-9; U.S. Patent Nos. 5,589,174, 5,631,350, 6,337,070, and 6,720,409; International Application No. PCT/US2007/068983 published as International Publication No. WO 2007/134237; International Application No. PCT/US2008/075998 published as International Publication No. WO 2009/036157;

International Application No. PCT/EP2007/059356 published as International Publication No. WO 2008/028946; and International Application No. PCT/US2008/085876 published as International Publication No. WO 2009/079259. These antibodies include CR6261, CR6325, CR6329, CR6307, CR6323, 2A, D7, D8, F10, G17, H40, A66, D80, E88, E90, H98, C179 (FERM BP-4517), ADC (FERM BP-4516), among others.

[00398] In some embodiments, a chimeric HA disclosed herein is assayed for proper folding by determination of the structure or conformation of the chimeric HA using any method known in the art such as, e.g., NMR, X-ray crystallographic methods, or secondary structure prediction methods, e.g., circular dichroism. In some embodiments, a chimeric HA disclosed is assayed for proper folding as described in Section 6, infra.

[00399] In some embodiments, a chimeric HA disclosed herein is assayed for retention of one, two, or more, or all of the functions of a wild-type influenza HA. Nonlimiting examples of functions of a wild-type influenza HA include fusogenic activity, receptor binding activity, budding, and particle formation. In a specific embodiment, a chimeric HA disclosed herein is assayed for fusogenic activity. Assays known to one skilled in the art can be utilized the assess the fusogenic activity of a chimeric influenza HA polypeptide described herein, such as, for example, immunofluorescence assays and pseudotyped virus-like-particle assays. In some embodiments, the activity of a chimeric HA polypeptide described herein is assessed in one or more of the following assays: hemagglutination assay(s), fusion assay(s) or budding assay(s).

5.6.2 Assays For Testing Activity Of Antibodies Generated Using Immunogenic Compositions

[00400] Antibodies generated using a chimeric HA may be characterized in a variety of ways known to one of skill in the art (e.g., ELISA, Surface Plasmon resonance display (BIAcore), Western blot, immunofluorescence, immunostaining and/or microneutralization assays. In some embodiments, antibodies are assayed for the ability to specifically bind to a chimeric HA, or an influenza A virus comprising a chimeric HA. In some embodiments, geometric mean titer (GMT) is assessed using techniques known to one of skill in the art, such as, e.g., an ELISA.

[00401] Specific binding of an antibody to an influenza virus HA or a domain thereof and cross-reactivity with other antigens can be assessed by any method known in the art. Immunoassays which can be used to analyze specific binding and cross-reactivity include, but are not limited to, competitive and non-competitive assay systems using techniques such as western blots, radioimmunoassays, ELISA (enzyme linked immunosorbent assay), "sandwich" immunoassays, immunoprecipitation assays, precipitin reactions, gel diffusion precipitin reactions, immunodiffusion assays, agglutination assays, complement-fixation assays, immunoradiometric assays, fluorescent immunoassays, protein A immunoassays, to name but a few. Such assays are routine and well known in the art (see, e.g., Ausubel et al., eds., 1994, Current Protocols in Molecular Biology, Vol. 1, John Wiley & Sons, Inc., New York, which is incorporated by reference herein in its entirety). [00402] The binding affinity of an antibody to an influenza virus HA or a domain thereof can be determined using techniques known to one of skill in the art. “Binding affinity” generally refers to the strength of the sum total of non- covalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen).

Unless indicated otherwise, as used herein, “binding affinity” refers to intrinsic binding affinity which reflects a 1 : 1 interaction between members of a binding pair (e.g., antibody and antigen). The affinity of a molecule X for its partner Y can generally be represented by the dissociation constant (KD). Affinity can be measured and/or expressed in a number of ways known in the art, including, but not limited to, equilibrium dissociation constant (KD), equilibrium association constant (KA), and IC50. The KD is calculated from the quotient of koff/kon, whereas KA is calculated from the quotient of kon/koff kon refers to the association rate constant of, e.g., an antibody to an antigen, and koff refers to the dissociation of, e.g., an antibody to an antigen. The kon and koff can be determined by techniques known to one of ordinary skill in the art, such as BIAcore™, Kinexa, or biolayer interferometry. Affinity can be measured by common methods known in the art, including those described herein. For example, individual association (kon) and dissociation (koff) rate constants can be calculated from the resulting binding curves using the BIAevaluation software available through the vendor. Data can then be fit to a 1 : 1 binding model, which includes a term to correct for mass transport limited binding, should it be detected. From these rate constants, the apparent dissociation binding constant (KD) for the interaction of the antibody (e.g., IgG) with the antigen (e.g., influenza A virus HA) can be calculated from the quotient of koff/kon. Low-affinity antibodies generally bind antigen slowly and tend to dissociate readily, whereas high-affinity antibodies generally bind antigen faster and tend to remain bound longer. A variety of methods of measuring binding affinity are known in the art, any of which can be used for purposes of the described herein. In some embodiments, the koff is determined using a monovalent antibody, such as a Fab fragment, as measured by, e.g., BIAcore™ surface plasmon resonance technology, Kinexa, or biolayer interferometry.

[00403] The neutralizing activity of an antibody can be determined utilizing any assay known to one skilled in the art. For example, an antibody may be assessed using a microneutralization assay described in Section 6, infra. Antibodies described herein can be assayed for their ability to inhibit the binding of an influenza virus, or any other composition comprising a chimeric HA to its host cell receptor (z.e., sialic acid) using techniques known to those of skill in the art. [00404] In some embodiments, an antibody suitable for use in the methods described herein does not inhibit influenza virus receptor binding, yet is still found to be neutralizing in an assay described herein. In some embodiments, an antibody suitable for use in accordance with the methods described herein reduces or inhibits virus-host membrane fusion in an assay known in the art or described herein.

[00405] In some embodiment, virus-host membrane fusion is assayed in an in vitro assay using an influenza virus containing a reporter and a host cell capable of being infected with the virus. An antibody inhibits fusion if reporter activity is inhibited or reduced compared to a negative control (e.g., reporter activity in the presence of a control antibody or in the absence of antibody).

[00406] In some embodiments, an antibody is assessed in a ADCC reporter assay known in the art or described in Section 6, infra.

5.6.3 Cytotoxicity Assays

[00407] Many assays well-known in the art can be used to assess viability of cells (infected or uninfected) or cell lines following exposure to an immunogenic composition described herein and, thus, determine the cytotoxicity of the composition. For example, cell proliferation can be assayed by measuring Bromodeoxyuridine (BrdU) incorporation (See, e.g., Hoshino et al., 1986, Int. J. Cancer 38, 369; Campana et al., 1988, J. Immunol. Meth. 107:79), (3H) thymidine incorporation (See, e.g., Chen, J., 1996, Oncogene 13: 1395-403; Jeoung, J., 1995, J. Biol. Chem.

270: 18367 73), by direct cell count, or by detecting changes in transcription, translation or activity of known genes such as proto-oncogenes (e.g., fos, myc) or cell cycle markers (Rb, cdc2, cyclin A, DI, D2, D3, E, etc). The levels of such protein and mRNA and activity can be determined by any method well known in the art. For example, protein can be quantitated by known immunodiagnostic methods such as ELISA, Western blotting or immunoprecipitation using antibodies, including commercially available antibodies. mRNA can be quantitated using methods that are well known and routine in the art, for example, using northern analysis, RNase protection, or polymerase chain reaction in connection with reverse transcription. Cell viability can be assessed by using trypan-blue staining or other cell death or viability markers known in the art. In a specific embodiment, the level of cellular ATP is measured to determined cell viability.

[00408] In specific embodiments, cell viability is measured in three-day and seven-day periods using an assay standard in the art, such as the CellTiter-Glo Assay Kit (Promega) which measures levels of intracellular ATP. A reduction in cellular ATP is indicative of a cytotoxic effect. In another specific embodiment, cell viability can be measured in the neutral red uptake assay. In other embodiments, visual observation for morphological changes may include enlargement, granularity, cells with ragged edges, a filmy appearance, rounding, detachment from the surface of the well, or other changes. These changes are given a designation of T (100% toxic), PVH (partially toxic-very heavy-80%), PH (partially toxic- heavy-60%), P (partially toxic-40%), Ps (partially toxic-slight-20%), or 0 (no toxicity-0%), conforming to the degree of cytotoxicity seen. A 50% cell inhibitory (cytotoxic) concentration (ICso) is determined by regression analysis of these data.

[00409] In specific embodiments, the cells used in the cytotoxicity assay are animal cells, including primary cells and cell lines. In some embodiments, the cells are human cells. In certain embodiments, cytotoxicity is assessed in one or more of the following cell lines: U937, a human monocyte cell line; primary peripheral blood mononuclear cells (PBMC); Huh7, a human hepatoblastoma cell line; 293 T, a human embryonic kidney cell line; and THP-1, monocytic cells. In certain embodiments, cytotoxicity is assessed in one or more of the following cell lines: MDCK, MEF, Huh 7.5, Detroit, or human tracheobronchial epithelial (HTBE) cells.

5.6.4 Animal Model Assays

[00410] A composition (e.g., an immunogenic composition) described herein is preferably assayed in vivo for the desired therapeutic or prophylactic activity prior to use in humans (see, e.g., Section 6 below). For example, to assess the use of composition (e.g., an immunogenic composition) described herein to prevent an influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus), the composition can be administered before the animal is infected with influenza virus. Alternatively, or in addition, composition (e.g., an immunogenic composition) described herein can be administered to the animal at the same time that the animal is infected with influenza virus. To assess the use of a composition described herein to treat an influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus), the composition may be administered after infecting the animal with influenza virus. In specific embodiments, a composition (e.g., an immunogenic composition) described herein is administered to the animal more than one time.

[00411] A composition (e.g., an immunogenic composition) described herein can be tested in animal model systems including, but are not limited to, rats, mice, chicken, cows, monkeys, pigs, ferrets, goats, sheep, dogs, rabbits, guinea pigs, etc. In a specific embodiment, a composition (e.g., an immunogenic composition) described herein is tested in a mouse model system. Such model systems are widely used and well-known to the skilled artisan. In some embodiments, the mouse model is one described in Section 6, infra. In some embodiments, an influenza virus animal models, such as ferret, mouse, guinea pig, squirrel monkey, macaque, and chicken, may be used to test the effectiveness of a composition (e.g., an immunogenic composition) described herein. See, e.g., Sidwell et al., Antiviral Res., 2000, 48: 1-16; Lowen A.C. et al., PNAS., 2006, 103: 9988-92; and McCauley et al., Antiviral Res., 1995, 27: 179-186; and Rimmelzwann et al., Avian Diseases, 2003, 47:931-933.

[00412] In general, animals are infected with influenza virus and concurrently or subsequently treated with a composition (e.g., an immunogenic composition) described herein, or placebo. Alternatively, animals are treated with a composition (e.g., an immunogenic composition) described herein or placebo and subsequently infected with influenza virus. Samples obtained from these animals (e.g., serum, urine, sputum, semen, saliva, plasma, or tissue sample) can be tested for viral replication via well known methods in the art, e.g., those that measure altered viral titers (as determined, e.g., by plaque formation), the production of viral proteins (as determined, e.g., by Western blot, ELISA, or flow cytometry analysis) or the production of viral nucleic acids (as determined, e.g., by RT-PCR or northern blot analysis). For quantitation of virus in tissue samples, tissue samples may be homogenized in phosphate-buffered saline (PBS), and dilutions of clarified homogenates are adsorbed for 1 hour at 37°C onto monolayers of cells (e.g., Vero, CEF or MDCK cells). In other assays, histopathologic evaluations may be performed after infection, preferably evaluations of the organ(s) the virus is known to target for infection. Virus immunohistochemistry can be performed using a viral-specific monoclonal antibody.

[00413] The effect of a composition (e.g., an immunogenic composition) described herein on, e.g., the immune response in an infected subject administered the composition, the number, duration and/or severity of the symptoms in an infected subject administered the composition, and/or the time period before onset of one or more symptoms in an infected subject administered the composition, is assessed. Techniques known to one of skill in the art can be used to measure such effects.

[00414] For mouse models of influenza, non-limiting examples of parameters that can be used to assay antiviral activity of active compounds administered to the influenza-infected mice include pneumonia-associated death, animal weight, lung virus assayed by hemagglutinin, lung virus assayed by plaque assays, and histopathological change in the lung. Statistical analysis is carried out to calculate significance (e.g., a P value of 0.05 or less).

[00415] Histopathologic evaluations may be performed after infection of an animal model subject. Nasal turbinates and trachea may be examined for epithelial changes and subepithelial inflammation. The lungs may be examined for bronchiolar epithelial changes and peribronchiolar inflammation in large, medium, and small or terminal bronchioles. The alveoli are also evaluated for inflammatory changes.

5.7 Kits

[00416] Provided herein is a kit comprising one or more containers filled with one or more of the ingredients of a pharmaceutical/immunogenic composition described herein. In some embodiments, provided herein is a kit comprising a container containing a chimeric HA described herein. In some embodiments, provided herein is a kit comprising a container containing an inactivated influenza virus described herein. In some embodiments, provided herein is a kit comprises a container containing an inactivated split influenza virus described herein. In some embodiments, provided herein is a kit comprising a container containing an inactivated influenza virus and a container containing a CpG oligonucleotide adjuvant. In some embodiments, provided herein is a kit comprising a container containing an inactivated split influenza virus and a container containing a CpG oligonucleotide adjuvant. In some embodiments, the kit further comprises a container containing an aluminum salt. In some embodiments, the kit does not further comprise a container containing an aluminum salt. In some embodiments, the aluminum salt comprises amorphous aluminum hydroxyphosphate sulfate, aluminum hydroxide, aluminum phosphate, and potassium aluminum sulfate. In some embodiments, provided herein is a kit comprising a container containing an antibody produced by a method described herein. Optionally associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration.

[00417] Also provided herein is a kit comprising one or more containers filled a composition described herein (e.g., an immunogenic composition described herein, or a pharmaceutical composition described herein). In some embodiments, provided herein is a pharmaceutical composition described herein. In some embodiments, provided herein is a kit comprising a container containing an immunogenic composition described herein. In some embodiments, provided herein is a kit comprising: (a) a first container containing a first immunogenic composition described herein; and (b) a second container containing a second immunogenic composition described herein, wherein the first and second immunogenic compositions are different. In some embodiments, the first and second immunogenic compositions are different because the inactivated or inactivated split influenza virus of the first and second immunogenic compositions comprise different chimeric HAs. The chimeric HAs may be different because the HA globular head domain of each chimeric HA comprises an amino acid sequence of the HA globular head domain of a different strain, subtype, or group. Optionally associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration.

[00418] In some embodiments, provided herein is a kit comprising: (a) a first container containing a first immunogenic composition comprising a first chimeric HA and a CpG oligonucleotide adjuvant described herein, wherein the first chimeric HA comprises a first influenza virus HA globular head domain and a first influenza virus HA stalk domain, wherein the first HA stalk domain comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA; and (b) a second container containing a second immunogenic composition comprising a second chimeric HA and a CpG oligonucleotide adjuvant described herein, wherein the second chimeric HA comprises a second influenza virus HA globular head domain and a second influenza virus HA stalk domain, wherein the second HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA, wherein the second HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the second HA globular head domain. In some embodiments, provided herein is a kit comprising: (a) a first container containing a first immunogenic composition comprising a first inactivated influenza virus and a CpG oligonucleotide adjuvant described herein, wherein the first inactivated influenza virus comprises a first chimeric HA, wherein the first chimeric HA comprises a first influenza virus HA globular head domain and a first influenza virus HA stalk domain, wherein the first HA stalk domain comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA; and (b) a second container containing a second immunogenic composition comprising a second inactivated influenza virus and a CpG oligonucleotide adjuvant described herein, wherein the second inactivated influenza virus comprises a second chimeric HA, wherein the second chimeric HA comprises a second influenza virus HA globular head domain and a second influenza virus HA stalk domain, wherein the second HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA, wherein the second HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the second HA globular head domain. In some embodiments, the CpG oligonucleotide adjuvant of the first and second immunogenic compositions is the same. In some embodiments, the group 2 influenza A virus HA is of subtype H3. In some embodiments, the group 2 influenza A virus HA is A/Hong Kong/4801/2014, NYMC X-263 HA or A/Hong Kong/4801/2014-like HA. In some embodiments, the influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA is a group 1 influenza A virus HA. In some embodiments, the influenza A virus HA of a different strain, subtype, or group is subtype than the group 2 influenza A virus HA is HA of subtype H2, H5, H6, H8, H9, Hl 1, H12, H13, H16, H17, or H18. In some embodiments, the influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA is HA of subtype H4, H7, H10, H14, or H15. In some embodiments, the influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA is A/wedge-tailed shearwater/Western Australia/2576/1979 HA or A/wedge-tailed shearwater/We stern Australia/2576/1979-like HA. In some embodiments, the influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA is A/Duck/Czechoslovakia/1956 HA or A/Duck/Czechoslovakia/1956-like HA. In some embodiments, the first immunogenic composition and/or the second immunogenic composition comprises an aluminum salt. In some embodiments, the first immunogenic composition and/or the second immunogenic composition does not comprise an aluminum salt. In some embodiments, the aluminum salt comprises amorphous aluminum hydroxyphosphate sulfate, aluminum hydroxide, aluminum phosphate, and potassium aluminum sulfate. In some embodiments, the first immunogenic composition and/or second immunogenic composition are formulated for intramuscular or intranasal administration. [00419] In some embodiments, provided herein is a kit comprising: (a) a first container containing a first immunogenic composition comprising a first inactivated split influenza virus and a CpG oligonucleotide adjuvant described herein, wherein the first inactivated split influenza virus comprises a first chimeric HA, and wherein the first chimeric HA comprises a first influenza virus HA globular head domain and a first influenza virus HA stalk domain, wherein the first HA stalk domain comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA; and (b) a second container containing a second immunogenic composition comprising a second inactivated split influenza virus and a CpG oligonucleotide adjuvant described herein, wherein the second inactivated split influenza virus comprises a second chimeric HA, and wherein the second chimeric HA comprises a second influenza virus HA globular head domain and a second influenza virus HA stalk domain, wherein the second HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA, and wherein the second HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the second HA globular head domain. In some embodiments, the CpG oligonucleotide adjuvant of the first and second immunogenic compositions is the same. In some embodiments, the group 2 influenza A virus HA is of subtype H3. In some embodiments, the group 2 influenza A virus HA is A/Hong Kong/4801/2014, NYMC X-263 HA or A/Hong Kong/4801/2014-like HA. In some embodiments, the influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA is a group 1 influenza A virus HA. In some embodiments, the influenza A virus HA of a different strain, subtype, or group is subtype than the group 2 influenza A virus HA is HA of subtype H2, H5, H6, H8, H9, Hl 1, H12, H13, H16, H17, or Hl 8. In some embodiments, the influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA is HA of subtype H4, H7, Hl 0, Hl 4, or Hl 5. In some embodiments, the influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA is A/wedge-tailed shearwater/Westem Australia/2576/1979 HA or A/wedge-tailed shearwater/We stern Australia/2576/1979-like HA. In some embodiments, the influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA is A/Duck/Czechoslovakia/1956 HA or A/Duck/Czechoslovakia/1956-like HA. In some embodiments, the first immunogenic composition and/or the second immunogenic composition comprises an aluminum salt. In some embodiments, the first immunogenic composition and/or the second immunogenic composition does not comprise an aluminum salt. In some embodiments, the aluminum salt comprises amorphous aluminum hydroxyphosphate sulfate, aluminum hydroxide, aluminum phosphate, and potassium aluminum sulfate. In some embodiments, the first immunogenic composition and/or second immunogenic composition are formulated for intramuscular or intranasal administration. [00420] In some embodiments, provided herein is a kit comprising: (a) a first container containing a first immunogenic composition comprising a first chimeric HA and a CpG oligonucleotide adjuvant described herein, wherein the first chimeric HA comprises the HA globular head domain of influenza virus A/wedge-tailed/ shearwater/ Western Australia/2576/1979 HA and the HA stalk domain of influenza virus A/Hong Kong/48012014 (H3N2) NYMC X-263; and (b) a second container containing a second immunogenic composition comprising a second chimeric HA and a CpG oligonucleotide adjuvant described herein, wherein the second chimeric HA comprises the HA globular head domain of influenza virus A/duck/Czechoslovakia/1956 (H4N6) and the HA stalk domain of influenza virus A/Hong Kong/48012014 (H3N2) NYMC X-263. In some embodiments, provided herein is a kit comprising: (a) a first container containing a first immunogenic composition comprising a first inactivated influenza virus and a CpG oligonucleotide adjuvant described herein, wherein the first inactivated influenza virus comprises a first chimeric HA, wherein the first chimeric HA comprises the HA globular head domain of influenza virus A/wedge-tailed/shearwater/ Western Australia/2576/1979 HA and the HA stalk domain of influenza virus A/Hong Kong/48012014 (H3N2) NYMC X-263; and (b) a second container containing a second immunogenic composition comprising a second inactivated influenza virus and a CpG oligonucleotide adjuvant described herein, wherein the second inactivated influenza virus comprises a second chimeric HA, wherein the second chimeric HA comprises the HA globular head domain of influenza virus A/duck/Czechoslovakia/1956 (H4N6) and the HA stalk domain of influenza virus A/Hong Kong/48012014 (H3N2) NYMC X-263. In some embodiments, the first inactivated influenza virus and/or the second inactivated influenza virus comprise the neuraminidase of influenza virus A/Hong Kong/48012014 (H3N2) NYMC X-263. In some embodiments, the first inactivated influenza virus and/or the second inactivated influenza virus comprise proteins (e.g., non-structural proteins and matrix protein) encoded by genes from influenza virus A/Puerto Rico/08/1934 (H1N1). In some embodiments, provided herein is a kit comprising: (a) a first container containing a first immunogenic composition comprising a first inactivated split influenza virus and a CpG oligonucleotide adjuvant described herein, wherein the first inactivated split influenza virus comprises a first chimeric HA, wherein the first chimeric HA comprises the HA globular head domain of influenza virus A/wedge- tailed/shearwater/ Western Australia/2576/1979 HA and the HA stalk domain of influenza virus A/Hong Kong/48012014 (H3N2) NYMC X-263; and (b) a second container containing a second immunogenic composition comprising a second inactivated split influenza virus and a CpG oligonucleotide adjuvant described herein, wherein the second inactivated split influenza virus comprises a second chimeric HA, wherein the second chimeric HA comprises the HA globular head domain of influenza virus A/duck/Czechoslovakia/1956 (H4N6) and the HA stalk domain of influenza virus A/Hong Kong/48012014 (H3N2) NYMC X-263. In some embodiments, the first inactivated split influenza virus and/or the second inactivated split influenza virus comprise the neuraminidase of influenza virus A/Hong Kong/48012014 (H3N2) NYMC X-263. In some embodiments, the first inactivated split influenza virus and/or the second inactivated split influenza virus comprise proteins (e.g., non-structural proteins and matrix protein) encoded by genes from influenza virus A/Puerto Rico/08/1934 (H1N1). In some embodiments, the first immunogenic composition and/or the second immunogenic composition comprises an aluminum salt. In some embodiments, the first immunogenic composition and/or the second immunogenic composition does not comprise an aluminum salt. In some embodiments, the kit further comprises a third container containing an aluminum salt. In some embodiments, the aluminum salt comprises amorphous aluminum hydroxyphosphate sulfate, aluminum hydroxide, aluminum phosphate, and potassium aluminum sulfate. In some embodiments, the first immunogenic composition and/or second immunogenic composition are formulated for intramuscular or intranasal administration.

[00421] In some embodiments, provided herein is a kit comprising: (a) a first immunogenic composition comprising a first chimeric HA and a CpG oligonucleotide adjuvant described herein, wherein the first chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8; and (b) a second immunogenic composition comprising a second inactivated influenza A virus and a CpG oligonucleotide adjuvant described herein, wherein the second inactivated influenza A virus comprises a second chimeric HA, and wherein the second chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8, wherein the second chimeric HA comprises the amino acid sequence of SEQ ID NO: 5 or 6, if the first chimeric HA comprises the amino acid sequence of SEQ ID NO: 7 or 8, and the second chimeric HA comprises the amino acid sequence of SEQ ID NO: 7 or 8, if the first chimeric HA comprises the amino acid sequence of SEQ ID NO:5 or 6. In some embodiments, provided herein is a kit comprising: (a) a first immunogenic composition comprising a first inactivated influenza virus and a CpG oligonucleotide adjuvant described herein, wherein the first inactivated influenza virus comprises a first chimeric HA, and wherein the first chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8; and (b) a second immunogenic composition comprising a second inactivated influenza virus and a CpG oligonucleotide adjuvant described herein, wherein the second inactivated influenza virus comprises a second chimeric HA, and wherein the second chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8, wherein the second chimeric HA comprises the amino acid sequence of SEQ ID NO: 5 or 6, if the first chimeric HA comprises the amino acid sequence of SEQ ID NO: 7 or 8, and the second chimeric HA comprises the amino acid sequence of SEQ ID NO: 7 or 8, if the first chimeric HA comprises the amino acid sequence of SEQ ID NO:5 or 6. In some embodiments, provided herein is a kit comprising: (a) a first immunogenic composition comprising a first inactivated split influenza virus and a CpG oligonucleotide adjuvant described herein, wherein the first inactivated split influenza A virus comprises a first chimeric HA, and wherein the first chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8; and (b) a second immunogenic composition comprising a second inactivated split influenza A virus and a CpG oligonucleotide adjuvant described herein, wherein the second inactivated split influenza virus comprises a second chimeric HA, and wherein the second chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8, wherein the second chimeric HA comprises the amino acid sequence of SEQ ID NO: 5 or 6, if the first chimeric HA comprises the amino acid sequence of SEQ ID NO: 7 or 8, and the second chimeric HA comprises the amino acid sequence of SEQ ID NO: 7 or 8, if the first chimeric HA comprises the amino acid sequence of SEQ ID NO:5 or 6. In some embodiments, the CpG oligonucleotide adjuvant of the first and second immunogenic compositions is the same. ). In some embodiments, the first immunogenic composition and/or the second immunogenic composition comprises an aluminum salt. In some embodiments, the first immunogenic composition and/or the second immunogenic composition does not comprise an aluminum salt. In some embodiments, the kit further comprises a third container containing an aluminum salt. In some embodiments, the aluminum salt comprises amorphous aluminum hydroxyphosphate sulfate, aluminum hydroxide, aluminum phosphate, and potassium aluminum sulfate. In some embodiments, the first immunogenic composition and/or second immunogenic composition are formulated for intramuscular or intranasal administration. [00422] In some embodiments, provided herein is a kit comprising: (a) a first container containing a first immunogenic composition comprising an inactivated influenza virus and a CpG oligonucleotide adjuvant described herein, wherein the inactivated influenza virus comprises a first chimeric HA, and wherein the first chimeric HA comprises a first influenza virus HA globular head domain and a first influenza virus HA stalk domain, wherein the first HA stalk domain comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA; and (b) a second container containing a second immunogenic composition comprising a live attenuated influenza A virus, wherein the live attenuated influenza A virus comprises a second chimeric HA, and wherein the second chimeric HA comprises a second influenza virus HA globular head domain and a second influenza virus HA stalk domain, wherein the second HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA, and wherein the second HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the second HA globular head domain. In some embodiments, the CpG oligonucleotide adjuvant of the first and second immunogenic compositions is the same. In some embodiments, the group 2 influenza A virus HA is of subtype H3. In some embodiments, the group 2 influenza A virus HA is A/Hong Kong/4801/2014, NYMC X-263 HA or A/Hong Kong/4801/2014-like HA. In some embodiments, the influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA is a group 1 influenza A virus HA. In some embodiments, the influenza A virus HA of a different strain, subtype, or group is subtype than the group 2 influenza A virus HA is HA of subtype H2, H5, H6, H8, H9, Hl 1, H12, H13, H16, H17, or Hl 8. In some embodiments, the influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA is HA of subtype H4, H7, Hl 0, Hl 4, or Hl 5. In some embodiments, the influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA is A/wedge-tailed shearwater/Westem Australia/2576/1979 HA or A/wedge-tailed shearwater/We stern Australia/2576/1979-like HA. In some embodiments, the influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA is A/Duck/Czechoslovakia/1956 HA or A/Duck/Czechoslovakia/1956-like HA. In some embodiments, the first immunogenic composition comprises an aluminum salt. In some embodiments, the first immunogenic composition does not comprise an aluminum salt. In some embodiments, the kit further comprises a third container containing an aluminum salt. In some embodiments, the aluminum salt comprises amorphous aluminum hydroxyphosphate sulfate, aluminum hydroxide, aluminum phosphate, and potassium aluminum sulfate. In some embodiments, the first immunogenic composition and/or second immunogenic composition are formulated for intramuscular or intranasal administration. [00423] In some embodiments, provided herein is a kit comprising: (a) a first container containing a first immunogenic composition comprising an inactivated split influenza virus and a CpG oligonucleotide adjuvant described herein, wherein the inactivated split influenza virus comprises a first chimeric HA, and wherein the first chimeric HA comprises a first influenza virus HA globular head domain and a first influenza virus HA stalk domain, wherein the first HA stalk domain comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA; and (b) a second container containing a second immunogenic composition comprising a live attenuated influenza A virus, wherein the live attenuated influenza A virus comprises a second chimeric HA, and wherein the second chimeric HA comprises a second influenza virus HA globular head domain and a second influenza virus HA stalk domain, wherein the second HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA, and wherein the second HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the second HA globular head domain. In some embodiments, the CpG oligonucleotide adjuvant of the first and second immunogenic compositions is the same. In some embodiments, the group 2 influenza A virus HA is of subtype H3. In some embodiments, the group 2 influenza A virus HA is A/Hong Kong/4801/2014, NYMC X-263 HA or A/Hong Kong/4801/2014-like HA. In some embodiments, the influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA is a group 1 influenza A virus HA. In some embodiments, the influenza A virus HA of a different strain, subtype, or group is subtype than the group 2 influenza A virus HA is HA of subtype H2, H5, H6, H8, H9, Hl 1, H12, H13, H16, H17, or Hl 8. In some embodiments, the influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA is HA of subtype H4, H7, Hl 0, Hl 4, or Hl 5. In some embodiments, the influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA is A/wedge-tailed shearwater/Westem Australia/2576/1979 HA or A/wedge-tailed shearwater/We stern Australia/2576/1979-like HA. In some embodiments, the influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA is A/Duck/Czechoslovakia/1956 HA or A/Duck/Czechoslovakia/1956-like HA. In some embodiments, the first immunogenic composition comprises an aluminum salt. In some embodiments, the first immunogenic composition does not comprise an aluminum salt. In some embodiments, the kit further comprises a third container containing an aluminum salt. In some embodiments, the aluminum salt comprises amorphous aluminum hydroxyphosphate sulfate, aluminum hydroxide, aluminum phosphate, and potassium aluminum sulfate. In some embodiments, the first immunogenic composition and/or second immunogenic composition are formulated for intramuscular or intranasal administration. [00424] The kits encompassed herein can be used in accordance with the methods described herein.

5.8 Sequences

TABLE 5: SEQUENCE INFORMATION

6. EXAMPLE 1: CHIMERIC HEMAGGLUTININ SPLIT VACCINES ELICIT BROADLY 1 CROSS-REACTIVE ANTIBODIES AND PROTECTION AGAINST GROUP 2 INFLUENZA VIRUSES IN MICE

[00425] This example provides data demonstrating that immunization with group 2 chimeric hemagglutinin (“cHA”) split vaccines in combination with the CpG 1018® adjuvant elicits broadly cross-reactive antibodies against all group 2 HAs, as well as systemic and local antigen-specific T cell responses. The antibodies elicited after sequential vaccination are directed to conserved regions of the HA such as the stalk and the trimer interface, and also to the N2 neuraminidase (NA). Immunized mice were fully protected from challenge with a broad panel of influenza A viruses, suggesting that this vaccine candidate represents a major step forward towards a universal influenza virus vaccine.

6.1.1 Introduction

[00426] Seasonal influenza virus vaccines are most effective when they are well matched to circulating strains. Because of antigenic drift/change in the immunodominant hemagglutinin (HA) head domain, annual vaccine reformulations are necessary to maintain a match with circulating strains. In addition, current seasonal influenza vaccines provide little to no protection against newly emerging pandemic strains. Therefore, the development of broadly protective vaccines is of high importance. One of the main approaches to develop this type of vaccine is to target conserved regions in the HA such as the receptor binding site and the trimer interface in the head domain (13), and the stalk domain (14). Several strategies that target the immunosubdominant HA stalk domain are currently under evaluation, including the use of hyperglycosylated HA heads, which direct the immune responses toward the stalk (15); and the construction of stabilized headless HA immunogens (16-19), and of chimeric HA (cHA) spikes (20). cHAs are generated by swapping the HA head domains of seasonal influenza viruses with those of other influenza virus subtypes that do not circulate in humans (20-22) (FIG. 2A). Sequential vaccination with different cHA constructs has been proven to elicit broadly cross-reactive HA stalk antibodies in different animals models (23-25) and in humans (26-28). Most of these studies have been conducted with group 1 cHA constructs as recombinant proteins, live-attenuated influenza vaccine (LAIV), vectored vaccines, or as inactivated split vaccines in combination with the AS03 adjuvant. However, group 1 cHA vaccines induce little cross-reactivity to group 2 HAs. Moreover, there is less information available on the protective efficacy mediated by group 2 cHA constructs (29, 30).

[00427] In this study, group 2 cHA vaccine candidates, CH15/3HKI4N2HKI4 and CH4/3HKI4N2HKI4, have been developed and tested them as live attenuated influenza vaccines (LAIV), inactivated split vaccines in combination with the toll-like receptor 9 agonist adjuvant, CpG 1018® adjuvant (31), and combinations of these two platforms in the mouse model. It was observed that sequential vaccination with these vaccines elicits broadly cross- reactive and protective responses against a variety of influenza A viruses (FIG. 2B). These results represent a step forward in the development of a universal influenza vaccine and will guide clinical development in humans. 6.1.2 Materials and Methods

[00428] Study design

[00429] This study was designed for the preclinical evaluation of group 2 cHA constructs as universal influenza virus vaccines in the mouse model. The protective efficacy of this vaccine was evaluated by comparing weight loss and survival profiles of sequentially immunized mice and controls against challenge with a broad range of heterologous and heterosubtypic influenza viruses. Different vaccine and adjuvant doses were tested. The analysis of serum cross-reactivity against different HAs and Nas, type of IgG response, the elicitation of HA stalk antibodies, competitive inhibition of HA head trimer interface antibodies, and screening of mouse sera for different effector functions including antibody dependent cell-mediated cytotoxicity (ADCC), neuraminidase inhibition (NAI), and microneutralization was performed. In addition, the presence of antigen specific CD4⁺ and CD8⁺ T cell responses, and the contribution of serum antibodies to protection was also assessed. Randomization was achieved by randomly distributing mice into different cages upon arrival. No animal subjects were excluded from the sample collection or analysis. No blinding was applied to the study design.

[00430] Cell lines

[00431] Baculovirus generation and amplification was performed in Sf9 cells (CRL-1771, ATCC), a clonal isolate of Spodoptera frugiperda Sf21 cells, and grown in Trichoplusia ni medium formulation Hink insect cell medium (TNM-FH, Gemini Bioproducts) supplemented with 10% (v/v) fetal bovine serum (FBS, Gibco), penicillin (100 U/mL) -streptomycin (100 pg/mL) solution (Gibco), and 0.1% (v/v) Pluronic F-68 (Gibco). High Five cells (BTI-TN- 5B1-4, B85502, Thermo Fisher Scientific) were grown in Express Five SFM (Gibco) supplemented with 16 mM L-glutamine (Gibco) and used for recombinant HA and NA production (32). Both adherent cell lines were grown at 27 °C. Adherent Madin-Darby canine kidney (MDCK) and Human Embryonic Kidney 293T cells were grown in modified Eagle’s medium (MEM) containing 10% (v/v) FBS and penicillin (100 U/mL) -streptomycin (100 pg/mL) solution in a humidified incubator at 37 °C and 5% CO2.

[00432] Recombinant proteins and monoclonal antibodies

[00433] Recombinant HA and NA were produced in High Five cells and purified from cell culture supernatant using a Ni²⁺ -nitrilotriacetic acid resin chromatography (32). The headless mini Hl protein was expressed in mammalian Expi293F cells (33). The anti- A/Philippines/2/1982 HA head murine monoclonal antibody 1F12 was produced from hybridomas previously generated using a classical hybridoma fusion protocol (34).

[00434] Viruses

[00435] Group 2 CH15/3HKI4N2HKI4 and CH4/3HKI4N2HKI4 viruses expressing different cHA proteins were generated by reverse genetics (35). The Hl 5 head domain of the CH15/3HKI4N2HKI4 virus was derived from the HA of A/shearwater/West Australia/2576/1979 (H15N9) virus, and the H4 head domain of the CH4/3HKI4N2HKI4 virus from A/duck/Czechoslovakia/1956 (H4N6) virus. The HA stalk domain and the NA of both viruses were derived from the A/Hong Kong/4801/2014 (H3N2) virus. As for inactivated split influenza virus (split) vaccines, the internal genes were derived from the donor vaccine strain A/Puerto Rico/8/1934 (A/PR/8/34) (H1N1) virus, whereas the internal genes for the LAIV were derived from the master donor A/Leningrad/134/17/1957 (H2N2) virus (36). The B-cH5/l virus was also generated by reverse genetics (37, 38). The head domain of the chimeric B-cH5/l virus was derived from the A/Vietnam/1203/2004 (H5N1) virus and the HA stalk domain from the A/Puerto Rico/8/1934 (H1N1) virus. Since the stalk domain was derived from the Hl HA, no polybasic cleavage site was included in this construct. In this case, the NA and the internal genes were derived from the B/Yamagata/16/1988 virus.

[00436] The influenza A virus A/Hong Kong/4801/2014 (H3N2, 6:2 A/Puerto Rico/8/1934 H1N1 reassortant) (39), H6N2A/Hon_gKon_g/480i/20i4 (6:2 A/PR/8/34 reassortant) (40), A/Switzerland/9715293/2013 (H3N2) (mouse-adapted) (41), A/Philippines/2/1982 (H3N2, X-79 6:2 A/PR/8/34 reassortant, mouse-adapted) (42), A/canine/Illinois/41915/2015 (H3N2) (43), A/swine/Missouri/AO 1727926/2015 (H4N6, 6:2 A/PR/8/34 reassortant) (44), A/Hunan/02285/2017 (H7N1, 7: 1 153 A/PR/8/34 reassortant) (45), virus A/Shanghai/1/2013 (H7N9, 6:2 A/PR/8/34 reassortant) (46), A/Jiangxi-Donghu/346/2013 (H10N8, 6:2 A/PR/8/34 reassortant) (47), A/mallard/Gurjev/263/1982 (H14N1, 7: 1 A/PR/8/34 reassortant), A/shearwater/West Australia/2576/1979 (H15N5) (6: 1 : 1 A/PR/8/34 reassortant), A/Singapore/GP 1908/2015 (H1N1, 6:2 A/Texas/1/1977 H3N2 reassortant) (National Institute for Biological Standards and Control), as well as the cHA viruses previously mentioned were grown in 10-day old embryonated chicken eggs at 37 °C for 48h, and cooled at 4 °C overnight (O/N). Cell debris was removed by low-speed centrifugation (4000*g, 4 °C, 20 min). Viruses were aliquoted, stored at -80 °C, and titrated by the plaque assay method on MDCK cells (48). The HA from H6N2A/Hong Kong/4801/2014 virus was derived from the A/turkey/Massachusetts/3740/1965 (H6N2) virus, and the NA from A/shearwater/West Australia/2576/1979 (H15N5) virus was derived from the A/mallard/Sweden/86/2003 (H12N5) virus.

[00437] All viruses described herein this Example were generated by reverse genetics except for A/Switzerland/9715293/2013 (H3N2), which was adapted to mice by serial passaging, and A/canine/Illinois/41915/2015, which was grown in MDCK cells after isolation.

[00438] Production of inactivated split influenza virus vaccines

[00439] Vaccine production was performed as previously described (49). Virus inactivation was performed with 0.05% (v/v) beta-propiolactone (Millipore Sigma) prepared in ice-cold water for injection (Gibco) for 30 min after pH buffering with 0.01 M disodium hydrogen phosphate (Millipore Sigma) and stopped by incubation at 37 °C for 2h. Then, the inactivated virus sample was centrifuged at 4000 rpm, 4 °C for 30 min. 25-30 mL of supernatant were loaded on 5 mL of 30% (w/v) sucrose cushion prepared in IX NTE buffer consisting of 1 M NaCl, 100 mM Tris-HCl, 10 mM ethylenediaminetetraacetic acid (EDTA) in water for injection with the pH adjusted to 7.4. The supernatant containing the inactivated virus was concentrated by high-speed centrifugation (25000 rpm, 4 °C for 2h), and the pelleted virus was resuspended in phosphate buffered saline (PBS, pH=7.4, Gibco). The resuspended virus was split with 1% (v/v) Triton X-100 (Fisher Bioreagents), and the detergent was removed by incubation with 0.2-0.3 g of Bio-Beads SM-2 (BioRad) per mL of inactivated split virus. The supernatant was collected, and the total protein concentration was adjusted to 0.5-1 mg/mL 184 with PBS (pH=7.4) using the Bradford assay (BioRad).

Vaccine samples were aliquoted and stored at -80 °C until use. The concentration of HA in the final CH15/3HKI4N2HKI4 and CH4/3HKI4N2HKI4 vaccine preparations was quantified in a non-reducing Western Blot with the 12D1 murine monoclonal antibody (50). Different dilutions of an H3 HK14 recombinant protein standard of known concentration from the A/Hong Kong/4801/2014 (H3N2) virus were also included for absolute HA quantification. [00440] Enzyme-linked immunosorbent assay [00441] Immulon 4HBX 96-well plates (Thermo Fisher Scientific) were coated with 2 pg/mL of recombinant protein (50 pL per well) in PBS (pH=7.4) at 4 °C O/N. The next day, plates were washed three times with PBS containing 0.1 % (v/v) Tween 20 (PBS-T) and blocked in blocking solution (3 % (v/v) goat serum, 0.5 % (w/v) non-fat dry milk in PBS-T) for Ih at room temperature (RT). After blocking, mouse serum was added to the first well at a 1 :30 dilution (150 pL/well) and serially diluted 1 :3 in blocking solution and incubated for 2h at 20 °C. Plates were washed three times with PBS-T before adding the secondary antibody (100 pL/well). For total IgG quantification, a 1 :3000 dilution of sheep anti-mouse IgG (H&L) peroxidase conjugated (Rockland) in blocking solution was added. For IgGl and IgG2a quantification, a 1 :20,000 and 1 :2,000 dilution in blocking solution of rabbit antimouse IgGl or rabbit anti-mouse IgG2a (Invitrogen) was added, respectively. Afterwards, plates were incubated for Ih at 20 °C and then washed four times with PBS-T with shaking. To develop plates, 100 pL of O-phenylenediamine dihydrochloride (OPD) substrate (SigmaFast OPD, Millipore Sigma) was added to each well. After a 10 min incubation, the reaction was stopped by adding 50 pL of 3M hydrochloric acid (HC1) to each well. The optical density at 490 nm (OD490) was measured on a Synergy Hl microplate reader (BioTek). A cut-off value of the average of the OD490 values of blank wells plus 3 times the standard deviation (SD) was established for each plate and used for calculating the area under the curve (AUC). AUC values were determined using GraphPad Prism 9 software.

[00442] Competition ELISA

[00443] Immulon 4HBX 96-well plates were coated with 2 pg/mL of recombinant A/Hong Kong/4801/2014 H3 (H3 HK14) protein (50 pL per well) in PBS (pH=7.4) O/N at 4 °C. Plates were washed three times with PBS-T and blocked in blocking solution for 1.5 h at RT. After discarding the blocking solution, mouse serum was added to the first well at a 1 :50 dilution (100 pL/well) and serially diluted 1 :3 in blocking solution and incubated for 2h at 20 °C. Plates were then washed three times with PBS-T, and 100 pL/well of biotinylated FluA- 20 monoclonal antibody (51) at a concentration of 0.05 pg/mL was added and plates incubated at 20 °C for Ih. Plates were washed three times with PBS-T and subsequently incubated with a 1 :3000 dilution of streptavidin conjugated to horseradish peroxidase (Thermo Fisher Scientific) in blocking solution (100 pL/well). After Ih incubation at 20 °C, plates were washed four times with PBS-T with shaking and then developed with 100 pL of OPD substrate per well. After 10 min incubation, the reaction was stopped by adding 50 pL of 3M HC1 to each well. The OD490 was measured on a Synergy Hl microplate reader. Antibody competition was defined as the percentage ratio between sample signal and the signal of FluA-20 mAb binding without serum, and calculated as (l-(ODsam_Pie/ODno serum control)) ^x 100. The data were analyzed using GraphPad Prism 9 software and values were expressed as AUC. The background of the assay was defined as the average of the AUC from the mice serum of the PBS group.

[00444] Antibody-Dependent Cellular Cytotoxicity (ADCC) reporter assay

[00445] ADCC activity in mouse sera was assessed using an FcyRIV cell-based ADCC reporter assay according to the manufacturer’s instructions (Promega) (52). Briefly, white 96-well plates (Corning) were seeded with 2 * 10⁴ cells of MDCK cells per well and incubated O/N at 37 °C and 5% CO2. After 24 h, MDCK cells were washed with PBS and infected with A/Hong Kong/4801/2014 (H3N2) virus at a multiplicity of infection of 5 for a single cycle of virus replication and incubated overnight at 37 °C and 5% CO2. The following day, the cell culture medium was removed and 25 pL of assay buffer (Roswell Park Memorial Institute (RPMI) 1640 medium supplemented with 4% (v/v) low IgG FBS, Gibco) was added to each well. Mouse sera previously heat-inactivated at 56 °C for Ih were serially diluted 2-fold in RPMI 1640 medium and added to the infected MDCK cells (25 pL/well). The sera were incubated with MDCK cells at 37 °C for 30 min. Then, 7.5 x 10⁴ Jurkat cells expressing the mouse FcyRIV with a luciferase reporter gene under transcriptional control of the nuclear factor-activated T cell promoter (Promega) were added per well (25 pL/well) and incubated at 37 °C for 6h. After incubation, 75 pL of Bio-Gio luciferase assay reagent (Promega) was added per well and incubated at RT in the dark for 10 min. The luminescence signal was measured using a Synergy Hl microplate reader. The fold induction was calculated as follows; (RLUinduced-RLUbackground)/(RLUno antibody control- RLUbackground), where RLU is relative luminescence units (52). The AUC values of the resulting fold-induction values were calculated using the GraphPad Prism 9 software.

[00446] Neuraminidase inhibition assay

[00447] The NA activity of H6N2A/Hon_g Kong/4801/2014 virus was assessed by NA assay on Immulon 4HBX 96-well plates coated with 100 pL of fetuin (Millipore Sigma) at 25 pg/mL in PBS at 4 °C O/N. Fetuin-coated plates were washed three times with PBS-T and blocked with PBS + 5% (v/v) bovine serum albumin (BSA, MP Biomedicals). On a separate plate, the virus was serially diluted 1 :2 in PBS + 1% (w/v) BSA, and 75 pL of pre-diluted virus samples were added to fetuin-coated plates already containing 75 pL of PBS + 1% (w/v) BSA. The fetuin-coated plates were incubated at 37 °C O/N. Afterwards, plates were washed four times with PBS-T with shaking, and 100 pL per well of peroxidase labeled lectin from A rach is hypogaea (peanut agglutinin, PNA, Millipore Sigma) at 5 pg/mL in PBS + 1% (v/v) BSA was added to the plates. Plates were incubated at 20 °C for 1.5h before washing four times with PBS-T with shaking. To develop the plates, 100 pL of OPD substrate were added per well, incubated for 10 min at RT, and the reaction was stopped by adding 50 pL of 3M HC1 per well. The OD490 was measured on a Synergy Hl microplate reader, and the half maximal effective concentration (EC50) was determined using the GraphPad Prism 9 software. [00448] For the NAI assay, Immulon 4HBX 96-well plates were coated with 100 pL of fetuin at 25 pg/mL in PBS at 4 °C O/N. Fetuin-coated plates were washed three times with PBS-T and blocked with PBS + 5% (v/v) BSA. In parallel, heat-inactivated sera at 56 °C for Ih were serially diluted 1 :2 in PBS + 1% (v/v) BSA with a starting dilution of 1 :30 in non- fetuin coated 96-well plates (75 pL/well). Then, 75 pL of the H6N2A/Hong Kong/4801/2014 virus corresponding to 2* EC50 was added per well to the pre-diluted sera plates and incubated at 20 °C for 1.5h. After incubation, 100 pL of the virus/serum mixture were transferred per well to fetuin coated plates and incubated at 37 °C O/N. After incubation, the rest of the assay was performed as described above for the NA assay. No serum (virus only) and background controls (PBS + 1% v/v BSA only) were also included to measure the NAI. The OD490 was measured on a Synergy Hl microplate reader, and the inhibition concentration (IC50) was calculated as: (ODmeasured-ODback_ground)/(ODno serum controi- ODbackground) in the GraphPad Prism 9 software.

[00449] Microneutralization assay

[00450] Mouse sera were treated with receptor destroying enzyme (RDE) II (Denka Seiken) and incubated in a 37 °C water bath for 18-20h. The same day, MDCK cells were seeded in 96-well cell-culture treated plates (Corning) at 1.8 * 10⁴ cells per well (100 pL/well) and incubated at 37 °C with 5% CO2 O/N. The following day, the RDE activity was stopped by the addition of a 2.5% (w/v) sodium citrate solution and incubation at 56 °C for Ih (53). RDE-treated sera were serially diluted 1 :2 in minimum essential medium (MEM, Gibco) with 10 mM of 2-[4 — (2-hydroxyethyl)-piperazin-l-yl]ethanesulfonic acid (HEPES, Gibco), 2 mM L-glutamine (Gibco), 3.2% (w/v) sodium bicarbonate (Corning), 1.2% (w/v) BSA, 100 U/mL penicillin and 100 pg/mL streptomycin (Gibco) (infection medium). Next, 120 pL of 100 x tissue culture infectious dose (TCID50) of virus prepared in infection medium and 120 pL of serially diluted sera were incubated on a shaker at RT for Ih. MDCK cells were washed with 220 pL of PBS and incubated with 100 pL of the incubated serumvirus mixture at 37 °C with 5% CO2 for Ih. Afterwards, the virus inoculum was aspirated, MDCK cells were washed with PBS, and 100 pL of the serially-diluted sera containing 1 pg/mL of N-tosyl-L-phenylalanine chloromethyl ketone (TPCK)-treated trypsin (Millipore Sigma) were added to the cells and incubated at 37 °C with 5% CO2 for 48h. After 48h, the presence of virus was assessed by hemagglutination assay. In brief, 50 pL of cell supernatant was added to 96-well V-bottom plates (Nunc) and serially diluted 1 :2. Then, 50 pL of 0.5% (v/v) turkey red blood cells (RBCs, Lampire Biological Laboratories) in PBS were added to each well, and plates were incubated on ice or at 4°C for 45 min. The HA titer was calculated as the endpoint titer at which no RBC tear drop formation (the absence is indicative of hemagglutination/presence of virus) after tilting the plate to 90° for 10 - 20 sec could be detected.

[00451] Animal studies

[00452] All animal experiments were performed under protocols approved by the Icahn School of Medicine at Mount Sinai Institutional Animal Care and Use Committee. For all animal experiments conducted, 6-8-week-old female BALB/c and DBA/2J mice (Jackson Laboratories) were used unless otherwise mentioned. The CpG 1018® adjuvant used in this study, a toll-like receptor 9 agonist, was provided by Dynavax Technologies. To simulate pre-existing immunity to the Hl HA stalk, mice were anesthetized intraperitoneally (i.p.) with a ketamine/xylazine in water cocktail and intranasally (i.n.) inoculated with 10⁵ plaque forming units (PFU) of the chimeric B-cH5/l virus (50 pL/mouse) (54). For intramuscular (i.m.) vaccination, 1 pg HA of group 2 cHA split vaccine prepared in PBS with or without the CpG 1018® adjuvant was given per mouse (50 pL) unless otherwise indicated. A negative control (PBS), an irrelevant protein (BSA) + CpG 1018® adjuvant, and a positive control (matched inactivated virus) were prepared in PBS to 50 pL total volume. The amount of BSA was adjusted to the maximum amount of total protein in the vaccine administered to the mice. When testing the combined effect of the CpG 1018® adjuvant and aluminum hydroxide gel 2% (alum) adjuvants, vaccines were prepared in a saline solution composed of 20 mM Tris, 100 mM NaCl (pH=7.5). For the LAIV, mice were vaccinated with 10⁵ PFU per mouse (50 pL) of group 2 cHA LAIV via the i.n. route. The vaccination regimen consisted of priming with the B-cH5/l virus (i.n.), and sequential vaccination with the cH15/3HK14N2HK14 split vaccine or LAIV after four weeks and boosted with cH4/3HK14N2HK14 split vaccine or LAIV after four additional weeks. Combinations of split vaccine and LAIV were also tested. Six weeks after vaccination, mice were anesthetized and intranasally infected with 50 pL of influenza virus containing 0.1 *, 0.5*, or 5* the mouse lethal dose (LD50) depending on what readout was used. LD50 values were calculated by challenging 6-8-week-old female BALB/c or DBA/2J mice with different doses of the respective influenza A viruses. The calculated LD50 values were 316.2 PFU/mouse in DBA/2J mice for A/Switzerland/9715293/2013 (H3N2), 17.8 PFU/mouse in BALB/c mice for A/Philippines/2/1982 (H3N2, X-79), 63.1 PFU/mouse in DBA/2J mice for A/canine/Illinois/41915/2015 (H3N2), 177.8 PFU/mouse in DBA/2J mice for A/swine/Missouri/AO 1727926/2015 (H4N6), 1778.3 PFU/mouse in BALB/c mice for A/Shanghai/1/2013 (H7N9), 1778.3 PFU/mouse in BALB/c mice for A/Jiangxi- Donghu/346/2013 (H10N8), 56234.1 PFU/mouse in DBA/2J mice for A/mallard/Gurjev/263/1982 (H14N1), 562.3 PFU/mouse in BALB/c mice for A/shearwater/West Australia/2576/1979 (H15N5), and 56.2 PFU/mouse in BALB/c mice for A/Singapore/GP 1908/2015 (H1N1). DBA/2J mice are more sensitive to influenza virus infection and were used in cases where viruses were non-lethal in BALB/C mice (55).

Importantly, the age of mice challenged after sequential immunization was in the range of 20- 22-week-old, meaning they were older than the mice used for the LD50 experiments and age can influence the lethal dose for a virus strain in the mouse model. In the past, we have performed studies to look at sex differences for stalk-based vaccination in mice in collaboration with Sabra Klein’s laboratory and found - in young mice - no differences in terms of protection (56). Therefore, since female mice are easier to handle, we have only used female mice here.

[00453] Additionally, mice were bled via submandibular bleeding for serological analysis at this time point. Blood was incubated at RT for Ih and centrifuged at 5000 *g for 30 min. Serum was separated from pellet and stored at 4 °C until analysis. After virus challenge, weight loss was monitored for 14 days and mice showing a weight loss of > 25% as compared with their initial body weight were humanely euthanized.

[00454] For the serum passive transfer experiment, 6-8-week-old female DBA/2J mice were prime-boosted as previously described. Mice were anesthetized, blood was collected by cardiac puncture, incubated at RT for Ih, and centrifuged at 5000 *g for 30 min. Serum was separated from pellet and stored at 4 °C until use. Naive mice were administered 200 pL of pooled sera per mouse via the i.p. route. After 2-3 h, mice were challenged with 3*LD50 of the A/Switzerland/9715293/2013 (H3N2) virus and weight loss monitored for the next 14 days.

[00455] For the duration of the experiments, mice were housed in individually ventilated cages on a 12h dark/light cycle with controlled temperature/humidity. Food and water were provided ad libitum.

[00456] Lung titers

[00457] Virus titers in the lungs of mice challenged with 0.1 *LD50 of the A/Philippines/2/1982 (H3N2, X-79) virus at days 3 and 6 after challenge were analyzed by the plaque assay method in 12-well plates (Corning). The lower challenge dose was used since it usually results in higher resolution for lung titer experiments that allows to better distinguish between groups. Briefly, harvested lungs were homogenized in 2 disruption cycles (10 seconds/cycle) using tubes that contained high impact zirconium beads (Andwin Scientific) and 1 mL of PBS. Lung homogenates were serially diluted 1 :10 in PBS. Samples were incubated for Ih with MDCK cells seeded at 3 * 105 cells per well (1 mL/well) the day before. After the Ih incubation, an agarose overlay containing a final concentration of 0.64% (w/v) agarose (Oxoid) in MEM supplemented with 2 mM L-glutamine, 0.1% (w/v) of sodium bicarbonate, 10 mM HEPES, 100 U/mL penicillin, 100 pg/mL streptomycin, 0.2% (w/v) BSA, 1 pg/mL TPCK-treated trypsin, and 0.1% (w/v) diethylaminoethyl-dextran was added to the cells. The cells were incubated at 37 °C for 48h, and visible plaques were counted after fixation with 3.7% (v/v) formaldehyde in PBS and visualization by immunostaining. All virus titers are presented as the log 10 PFU/mL.

[00458] Flow cytometry

[00459] For lung collection, mice were euthanized, the chest opened, and the right ventricle of the heart perfused with 10 mL of cold PBS. Lungs were minced and incubated in a collagenase-I (150 U/mL, Gibco)/DNAse-I (50 U/mL, Millipore Sigma) solution on a 37 °C water bath for 30 min. Following digestion, tissue was pushed several times through an 18G needle and filtered through a 70 pm cell strainer (BD Biosciences). Spleens were mechanically disrupted with pestle homogenizers for 1.5 ml tubes (Fisher Scientific) and filtered as described above. Erythrocytes were lysed with RBC lysis buffer (BioLegend) in accordance with the manufacturer’s instructions. Cells were washed with 2% (v/v) FBS in PBS and reconstituted in 5 mL of complete media (RPMI 1640 supplemented with 10% (v/v) FBS, 100 U/mL penicillin, and 100 pg/mL streptomycin). Cell count and viability were analyzed in a Countess II automated cell counter (Thermo Fisher Scientific) using a 0.4% (v/v) Trypan blue solution. 2* 10⁶ cells per well were seeded in 96-well cell culture treated plates. For antigen-specific T-cellular immune response analysis, cells were stimulated with 1 pL/well of peptide pool libraries containing 15 amino acid peptides with 11 amino acid overlap (5 pg/mL) covering the whole sequences of HA and NA proteins of the

A/Perth/16/2009 (H3N2) influenza virus strain (NR- 19266 for HA, NR- 19267 for NA, BEI Resources), as well as the whole sequence of the NP protein of A/PR/8/34 (H1N1) virus (Miltenyi Biotec). Stimulation was performed at 37 °C with 5% CO2 for 6h in the presence of 5 pg/mL Brefeldin A (BioLegend), 2 pM Monensin (BioLegend), and 25 pg/mL of costimulatory anti-CD28 antibodies (BioLegend). Positive control samples were stimulated with Cell Activation Cocktail (BioLegend) in accordance with the manufacturer’s instructions. The negative control samples were incubated in the presence of all the aforementioned reagents, except the specific antigens. [00460] Following stimulation, cells were stained with fluorescently labeled antibodies (BioLegend) targeting different surface markers for the discrimination of naive, effector memory, and central memory T-lymphocyte subpopulations (0.5 pL/sample CD3-BV711, 0.125 pL/sample CD4-PerCP/Cy5.5, 0.25 pL/sample CD8-BV785, 0.125 pL/sample CD62L- APC/Cy7, 0.25 pL/sample CD44-PE/Cy7). Intracellular staining of cytokines was performed with Cytofix/Cytoperm Fixation/Permeabilization Solution Kit (BD Biosciences) according to the manufacturer’s instructions. TNFa-AF488 (0.25 pL/sample), IFNy-BV605 (1 pL/sample), and IL-2-phycoerythrin (PE) (0.5 pL/sample) antibodies (BioLegend) were used to identify the corresponding cytokines. Data were collected on an Attune flow cytometer (Thermo Fisher Scientific) and analyzed with the FlowJo_vl0.8.1 software. The gating strategy is shown FIG. 9C. To calculate statistical differences between groups, the percentage of cytokine-producing cells in non-stimulated samples was subtracted from the corresponding values for peptide-stimulated samples. Groups were compared using one-way ANOVA corrected for Dunn’s multiple comparison test with the Rstudio software (R version 4.2.0, Rstudio Inc).

[00461] Statistical analysis

[00462] The details about the type of statistical analyses performed for each experiment are listed in the respective figure legends. Briefly, GraphPad Prism 9 was used for statistical analysis of antibody titers, NAI, competition ELISA, and microneutralization assays using one-way ANOVA corrected for Dunnett’s multiple comparison test. One-way ANOVA corrected for Dunn’s multiple comparison test was employed for the comparison of viral titers in lungs and T-cell studies. Significance was considered with p-values equal or less than 0.05. The chosen sample size in each experiment is sufficient to generate statistically significant results.

6.1.3 Results

[00463] Sequential vaccination with cHA constructs elicits broadly cross-reactive HA stalk antibodies and induces protective immune responses against challenge with a heterologous influenza virus

[00464] Inactivated split (split vaccine) and live attenuated influenza vaccines (LAIV) were evaluated as platforms to sequentially deliver our cH15/3HK14N2HK14 and cH4/3HK14N2HK14 virus constructs (FIG. 2C). These chimeric viruses contain the HA stalk domain and the NA of the A/Hong Kong/4801/2014 (H3N2) seasonal influenza virus, while the HA head domains are derived from exotic influenza viruses that do not circulate in humans. Split vaccines were tested in combination with the human-approved toll-like receptor 9 agonist adjuvant, CpG 1018® adjuvant, via the intramuscular (i.m.) route, whereas LAIV were administered intranasally (i.n.). Before vaccination, mice were primed with a sublethal infection (i.n.) of the B-cH5/l virus to mimic pre-existing immunity against the HA stalk domain in humans. Pre-existing immunity to the group 1/H1 stalk is much higher in humans than group 2/H3 stalk priming and therefore this is a realistic priming scenario (57, 58). It has also been hypothesized that priming with group 1/H1 HA may negatively impact on group 2/H3 stalk immunity (59, 60). Seeing protection against group 2 viruses despite this ‘negative’ imprinting would demonstrate the real world potential of the tested vaccine candidates. Mice sequentially vaccinated with unadjuvanted split vaccines were almost completely protected (80% survival) from challenge with a lethal dose of the heterologous A/Philippines/2/1982 (H3N2, X-79) virus (FIG. 3A, the X-79 HA stalk domain is 94.8% identical to A/Hong Kong/4801/2014 stalk in amino acid sequence). The combination of cHA split vaccines with the CpG 1018® adjuvant provided full protection from mortality with little to no morbidity, in the same range as LAIV, hybrid vaccination strategies (LAIV + split vaccine), and the matched inactivated H3N2 virus control.

[00465] The protection conferred by sequential vaccination with cHA vaccines correlated with the presence of cross-reactive IgG antibodies against a broad panel of group 2 HAs (FIG. 2B), and these antibodies also targeted group 1 and 2 HA stalks (mini Hl and mini H3) (FIG. 3B). The level of cross-reactive antibodies was substantially lower for whole inactivated virus (WIV) controls. The combination of the split vaccine with the CpG 1018® adjuvant increased the level of HA cross-reactive and vaccine-matched N2 antibodies between 2 to 10-fold and to the same range as for LAIV and hybrid vaccinations. Interestingly, no cross-reactive antibodies were elicited against the influenza B virus HA (FIG. 3B), but - as expected - priming with the B-cH5/l virus resulted in detectable antibody titers against the influenza B virus NA (FIG. 7).

[00466] Additionally, all vaccine types were able to induce cross-reactive antibodies targeting the HA head trimer interface. HA head trimer interface antibodies were also detected after priming only with the B-cH5/l virus, although at lower levels compared to mice sequentially vaccinated with cHA vaccines (FIG. 3C). Analysis of the type of immune response elicited by these different vaccine platforms revealed that combining cHA split vaccines with CpG 1018® adjuvant boosted the production of IgG2a antibodies in comparison to unadjuvanted vaccines and to similar levels as LAIV and hybrid vaccinations (FIGS. 3D - 3F). [00467] Analysis of functional antibody responses revealed that mice vaccinated with split vaccine + CpG 1018® adjuvant elicited antibodies that were active in an ADCC reporter assay against homologous and heterologous H3N2 viruses (FIGS. 3G, 8). Similarly, the antibodies elicited in these groups of vaccinated mice could inhibit the NA activity of the vaccine-matched N2 in the reassortant H6N2A/Hong Kong/4801/2014 virus, which contains an H6 glycoprotein to avoid H3 -directed NAI activity (61) (FIG. 3H). Of note, no measurable neutralizing antibody titers could be measured against the heterologous A/Philippines/2/1982 (H3N2, X-79) virus, while some level of neutralizing antibodies against the vaccine-matched A/Hong Kong/4801/2014 (H3N2) virus were induced by these vaccines (FIGS. 31 - 3 J). Overall, the different group 2 cHA vaccine platforms elicited potent humoral immune responses. However, the LAIV or hybrid vaccination strategies with group 1 cHA constructs showed lower immunogenicity results in humans in comparison to split vaccines, likely because the cHA-based LAIVs are hyper-attenuated in humans (26, 28). Split vaccines in combination with the CpG 1018® adjuvant were therefore selected as the platform for further group 2 cHA vaccine development.

[00468] Antibodies elicited after vaccination with cHA split vaccines reduce viral lung titers and protect against influenza virus challenge in a serum passive transfer experiment

[00469] Sequential vaccination with split vaccines adjuvanted with CpG 1018® adjuvant showed excellent immunogenicity results similar to levels observed following LAIV or hybrid vaccinations. To assess the control of virus replication in the lungs, mice were sequentially immunized with adjuvanted split vaccines and challenged with the X-79 virus. High levels of viral titers were found in the lung homogenates of mice vaccinated with PBS (negative control), and mice primed with the B-cH5/l virus and vaccinated with the irrelevant protein bovine serum albumin (BSA) + CpG 1018® adjuvant in comparison to mice vaccinated with split vaccine + CpG 1018® adjuvant (FIG. 4A).

[00470] A passive transfer experiment was also conducted to determine whether antibodies induced by split vaccine + CpG 1018® adjuvant could protect and reduce morbidity following infection with a heterologous influenza virus. To this end, sera from mice sequentially vaccinated with PBS, BSA + CpG 1018, and split vaccine + CpG 1018® adjuvant were collected, pooled, and administered intraperitoneally to naive DBA/2J mice. After 2-3 h, mice were challenged with the A/Switzerland/9715293/2013 (H3N2) virus. Mice receiving serum from PBS and BSA + CpG 1018® adjuvant vaccinated mice exhibited a pronounced weight loss or succumbed to the challenge, while mice receiving serum from split vaccine + CpG 1018® adjuvant vaccinated mice were fully protected without any sign of morbidity (FIG. 4B).

[00471] Lower doses of cHA split vaccines and CpG 1018® adjuvant protect mice against challenge with a heterologous influenza virus

[00472] After observing that adjuvanted split vaccines elicited broad protection at a 1 ug dose against heterologous influenza virus infection, we next assessed protection conferred by a range of different split vaccine and CpG 1018® adjuvant doses. To this end, different groups of mice were vaccinated with different doses of split vaccine ranging from 0.1 to 3 pg HA/mouse. All groups of mice vaccinated with split vaccine + CpG 1018® adjuvant exhibited full protection against lethal challenge with the X-79 virus independently of the dose used (FIG. 9A).

[00473] Different doses of CpG 1018® adjuvant in combination with the split vaccine were also evaluated (3, 10, 30 pg of CpG 1018® adjuvant /mouse) to determine if the dose of adjuvant could be lowered. In addition, the combination of the CpG 1018® adjuvant with alum at different doses (10:50, 3: 15, 1 :5 pg of CpG 1018® adjuvant:alum/mouse) was evaluated as a potential combination to increase the breadth of protection elicited by split vaccines. In all cases, complete protection from lethal challenge with the X-79 virus was achieved (FIG. 9B). Complete protection was also observed when combining CpG 1018® adjuvant and alum, but this combination did not provide an additional benefit in reducing weight loss in mice. Indeed, a trend to more weight loss was detected in all groups of mice vaccinated with CpG 1018® adjuvant + alum compared to the CpG 1018® adjuvant only groups. Analysis of the antibody response elicited in mice vaccinated with split vaccine adjuvanted with different doses of CpG 1018® adjuvant (with or without alum) showed a statistically significant increase in total IgG and HA stalk antibody levels in the highest dose of CpG 1018® adjuvant + alum (10:50 pg/mouse) tested in comparison with CpG 1018® adjuvant alone (10 pg/mouse) (FIGS. 4C-4D). Interestingly, higher levels of IgGl antibodies were detected with low amounts of CpG 1018® adjuvant and with the combination of CpG 1018® adjuvant + alum, whereas the IgG2a levels remained the same in all the conditions tested (FIGS. 4E - 4F). Therefore, a significant decrease in the ratio of IgG2a/IgGl antibodies was detected in the groups of mice vaccinated with CpG 1018® adjuvant + alum (FIG. 4G).

[00474] The combination of split vaccines and CpG 1018® adjuvant provided 100% protection, without an additional benefit of combining cHA split vaccines with CpG 1018® adjuvant + alum. Moreover, different doses of split vaccine and CpG 1018® adjuvant provided similar levels of protection. The split vaccine + CpG 1018® adjuvant condition selected for further evaluation in the mouse model was 1 pg of HA and 10 pg of CpG 1018® adjuvant per mouse. Of note, minor differences in weight loss in the corresponding groups in FIGS. 9A-9B and FIG. 3 A are likely the result of experimental variation.

[00475] Vaccination with cHA split vaccines elicits HA stalk and NA-specific cellular immune responses

[00476] To assess antigen-specific T-cellular immune responses elicited by sequential vaccination with cHA split vaccines + CpG 1018® adjuvant, lymphocytes from the lungs and spleens of immunized mice were stimulated with HA, NA, and NP overlapping peptide pools 6 days after challenge with the X-79 virus (FIGs. 5A, 5B, 9C). No significant differences in the frequency of HA, NA, or NP-specific CD8+ T effector memory (EM) cells were observed between groups of mice (FIGS. 10A-10B). In the same line, no remarkable differences were detected in the frequency of monofunctional HA, NA, NP-specific CD4+ T EM cells between the different groups of vaccinated mice. However, the frequency of polyfunctional HA, NA, and NP-specific CD4+ EM T cells increased in the split vaccine group, especially in the spleens. Polyfunctional cells have been previously defined as a correlate of T cell efficacy and immune protection (62). The most prominent T-cellular immune response was observed in the spleens of vaccinated mice after H3 peptide pool stimulation and was associated with the formation of polyfunctional TNFa+IL-2+ and, to a lesser extent, TNFa+IFNy+ and TNFaHL-2HFNy+ cell subpopulations (FIG. 5C). Both NA and NP peptide pools also induced the activation of a specific T-cellular immune response, but with a lower magnitude compared to HA-stimulated cells. The T-cellular immune response in the lungs of mice vaccinated with split vaccine was also primarily mediated by polyfunctional HA-specific CD4+ EM T-cells. In PBS and BSA vaccinated mice, the majority of cytokine-secreting T- cells were represented by monofunctional TNFa-IL-2+IFNY- cells. The number of T- lymphocytes of this phenotype was similar in all three groups. However, almost no polyfunctional cells were detected in PBS and BSA vaccinated mice after virus challenge (FIG. 5C).

[00477] Mice vaccinated with cHA split vaccines are protected from challenge with a broad panel of influenza A viruses

[00478] Previous experiments showed that sequential vaccination with split vaccines + CpG 1018® adjuvant provided protection against lethal challenge with heterologous influenza viruses. Next, the protective efficacy of these vaccines against challenge with other heterologous H3N2 viruses, including the A/Switzerland/9715293/2013 (H3N2) virus and the more phylogenetically distant A/canine/Illinois/41915/2015 (H3N2) virus, was evaluated. Mice vaccinated with split vaccine + CpG 1018® adjuvant were fully protected against challenge with these viruses, with little to no weight loss (FIGS. 6A-6C).

[00479] To further test the breadth of protection elicited by split vaccines, mice were challenged with different heterosubtypic viruses containing all the other group 2 HAs, including the A/swine/Missouri/AO 1727926/2015 (H4N6), A/Shanghai/1/2013 (H7N9), A/Jiangxi-Donghu/346/2013 (H10N8), A/mallard/Guijev/263/1982 (H14N1), and A/shearwater/West Australia/2576/1979 (H15N5) viruses (FIG. 2B). All mice vaccinated with split vaccine + CpG 1018® adjuvant were fully protected against challenge with these viruses, with substantial weight loss differences between the split vaccine group and the PBS and BSA-vaccinated groups (FIGS. 6D-6H). As for H4N6 and H15N5 virus challenges, contribution of the heterologous H4 head of the cH4/3HK14 vaccine strain and the homologous H15 head of the cH15/3HK14 vaccine strain might have also contributed to the protection against challenge. Despite being fully protected from mortality, mice vaccinated with split vaccines and challenged with the H10N8 virus showed the highest level of morbidity.

[00480] To test the possibility of inter-group influenza virus protection, mice vaccinated with split vaccine were also challenged with the group 1 A/Singapore/GP 1908/2015 (H1N1) virus. Split vaccines provided complete protection from mortality in this case as well (FIG. 61).

6.1.4 Discussion

[00481] The development of a universal influenza virus vaccine that protects against different H3N2 viruses as well as other phylogenetically distant group 2 influenza viruses is of paramount importance. Sequential vaccination with group 1 cHA constructs was proven successful to induce cross-group 1 HA immunity in different animal models (23, 25, 63) and more recently in a phase I/II clinical trials in humans (26-28). Initial pre-clinical studies with other group 2 cHA constructs using the recombinant protein or viral vector platforms have shown promising results as well (29, 30, 64). Compared with the recombinant protein platform, cHA inactivated split vaccines can provide additional protection mediated by other viral components, such as the NA. Recently, we have developed a bioprocess to manufacture group 2 cHA split vaccines with correctly folded HA and enzymatically active NA (49). In this study, the aim was to evaluate the protective efficacy and the humoral and cellular immune responses elicited by our group 2 cHA inactivated split vaccines in the mouse model in the context of the more prevalent pre-existing immunity against the Hl HA stalk. The CpG 1018® adjuvant was selected due to its extensive and excellent safety track record as part of HEPLISAV-B (65) and because it is available for pre-clinical and clinical development in Good Manufacturing Practice (GMP) quality.

[00482] Sequential vaccination with split vaccines adjuvanted with CpG 1018® adjuvant provided full protection against challenge with heterologous influenza viruses to levels similar to those observed for LAIV or hybrid vaccinations. The presence of broadly cross- reactive IgG antibodies against all group 2 HAs was detected in the sera of mice vaccinated with all cHA vaccine platforms. The level of broadly cross-reactive antibodies was higher in cHA split vaccines adjuvanted with CpG 1018® adjuvant and hybrid vaccinations in comparison to unadjuvanted split vaccines, indicating that the combination with this adjuvant is key to elicit a potent antibody response. These antibodies target the stalk domain, which might explain the high level of cross-reactivity to heterologous H3 HAs and heterosubtypic group 2 HAs observed. Interestingly, inter-group cross-reactive antibodies targeting the Hl (group 1) stalk were also detected, possibly indicating some level of FI6-like antibodies were elicited (66). Detectable neutralization activity was measured but only against the stalk- homologous H3N2 strain, which agrees with the low neutralizing activity of HA stalk antibodies observed for group 1 cHAs (25). The mechanism of protection mediated by these HA stalk binding antibodies could be through the engagement of innate immune cells via Fc receptors since mice sera were active in an ADCC reporter assay (67). Antibodies that targeted the conserved HA head trimer interface similarly to the FluA-20 mAb were also detected after vaccination with the cHA constructs. These antibodies have been proven to mediate in vivo protection by disrupting the integrity of native HA trimers and limiting virus spread (51). The intact HA stalk and the more open HA head conformation of cH15/3HK14 and cH4/3HK14 HAs in comparison to wild-type influenza virus HAs might facilitate the accessibility of this epitope leading to the induction of antibodies targeting this conserved site (22). Antibodies binding to the vaccine matched N2 were also detected in mice vaccinated with the different vaccine platforms and were also able to inhibit the NA activity, a mechanism that has been correlated with a reduction in viral shedding (68) and protection from morbidity and mortality by influenza virus challenge (69). The sera of mice containing antibodies capable of inducing different effector functions fully protected naive mice from lethal challenge with the heterologous A/Switzerland/9715293/2013 (H3N2) virus in a serum passive transfer experiment. This strain has been chosen because it is a recent, complete H3N2 strain that was mouse adapted and represents current human H3N2 strains better than ‘old’ H3N2 reassortant strains. However, it may be possible that the same experiment with a more aggressive historic reassortant strain may lead to less protection.

[00483] LAIV are known to induce all arms of the adaptive immune system and a strong mucosal response (70). Thus, LAIV-LAIV or LAIV-inactivated vaccine regimens generally result in a better protection against virus challenge in animal models (24, 25, 63, 71). However, pre-existing immunity or hyperattenuation might limit the efficacy of the LAIV in adults as recently observed with group 1 cHA LAIV constructs (26, 28). For this reason, due to the robust immunogenicity results obtained with adjuvanted cHA split vaccines, and the fact that split vaccines are the most widely used platform for influenza vaccine production, we are moving cHA inactivated split vaccines forward for future clinical development.

[00484] The combination of CpG 1018® adjuvant with our split vaccines allowed for dose sparing. Moreover, the data shows that the amount of adjuvant could be reduced. The CpG 1018® adjuvant is regarded as favoring a T cell helper 1 (Thl) immune response profile (31, 72). This was observed in the induction of similar IgGl antibody titers between unadjuvanted and CpG 1018® adjuvant adjuvanted vaccines, but with a higher level of IgG2a antibodies induced in the latter. Additionally, the combination of CpG 1018® adjuvant with alum did not reduce weight loss in mice despite an increase in total IgG titers. Alum adjuvants are known to induce a Th2-skewed immune response, but their combination with CpG 1018® adjuvant can Thl-bias the immune response as recently seen in different recombinant protein-based vaccines (73, 74). However, the combination of CpG 1018® adjuvant + alum with the split vaccines described in this Example resulted in a more Th2- biased response in comparison to CpG 1018® adjuvant alone. This could be associated with the different nature of the immunogens, being larger and also more heterogeneous in size, structure, and composition than a defined soluble recombinant protein vaccine (49, 75).

[00485] Sequential vaccination of mice with split vaccine + CpG 1018® adjuvant reduced viral replication in the lungs. Analysis of T-cell responses after sequential vaccination and challenge did not show significant differences between the groups of mice in the induction of antigen-specific CD8+ T-lymphocyte responses, which is in agreement with described immune responses to influenza virus split vaccines (37). Nevertheless, the formation of a HA, NA, or NP-specific polyfunctional CD4+ EM T-cellular immune response in the spleens and lungs of mice was observed, especially against the HA. The presence of antigen specific polyfunctional T cells has been correlated with an improved control of virus replication and a better promotion of virus clearance in comparison to monofunctional T cells (62, 76, 77). This indicates that adjuvanted split vaccines can induce a systemic immune response but can also recruit immune mediators that tackle the infection locally, resulting in a reduction of virus replication in the lungs. Of note, the combination of both humoral and cellular responses fully protected mice sequentially vaccinated with split vaccine + CpG 1018® adjuvant from lethal challenge with a broad range of influenza A viruses. Despite achieving complete protection, a higher level of morbidity was observed for the heterosubtypic A/Jiangxi-Donghu/346/2013 (H10N8) virus, which correlated with a lower level of cross- reactive IgG antibodies measured by ELISA against this H10 subtype. However, a 3-fold increase in cross-reactive IgG antibody titers was measured against another H10 from the A/mallard/Interior Alaska/9BM3355R0/2009 (H10N7) virus. Due to existing lack of knowledge about antigenic/immunogenic differences between H10 HAs, it is currently not clear what drives these differences. Also, the contribution of cross-reactive antibodies against the Hl 5 (same head) and H4 (distant head) domains in the heterosubtypic H15N5 and H4N6 challenge experiments cannot be excluded. Interestingly, cross-protection against challenge with the inter-group A/Singapore/GP 1908/2015 (H1N1) virus was also observed. Mice primed only with the B-cH5/l virus were also fully protected from mortality but showed a substantially higher weight loss. This indicated that priming with the B-cH5/l virus might have elicited cross-reactive antibodies to conserved epitopes in the HA such as the stalk or the trimer interface, and that vaccination with split vaccines could have boosted these antibodies as seen by ELISA against an Hl and stalk-only version of the Hl (mini-Hl). Of note, while the B-cH5/l pre-infection primes B-cells for antibodies in the stalk region, this model does not take Hl or H3 head specific priming into account which may influence the formation of FluA20-like antibodies.

[00486] This study showed that sequential vaccination with group 2 cHA inactivated split vaccines in combination with CpG 1018® adjuvant can elicit broadly cross-reactive immune responses that provide complete protection against challenge with any group 2 influenza virus in the mouse model as well as boosting inter-group HA cross-reactive antibodies. The study has also several limitations including the use of only one animal model and the focus on parenteral immunization. Further studies in additional animal models are ongoing and mucosal administration of this vaccine candidate will be tested in future studies. These results warrant further research in other animal models and provide the basis for the upcoming clinical development of this vaccine platform. Ultimately, the group 2 constructs will likely be combined with group 1 cHA (23, 26) and mosaic HA influenza B (52) constructs into a trivalent vaccine for universal protection against all influenza A and B viruses. 6.1.5 References Cited in the Background, Detailed Description, and Examples

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7. EMBODIMENTS

1. An immunogenic composition, comprising: a. a chimeric hemagglutinin (HA) comprising an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the HA globular head domain of the chimeric HA comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and b) a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

2. An immunogenic composition, comprising: a. an inactivated influenza virus comprising a chimeric hemagglutinin (HA), wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the HA globular head domain of the chimeric HA comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and b. a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

3. The immunogenic composition according to embodiment 2, wherein the inactivated influenza virus comprises neuraminidase of the group 2 influenza A virus. 4. The immunogenic composition according to embodiment 2 or 3, wherein the inactivated influenza virus comprises one or more proteins encoded by one or more genes of influenza A virus A/Puerto Rico/8/1934.

5. An immunogenic composition, comprising: a. an inactivated split influenza virus comprising a chimeric hemagglutinin (HA), wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the HA globular head domain of the chimeric HA comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and b. a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

6. The immunogenic composition according to embodiment 5, wherein the inactivated split influenza virus comprises neuraminidase of the group 2 influenza A virus.

7. The immunogenic composition according to embodiment 5 or 6, wherein the inactivated split influenza virus comprises one or more proteins encoded by one or more genes of influenza A virus A/Puerto Rico/8/1934.

8. The immunogenic composition according to any one of embodiments 1 to 7, wherein the group 2 influenza A virus HA of interest is of subtype H3.

9. The immunogenic composition according to any one of embodiments 1 to 7, wherein the group 2 influenza A virus HA of interest is A/Hong Kong/4801/2014, NYMC X-263 HA or A/Hong Kong/4801/2014-like HA.

10. The immunogenic composition according to any one of embodiments 1 to 9, wherein the influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest is a group 1 influenza A virus HA. 11. The immunogenic composition according to any one of embodiments 1 to 9, wherein the influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest is of subtype H2, H5, H6, H8, H9, Hl l, H12, H13, H16, H17, or H18.

12. The immunogenic composition according to embodiment 1 or 9, wherein the influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest is of subtype H4, H7, H10, H14, or Hl 5.

13. The immunogenic composition according to embodiment 8 or 9, wherein the influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest is A/wedge-tailed shearwater/Westem Australia/2576/1979 HA or A/wedge-tailed shearwater/Western Australia/2576/1979-like HA.

14. The immunogenic composition according to embodiment 8 or 9, wherein the influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest is A/Duck/Czechoslovakia/1956 HA or A/Duck/Czechoslovakia/1956- like HA.

15. An immunogenic composition, comprising: a. an inactivated influenza virus comprising a chimeric hemagglutinin (HA), wherein the chimeric HA comprises an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:5, 6, 7 or 8, or the amino acid sequence of SEQ ID NO:5, 6, 7, or 8; and b. a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

16. An immunogenic composition, comprising: a. an inactivated split influenza virus comprising a chimeric hemagglutinin (HA), wherein the chimeric HA comprises an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:5, 6, 7 or 8, or the amino acid sequence of SEQ ID NO:5, 6, 7, or 8; and b. a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3). 17. The immunogenic composition according to any one of embodiments 1 to 16, wherein the oligonucleotide comprises the nucleotide sequence of 5’- TGACTGTGAACGTTCGAGATGA-3’ (SEQ ID NO:4).

18. The immunogenic composition according to any one of embodiments 1 to 17, wherein the oligonucleotide is 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 nucleotides in length.

19. The immunogenic composition according to any one of embodiments 1 to 18, wherein the oligonucleotide is a single stranded oligodeoxynucleotide.

20. The immunogenic composition according to any one of embodiments 1 to 19, wherein the oligonucleotide comprises only phosphorothioate linkages, or a combination of one or more phosphodiester linkages and one or more phosphorothioate linkages.

21. The immunogenic composition according to any one of embodiments 1 to 20, wherein the oligonucleotide is fully RNA or is an RNA/DNA chimera.

22. The immunogenic composition according to any one of embodiments 1 to 21, wherein the composition further comprises an aluminum salt.

23. The immunogenic composition according to embodiment 22, wherein the aluminum salt comprises one or more selected from the group consisting of amorphous aluminum hydroxyphosphate sulfate, aluminum hydroxide, aluminum phosphate, and potassium aluminum sulfate.

24. The immunogenic composition according to embodiment 22, wherein the aluminum salt comprises aluminum hydroxide or aluminum phosphate.

25. A method of preventing influenza virus disease in a subject, comprising administering to the subject the immunogenic composition of any one of embodiments 1 to 24.

26. A method of immunizing a subject against influenza virus disease, comprising administering to the subject the immunogenic composition of any one of embodiments 1 to 24. 27. A method of inducing a cross-reactive immune response to at least two group 2 influenza A viruses in a subject, comprising administering to the subject the immunogenic composition of any one of embodiments 1 to 24.

28. The method according to any one of embodiments 25 to 27, wherein the immunogenic composition is administered intramuscularly to the subject.

29. A method of preventing influenza virus disease in a subject, comprising: a) administering to the subject a first immunogenic composition comprising a first inactivated influenza virus and a CpG oligonucleotide adjuvant, wherein the first inactivated influenza virus comprises a first chimeric HA, wherein the first chimeric HA comprises a first influenza virus HA globular head domain and a first influenza virus HA stalk domain, wherein the first HA stalk domain comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second inactivated influenza virus and a CpG oligonucleotide adjuvant, wherein the second inactivated influenza virus comprises a second chimeric HA, wherein the second chimeric HA comprises a second influenza virus HA globular head domain and a second influenza virus HA stalk domain, wherein the second HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA of interest, and wherein the second HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the second HA globular head domain, and wherein each CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID N0:3).

30. A method of immunizing a subject against influenza virus disease, comprising: a) administering to the subject a first immunogenic composition comprising a first inactivated influenza virus and a CpG oligonucleotide adjuvant, wherein the first inactivated influenza virus comprises a first chimeric HA, wherein the first chimeric HA comprises a first influenza virus HA globular head domain and a first influenza virus HA stalk domain, wherein the first HA stalk domain comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second inactivated influenza virus and a CpG oligonucleotide adjuvant, wherein the second inactivated influenza virus comprises a second chimeric HA, wherein the second chimeric HA comprises a second influenza virus HA globular head domain and a second influenza virus HA stalk domain, wherein the second HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA of interest, and wherein the second HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the second HA globular head domain, and wherein each CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

31. A method of inducing a cross-reactive immune response to at least two group 2 influenza A viruses in a subject, comprising: a) administering to the subject a first immunogenic composition comprising a first inactivated influenza virus and a CpG oligonucleotide adjuvant, wherein the first inactivated influenza virus comprises a first chimeric HA, wherein the first chimeric HA comprises a first influenza virus HA globular head domain and a first influenza virus HA stalk domain, wherein the first HA stalk domain comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second inactivated influenza virus and a CpG oligonucleotide adjuvant, wherein the second inactivated influenza virus comprises a second chimeric HA, wherein the second chimeric HA comprises a second influenza virus HA globular head domain and a second influenza virus HA stalk domain, wherein the second HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA of interest, and wherein the second HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the second HA globular head domain, and wherein each CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

32. The method according to any one of embodiments 29 to 31, wherein the first inactivated influenza virus and the second inactivated influenza virus each comprise neuraminidase of the group 2 influenza A virus.

33. The method according to any one of embodiments 29 to 32, wherein the first inactivated influenza virus and the second inactivated influenza virus each comprise one or more proteins encoded by one or more genes of influenza A virus A/Puerto Rico/8/1934. 34. The method according to any one of embodiments 29 to 33, wherein the method further comprises administering to the subject a third immunogenic composition a certain time after the administration of the second immunogenic composition to the subject, wherein the third immunogenic composition comprises a third inactivated influenza virus and a CpG oligonucleotide adjuvant, wherein the third inactivated influenza virus comprises a third chimeric HA, wherein the third chimeric HA comprises a third influenza virus HA globular head domain and a third influenza virus HA stalk domain, wherein the third HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA of interest, wherein the third HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest, and wherein the third HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the first HA globular head domain and the second HA globular head domain.

35. A method of preventing influenza virus disease in a subject, comprising: a) administering to the subject a first immunogenic composition comprising a first inactivated split influenza virus and a CpG oligonucleotide adjuvant, wherein the first inactivated split influenza virus comprises a first chimeric HA, wherein the first chimeric HA comprises a first influenza virus HA globular head domain and a first influenza virus HA stalk domain, wherein the first HA stalk domain comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second inactivated split influenza virus and a CpG oligonucleotide adjuvant, wherein the second inactivated split influenza virus comprises a second chimeric HA, and wherein the second chimeric HA comprises a second influenza virus HA globular head domain and a second influenza virus HA stalk domain, wherein the second HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA of interest, and wherein the second HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the second HA globular head domain, and wherein each CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID N0:3).

36. A method of immunizing a subject against influenza virus disease, comprising: a) administering to the subject a first immunogenic composition comprising a first inactivated split influenza virus and a CpG oligonucleotide adjuvant, wherein the first inactivated split influenza virus comprises a first chimeric HA, wherein the first chimeric HA comprises a first influenza virus HA globular head domain and a first influenza virus HA stalk domain, wherein the first HA stalk domain comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second inactivated split influenza virus and a CpG oligonucleotide adjuvant, wherein the second inactivated split influenza virus comprises a second chimeric HA, wherein the second chimeric HA comprises a second influenza virus HA globular head domain and a second influenza virus HA stalk domain, wherein the second HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA of interest, and wherein the second HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the second HA globular head domain, and wherein each CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID N0:3).

37. A method of inducing a cross-reactive immune response to at least two group 2 influenza A viruses in a subject, comprising: a) administering to the subject a first immunogenic composition comprising a first inactivated split influenza virus and a CpG oligonucleotide adjuvant, wherein the first inactivated split influenza virus comprises a first chimeric HA, wherein the first chimeric HA comprises a first influenza virus HA globular head domain and a first influenza virus HA stalk domain, wherein the first HA stalk domain comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second inactivated split influenza virus and a CpG oligonucleotide adjuvant, wherein the second inactivated split influenza virus comprises a second chimeric HA, wherein the second chimeric HA comprises a second influenza virus HA globular head domain and a second influenza virus HA stalk domain, wherein the second HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA of interest, and wherein the second HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the second HA globular head domain, and wherein each CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3). 38. The method according to any one of embodiments 35 to 37, wherein the first inactivated split influenza virus and the second inactivated split influenza virus each comprise neuraminidase of the group 2 influenza A virus.

39. The method according to any one of embodiments 35 to 38, the first inactivated split influenza virus and the second inactivated split influenza virus each comprise one or more proteins encoded by one or more genes of influenza A virus A/Puerto Rico/8/1934.

40. The method according to any one of embodiments 35 to 39, wherein the method further comprises administering to the subject a third immunogenic composition a certain time after the administration of the second immunogenic composition to the subject, wherein the third immunogenic composition comprises a third inactivated split influenza virus and a CpG oligonucleotide adjuvant, wherein the third inactivated split influenza virus comprises a third chimeric HA, and wherein the third chimeric HA comprises a third influenza virus HA globular head domain and a third influenza virus HA stalk domain, wherein the third HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA of interest, wherein the third HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest, and wherein the third HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the first HA globular head domain and the second HA globular head domain.

41. A method of preventing influenza virus disease in a subject, comprising: a) administering to the subject a first immunogenic composition comprising a first chimeric hemagglutinin (HA) and a CpG oligonucleotide adjuvant, wherein the first chimeric HA comprises a first influenza virus HA globular head domain and a first influenza virus HA stalk domain, wherein the first HA stalk domain comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second chimeric HA and a CpG oligonucleotide adjuvant, wherein the second chimeric HA comprises a second influenza virus HA globular head domain and a second influenza virus HA stalk domain, wherein the second HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA of interest, and wherein the second HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest, and wherein the first globular head comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the second HA globular head domain, and wherein each CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

42. A method of immunizing a subject against influenza virus disease, comprising: a) administering to the subject a first immunogenic composition comprising a first chimeric hemagglutinin (HA) and a CpG oligonucleotide adjuvant, wherein the first chimeric HA comprises a first influenza virus HA globular head domain and a first influenza virus HA stalk domain, wherein the first HA stalk domain comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second chimeric HA and a CpG oligonucleotide adjuvant, wherein the second chimeric HA comprises a second influenza virus HA globular head domain and a second influenza virus HA stalk domain, wherein the second HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA of interest, and wherein the second HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the second HA globular head domain, and wherein each CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID N0:3).

43. A method of inducing a cross-reactive immune response to at least two group 2 influenza A viruses in a subject, comprising: a) administering to the subject a first immunogenic composition comprising a first chimeric hemagglutinin (HA) and a CpG oligonucleotide adjuvant, wherein the first chimeric HA comprises a first influenza virus HA globular head domain and a first influenza virus HA stalk domain, wherein the first HA stalk domain comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second chimeric HA and a CpG oligonucleotide adjuvant, wherein the second chimeric HA comprises a second influenza virus HA globular head domain and a second influenza virus HA stalk domain, wherein the second HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA of interest, and wherein the second HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest, and wherein the first globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the second HA globular head domain, and wherein each CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID N0:3).

44. The method according to any one of embodiments 29 to 43, wherein the group 2 influenza A virus HA of interest is of subtype H3.

45. The method according to any one of embodiments 29 to 44, wherein the group 2 influenza A virus HA of interest is A/Hong Kong/4801/2014, NYMC X-263 HA, or A/Hong Kong/4801/2014-like HA.

46. The method according to any one of embodiments 29 to 45, wherein the first HA globular head domain or the second HA globular head domain is the HA globular head domain of a group 1 influenza A virus HA.

47. The method according to any one of embodiments 29 to 45, wherein the first HA globular head domain and the second HA globular head domain are the HA globular head domain of group 1 influenza A virus Has.

48. The method according to any one of embodiments 29 to 45, wherein the first HA globular head domain or the second HA globular head domain is the HA globular head domain of an HA of subtype H2, H5, H6, H8, H9, Hl l, H12, H13, H16, H17, or H18.

49. The method according to any one of embodiments 29 to 45, wherein the first HA globular head domain and the second HA globular head domain are the HA globular head domain of an HA of subtype H2, H5, H6, H8, H9, Hl l, H12, H13, H16, H17, or H18.

50. The method according to embodiment 44 or 45, wherein the first HA globular head domain and the second HA globular head domain are the HA globular head domain of subtype H4, H7, H10, H14, or H15.

51. The method according to embodiment 44 or 45, wherein the first HA globular head domain is the HA globular head domain of A/wedge-tailed shearwater/W estern Australia/2576/1979 HA or A/wedge-tailed shearwater/W estem Australia/2576/1979-like HA. 52. The method according to embodiment 44 or 45, wherein the second HA globular head domain is the HA globular head domain of A/Duck/Czechoslovakia/1956 HA or A/Duck/Czechoslovakia/1956-like HA.

53. A method of preventing influenza virus disease in a subject, comprising: a) administering to the subject a first immunogenic composition comprising a first inactivated influenza virus and a CpG oligonucleotide adjuvant, wherein the first inactivated influenza virus comprises a first chimeric HA, and wherein the first chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8; and b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second inactivated influenza virus and a CpG oligonucleotide adjuvant, wherein the second inactivated influenza virus comprises a second chimeric HA, and wherein the second chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8, wherein

(i) the second chimeric HA comprises the amino acid sequence of SEQ ID NO: 5 or 6, if the first chimeric HA comprises the amino acid sequence of SEQ ID NO: 7 or 8; or

(ii) the second chimeric HA comprises the amino acid sequence of SEQ ID NO: 7 or 8, if the first chimeric HA comprises the amino acid sequence of SEQ ID NO: 5 or 6, and wherein each CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

54. A method of immunizing a subject against influenza virus disease, comprising: a) administering to the subject a first immunogenic composition comprising a first inactivated influenza virus and a CpG oligonucleotide adjuvant, wherein the first inactivated influenza virus comprises a first chimeric HA, and wherein the first chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8; and b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition, wherein the second immunogenic composition comprises a second inactivated influenza virus and a CpG oligonucleotide adjuvant, wherein the second inactivated influenza virus comprises a second chimeric HA, and wherein the second chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8, wherein

(ii) the second chimeric HA comprises the amino acid sequence of SEQ ID NO:7 or 8, if the first chimeric HA comprises the amino acid sequence of SEQ ID NO: 5 or 6, and wherein each CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

55. A method of inducing a cross-reactive immune response to at least two group 2 influenza A viruses in a subject, comprising: a) administering to the subject a first immunogenic composition comprising a first inactivated influenza virus and a CpG oligonucleotide adjuvant, wherein the first inactivated influenza virus comprises a first chimeric HA, and wherein the first chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8; and b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition, wherein the second immunogenic composition comprises a second inactivated split influenza virus and a CpG oligonucleotide adjuvant, wherein the second inactivated split influenza virus comprises a second chimeric HA, and wherein the second chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8, wherein

(i) the second chimeric HA comprises the amino acid sequence of SEQ ID NO:5 or 6, if the first chimeric HA comprises the amino acid sequence of SEQ ID NO:7 or 8; or

(ii) the second chimeric HA comprises the amino acid sequence of SEQ ID NO:7 or 8, if the first chimeric HA comprises the amino acid sequence of SEQ ID NO: 5 or 6, and wherein each CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID N0:3).

56. A method of preventing influenza virus disease in a subject, comprising: a) administering to the subject a first immunogenic composition comprising a first inactivated split influenza virus and a CpG oligonucleotide adjuvant, wherein the first inactivated split influenza virus comprises a first chimeric HA, and wherein the first chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8; and b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second inactivated split influenza virus and a CpG oligonucleotide adjuvant, wherein the second inactivated split influenza virus comprises a second chimeric HA, and wherein the second chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8, wherein

57. A method of immunizing a subject against influenza virus disease, comprising: a) administering to the subject a first immunogenic composition comprising a first inactivated split influenza virus and a CpG oligonucleotide adjuvant, wherein the first inactivated split influenza virus comprises a first chimeric HA, and wherein the first chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8; and b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second inactivated split influenza virus and a CpG oligonucleotide adjuvant, wherein the second inactivated split influenza virus comprises a second chimeric HA, and wherein the second chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8, wherein

58. A method of inducing a cross-reactive immune response to at least two group 2 influenza A viruses in a subject, comprising: a) administering to the subject a first immunogenic composition comprising a first inactivated split influenza virus and a CpG oligonucleotide adjuvant, wherein the first inactivated split influenza virus comprises a first chimeric HA, and wherein the first chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8; and b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second inactivated split influenza virus and a CpG oligonucleotide adjuvant, wherein the second inactivated split influenza virus comprises a second chimeric HA, and wherein the second chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8, wherein

(i) the second chimeric HA comprises the amino acid sequence of SEQ ID NO: 5 or 6, if the first chimeric HA comprises the amino acid sequence of SEQ ID NO:7 or 8; or

59. A method of preventing influenza virus disease in a subject, comprising: a) administering to the subject a first immunogenic composition comprising a first chimeric HA and a CpG oligonucleotide adjuvant, wherein the first chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8; and b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second chimeric HA and a CpG oligonucleotide adjuvant, wherein the second chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8, wherein

(i) the second chimeric HA comprises the amino acid sequence of SEQ ID

NO: 5 or 6, if the first chimeric HA comprises the amino acid sequence of SEQ ID NO: 7 or 8; or

60. A method of immunizing a subject against influenza virus disease, comprising: a) administering to the subject a first immunogenic composition comprising a first chimeric HA and a CpG oligonucleotide adjuvant, wherein the first chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8; and b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second chimeric HA and a CpG oligonucleotide adjuvant, wherein the second chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8, wherein

(i) the second chimeric HA comprises the amino acid sequence of SEQ ID

NO: 5 or 6, if the first chimeric HA comprises the amino acid sequence of SEQ ID

NO: 7 or 8; or (ii) the second chimeric HA comprises the amino acid sequence of SEQ ID NO:7 or 8, if the first chimeric HA comprises the amino acid sequence of SEQ ID NO: 5 or 6, and wherein each CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

61. A method of inducing a cross-reactive immune response to at least two group 2 influenza A viruses in a subject, comprising: a) administering to the subject a first immunogenic composition comprising a first chimeric HA and a CpG oligonucleotide adjuvant, wherein the first chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8; and b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second chimeric HA and a CpG oligonucleotide adjuvant, wherein the second chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8, wherein

62. The method according to any one of embodiments 29 to 61, wherein the second immunogenic composition is administered to the subject about 21 to about 6 months after the administration of the first immunogenic composition to the subject.

63. The method according to any one of embodiments 29 to 62, wherein the oligonucleotide comprises the nucleotide sequence of 5’- TGACTGTGAACGTTCGAGATGA-3’ (SEQ ID NO:4). 64. The method according to any one according to embodiments 29 to 63, wherein the oligonucleotide is 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 nucleotides in length.

65. The method according to any one of embodiments 29 to 64, wherein the oligonucleotide is a single stranded oligodeoxynucleotide.

66. The method according to any one of embodiments 29 to 65, wherein the oligonucleotide comprises only phosphorothioate linkages, or a combination of one or more phosphodiester linkages and one or more phosphorothioate linkages.

67. The method according to any one of embodiments 29 to 66, wherein the oligonucleotide is fully RNA or is an RNA/DNA chimera.

68. The method according to any one of embodiments 29 to 67, wherein the composition further comprises an aluminum salt.

69. The method according to embodiment 68, wherein the aluminum salt comprises one or more selected from the group consisting of amorphous aluminum hydroxyphosphate sulfate, aluminum hydroxide, aluminum phosphate, and potassium aluminum sulfate.

70. The method according to embodiment 68, wherein the aluminum salt comprises aluminum hydroxide or aluminum phosphate.

71. The method according to any one of embodiments 29 to 70, wherein the first immunogenic composition or second immunogenic is administered to the subject intramuscularly or intranasally.

72. The method according to any one of embodiments 29 to 70, wherein the first immunogenic composition and second immunogenic are administered to the subject intramuscularly or intranasally.

73. The method according to any one of embodiments 25 to 72, wherein the subject is human.

74. A method of preventing an influenza virus disease in a subject, comprising: a) administering to the subject an immunogenic composition comprising a chimeric hemagglutinin (HA), wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises an amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, wherein the HA globular head domain of the chimeric HA is heterologous to the HA stalk domain of the group 2 influenza A virus HA of interest, and wherein the HA globular head domain of the chimeric HA is from an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and b) administering to the subject a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

75. A method of immunizing a subject against influenza virus disease, comprising: a) administering to the subject an immunogenic composition comprising a chimeric hemagglutinin (HA), wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises an amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, wherein the HA globular head domain of the chimeric HA is heterologous to the HA stalk domain of the group 2 influenza A virus HA of interest, and wherein the HA globular head domain of the chimeric HA is from an influenza A virus HA of a different strain, subtype, or group than the globular head domain of the group 2 influenza A virus HA of interest; and b) administering to the subject a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

76. A method of inducing a cross-reactive immune response to at least two group 2 influenza A viruses in a subject, comprising: a) administering to the subject an immunogenic composition comprising a chimeric hemagglutinin (HA), wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises an amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, wherein the HA globular head domain of the chimeric HA is heterologous to the HA stalk domain of the group 2 influenza A virus HA of interest, and wherein the HA globular head domain of the chimeric HA is from an influenza A virus HA of a different strain, subtype, or group than the globular head domain of the group 2 influenza A virus HA of interest; and b) administering to the subject a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

77. A method of preventing an influenza virus disease in a subject, comprising: a) administering to the subject an immunogenic composition comprising an inactivated influenza virus in an admixture with a pharmaceutically acceptable carrier, wherein the inactivated influenza virus comprises a chimeric hemagglutinin (HA), wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises an amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the HA globular head domain of the chimeric HA comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and b) administering to the subject a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

78. A method of immunizing a subject against influenza virus disease, comprising: a) administering to the subject an immunogenic composition comprising an inactivated influenza virus in an admixture with a pharmaceutically acceptable carrier, wherein the inactivated influenza virus comprises a chimeric hemagglutinin (HA), wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises an amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and the HA globular head domain of the chimeric HA comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and b) administering to the subject a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

79. A method of inducing a cross-reactive immune response to at least two group 2 influenza A viruses in a subject, comprising: a) administering to the subject an immunogenic composition comprising an inactivated influenza virus in an admixture with a pharmaceutically acceptable carrier, wherein the inactivated influenza virus comprises a chimeric hemagglutinin (HA), wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises an amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the HA globular head domain of the chimeric HA comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and b) administering to the subject a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

80. The method according to any one of embodiments 77 to 79, wherein the inactivated influenza virus comprises neuraminidase of the group 2 influenza A virus.

81. The method according to any one of embodiments 77 to 80, wherein the inactivated influenza virus comprises one or more proteins encoded by one or more genes of influenza A virus A/Puerto Rico/8/1934.

82. A method of preventing an influenza virus disease in a subject, comprising: a) administering to the subject an immunogenic composition comprising an inactivated split influenza virus in an admixture with a pharmaceutically acceptable carrier, wherein the inactivated split influenza virus comprises a chimeric hemagglutinin (HA), wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises an amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the HA globular head domain of the chimeric HA comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and b) administering to the subject a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

83. A method of immunizing a subject against influenza virus disease, comprising: a) administering to the subject an immunogenic composition comprising an inactivated split influenza virus in an admixture with a pharmaceutically acceptable carrier, wherein the inactivated split influenza virus comprises a chimeric hemagglutinin (HA), wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises an amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the HA globular head domain of the chimeric HA comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and b) administering to the subject a CpG oligonucleotide adjuvant, wherein the CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

84. A method of inducing a cross-reactive immune response to at least two group 2 influenza A viruses in a subject, comprising: a) administering to the subject an immunogenic composition comprising an inactivated split influenza virus in an admixture with a pharmaceutically acceptable carrier, wherein the inactivated split influenza virus comprises a chimeric hemagglutinin (HA), wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises an amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the HA globular head domain of the chimeric HA comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and b) administering to the subject a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

85. The method according to any one of embodiments 82 to 84, wherein the inactivated split influenza virus comprises neuraminidase of the group 2 influenza A virus.

86. The method according to any one of embodiments 82 to 85, wherein the inactivated split influenza virus comprises one or more proteins encoded by one or more genes of influenza A virus A/Puerto Rico/8/1934.

87. The method according to any one of embodiments 74 to 86, wherein the group 2 influenza A virus HA of interest is of subtype H3.

88. The method according to any one of embodiments 74 to 86, wherein the group 2 influenza A virus HA of interest is A/Hong Kong/4801/2014, NYMC X-263 HA or A/Hong Kong/4801/2014-like HA.

89. The method according to any one of embodiments 74 to 88, wherein the influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest is a group 1 influenza A virus HA.

90. The method according to any one of embodiments 74 to 88, wherein the influenza A virus HA of a different strain, subtype, or group is subtype than the group 2 influenza A virus HA of interest is HA of subtype H2, H5, H6, H8, H9, Hl l, H12, H13, H16, H17, or H18.

91. The method according to embodiment 74 or 88, wherein the influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest is HA of subtype H4, H7, H10, H14, or H15.

92. The method according to embodiment 87 or 88, wherein the influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest is A/wedge-tailed shearwater/We stern Australia/2576/1979 HA or A/wedge-tailed shearwater/Western Australia/2576/1979-like HA. 93. The method according to embodiment 87 or 88, wherein the influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest is A/Duck/Czechoslovakia/1956 HA or A/Duck/Czechoslovakia/1956-like HA.

94. The method according to any one of embodiments 74 to 93, wherein the oligonucleotide comprises the nucleotide sequence of 5’- TGACTGTGAACGTTCGAGATGA-3’ (SEQ ID NO:4).

95. The method according to any one of embodiments 74 to 94, wherein the oligonucleotide is 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 nucleotides in length.

96. The method according to any one of embodiments 74 to 95, wherein the oligonucleotide is a single stranded oligodeoxynucleotide.

97. The method according to any one of embodiments 74 to 96, wherein the oligonucleotide comprises only phosphorothioate linkages, or a combination of one or more phosphodiester linkages and one or more phosphorothioate linkages.

98. The method according to any one of embodiments 74 to 97, wherein the oligonucleotide is fully RNA or is an RNA/DNA chimera.

99. The method according to any one of method 74 to 98, wherein the immunogenic composition, the CpG oligonucleotide adjuvant, or both are administered intramuscularly to the subject.

100. The method according to any one of embodiments 74 to 99, wherein the composition further comprises an aluminum salt.

101. The method according to embodiment 100, wherein the aluminum salt comprises one or more selected from the group consisting of amorphous aluminum hydroxyphosphate sulfate, aluminum hydroxide, aluminum phosphate, and potassium aluminum sulfate.

102. The method according to embodiment 100, wherein the aluminum salt comprises aluminum hydroxide or aluminum phosphate. 103. The method according to any one of embodiments 74 to 102, wherein the subject is human.

104. The method according to any one of embodiments 74 and 103, wherein the immunogenic composition and CpG oligonucleotide adjuvant are administered concurrently to the subj ect.

105. The method according to any one of embodiments 74 and 103, wherein the immunogenic composition and CpG oligonucleotide adjuvant are administered to the subject within 30 minutes of each other.

106. The method according to any one of embodiments 74 and 103, wherein the immunogenic composition and CpG oligonucleotide adjuvant are administered to the subject within 15 minutes of each other.

107. A kit comprising a container containing an immunogenic composition comprising a chimeric hemagglutinin (HA) and a CpG oligonucleotide adjuvant, wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises an amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, wherein the HA globular head domain of the chimeric HA is heterologous to the HA stalk domain of the group 2 influenza A virus HA of interest, wherein the HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest, and wherein the CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

108. A kit comprising a container containing an immunogenic composition comprising an inactivated influenza virus and a CpG oligonucleotide adjuvant, wherein the inactivated influenza virus comprises a first chimeric HA, and wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, wherein the HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest, and wherein the CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

109. A kit comprising a container containing an immunogenic composition comprising an inactivated split influenza virus and a CpG oligonucleotide adjuvant, wherein the inactivated split influenza virus comprises a first chimeric HA, and wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, wherein the HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest, and wherein the CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

110. A kit compri sing : a) a first container containing an immunogenic composition comprising a chimeric HA, wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises an amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, wherein the HA globular head domain of the chimeric HA is heterologous to the HA stalk domain of the group 2 influenza A virus HA of interest, wherein the HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and b) a second container containing a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

111. A kit comprising: a) a first container containing an immunogenic composition comprising a first inactivated influenza virus, wherein the first inactivated influenza virus comprises a first chimeric HA, wherein the first chimeric HA comprises a first influenza virus HA globular head domain and a first influenza virus HA stalk domain, wherein the first HA stalk domain comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and b) a second container containing a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

112. A kit compri sing : a) a first container containing an immunogenic composition comprising a first inactivated split influenza virus, wherein the first inactivated split influenza virus comprises a first chimeric HA, and wherein the first chimeric HA comprises a first influenza virus HA globular head domain and a first influenza virus HA stalk domain, wherein the first HA stalk domain comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and b) a second container containing a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

113. A kit compri sing : a) a first container containing a first immunogenic composition comprising a first inactivated influenza virus and a CpG oligonucleotide adjuvant, wherein the first inactivated influenza virus comprises a first chimeric HA, and wherein the first chimeric HA comprises a first influenza virus HA globular head domain and a first influenza virus HA stalk domain, wherein the first HA stalk domain comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and b) a second container containing a second immunogenic composition comprising a second inactivated influenza virus and a CpG oligonucleotide adjuvant, wherein the second inactivated influenza virus comprises a second chimeric HA, and wherein the second chimeric HA comprises a second influenza virus HA globular head domain and a second influenza virus HA stalk domain, wherein the second HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA of interest, and wherein the second HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest, wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the second HA globular head domain, and wherein the CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

114. A kit compri sing : a) a first container containing a first immunogenic composition comprising a first inactivated split influenza virus and a CpG oligonucleotide adjuvant, wherein the first inactivated split influenza virus comprises a first chimeric HA, and wherein the first chimeric HA comprises a first influenza virus HA globular head domain and a first influenza virus HA stalk domain, wherein the first HA stalk domain comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and b) a second container containing a second immunogenic composition comprising a second inactivated split influenza virus and a CpG oligonucleotide adjuvant, wherein the second inactivated split influenza virus comprises a second chimeric HA, and wherein the second chimeric HA comprises a second influenza virus HA globular head domain and a second influenza virus HA stalk domain, wherein the second HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA of interest, and the second HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest, wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the second HA globular head domain, and wherein the CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

[00487] The foregoing is not to be limited in scope by the specific embodiments described herein. Indeed, various modifications of the compositions, antibodies, and methods provided herein and their equivalents, in addition to those described herein will become apparent to those skilled in the art from the foregoing description and accompanying figures. Such modifications are intended to fall within the scope of the appended claims.

[00488] All references cited herein are incorporated herein by reference in their entirety and for all purposes to the same extent as if each individual publication or patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety for all purposes.

Claims

We Claim:

1. An immunogenic composition, comprising: a) a chimeric hemagglutinin (HA) comprising an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the HA globular head domain of the chimeric HA comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and b) a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

2. An immunogenic composition, comprising: a) an inactivated influenza virus comprising a chimeric hemagglutinin (HA), wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the HA globular head domain of the chimeric HA comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and b) a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

3. The immunogenic composition according to claim 2, wherein the inactivated influenza virus comprises neuraminidase of the group 2 influenza A virus.

4. The immunogenic composition according to claim 2 or 3, wherein the inactivated influenza virus comprises one or more proteins encoded by one or more genes of influenza A virus A/Puerto Rico/8/1934.

5. An immunogenic composition, comprising: a) an inactivated split influenza virus comprising a chimeric hemagglutinin (HA), wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the HA globular head domain of the chimeric HA comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and b) a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

6. The immunogenic composition according to claim 5, wherein the inactivated split influenza virus comprises neuraminidase of the group 2 influenza A virus.

7. The immunogenic composition according to claim 5 or 6, wherein the inactivated split influenza virus comprises one or more proteins encoded by one or more genes of influenza A virus A/Puerto Rico/8/1934.

8. The immunogenic composition according to any one of claims 1 to 7, wherein the group 2 influenza A virus HA of interest is of subtype H3.

9. The immunogenic composition according to any one of claims 1 to 7, wherein the group 2 influenza A virus HA of interest is A/Hong Kong/4801/2014, NYMC X-263 HA or A/Hong Kong/4801/2014-like HA.

10. The immunogenic composition according to any one of claims 1 to 9, wherein the influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest is a group 1 influenza A virus HA.

11. The immunogenic composition according to any one of claims 1 to 9, wherein the influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest is of subtype H2, H5, H6, H8, H9, Hl l, H12, H13, H16, H17, or H18.

12. The immunogenic composition according to claim 1 or 9, wherein the influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest is of subtype H4, H7, H10, H14, or Hl 5.

13. The immunogenic composition according to claim 8 or 9, wherein the influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest is A/wedge-tailed shearwater/Westem Australia/2576/1979 HA or A/wedge-tailed shearwater/Western Australia/2576/1979-like HA.

14. The immunogenic composition according to claim 8 or 9, wherein the influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest is A/Duck/Czechoslovakia/1956 HA or A/Duck/Czechoslovakia/1956-like HA.

15. The immunogenic composition of claim 1, wherein the chimeric HA comprises an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:5, 6, 7, or 8, or the amino acid sequence of SEQ ID NO:5, 6, 7, or 8.

16. An immunogenic composition, comprising: a) an inactivated influenza virus comprising a chimeric hemagglutinin (HA), wherein the chimeric HA comprises an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:5, 6, 7, or 8, or the amino acid sequence of SEQ ID NO:5, 6, 7, or 8; and b) a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

17. An immunogenic composition, comprising: a) an inactivated split influenza virus comprising a chimeric hemagglutinin (HA), wherein the chimeric HA comprises an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:5, 6, 7, or 8, or the amino acid sequence of SEQ ID NO:5, 6, 7, or 8; and b) a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

18. The immunogenic composition according to any one of claims 1 to 17, wherein the oligonucleotide comprises the nucleotide sequence of 5’- TGACTGTGAACGTTCGAGATGA-3’ (SEQ ID NO:4).

19. The immunogenic composition according to any one of claims 1 to 18, wherein the oligonucleotide is 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 nucleotides in length.

20. The immunogenic composition according to any one of claims 1 to 19, wherein the oligonucleotide is a single stranded oligodeoxynucleotide.

21. The immunogenic composition according to any one of claims 1 to 20, wherein the oligonucleotide comprises only phosphorothioate linkages, or a combination of one or more phosphodiester linkages and one or more phosphorothioate linkages.

22. The immunogenic composition according to any one of claims 1 to 21, wherein the oligonucleotide is fully RNA or is an RNA/DNA chimera.

23. The immunogenic composition according to any one of claims 1 to 22, wherein the composition further comprises an aluminum salt.

24. The immunogenic composition according to claim 23, wherein the aluminum salt comprises one or more selected from the group consisting of amorphous aluminum hydroxyphosphate sulfate, aluminum hydroxide, aluminum phosphate, and potassium aluminum sulfate.

25. The immunogenic composition according to claim 23, wherein the aluminum salt comprises aluminum hydroxide or aluminum phosphate.

26. A method of preventing influenza virus disease in a subject, comprising administering to the subject the immunogenic composition of any one of claims 1 to 25.

27. A method of immunizing a subject against influenza virus disease, comprising administering to the subject the immunogenic composition of any one of claims 1 to 25.

28. A method of inducing a cross-reactive immune response to at least two group 2 influenza A viruses in a subject, comprising administering to the subject the immunogenic composition of any one of claims 1 to 25.

29. The method according to any one of claims 26 to 28, wherein the immunogenic composition is administered intramuscularly to the subject.

30. A method of preventing influenza virus disease in a subject, comprising: a) administering to the subject a first immunogenic composition comprising a first inactivated influenza virus and a CpG oligonucleotide adjuvant, wherein the first inactivated influenza virus comprises a first chimeric HA, wherein the first chimeric HA comprises a first influenza virus HA globular head domain and a first influenza virus HA stalk domain, wherein the first HA stalk domain comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second inactivated influenza virus and a CpG oligonucleotide adjuvant, wherein the second inactivated influenza virus comprises a second chimeric HA, wherein the second chimeric HA comprises a second influenza virus HA globular head domain and a second influenza virus HA stalk domain, wherein the second HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA of interest, and wherein the second HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the second HA globular head domain, and wherein each CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

31. A method of immunizing a subject against influenza virus disease, comprising: a) administering to the subject a first immunogenic composition comprising a first inactivated influenza virus and a CpG oligonucleotide adjuvant, wherein the first inactivated influenza virus comprises a first chimeric HA, wherein the first chimeric HA comprises a first influenza virus HA globular head domain and a first influenza virus HA stalk domain, wherein the first HA stalk domain comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second inactivated influenza virus and a CpG oligonucleotide adjuvant, wherein the second inactivated influenza virus comprises a second chimeric HA, wherein the second chimeric HA comprises a second influenza virus HA globular head domain and a second influenza virus HA stalk domain, wherein the second HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA of interest, and wherein the second HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the second HA globular head domain, and wherein each CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

32. A method of inducing a cross-reactive immune response to at least two group 2 influenza A viruses in a subject, comprising: a) administering to the subject a first immunogenic composition comprising a first inactivated influenza virus and a CpG oligonucleotide adjuvant, wherein the first inactivated influenza virus comprises a first chimeric HA, wherein the first chimeric HA comprises a first influenza virus HA globular head domain and a first influenza virus HA stalk domain, wherein the first HA stalk domain comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second inactivated influenza virus and a CpG oligonucleotide adjuvant, wherein the second inactivated influenza virus comprises a second chimeric HA, wherein the second chimeric HA comprises a second influenza virus HA globular head domain and a second influenza virus HA stalk domain, wherein the second HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA of interest, and wherein the second HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the second HA globular head domain, and wherein each CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

33. The method according to any one of claims 30 to 32, wherein the first inactivated influenza virus and the second inactivated influenza virus each comprise neuraminidase of the group 2 influenza A virus.

34. The method according to any one of claims 30 to 33, wherein the first inactivated influenza virus and the second inactivated influenza virus each comprise one or more proteins encoded by one or more genes of influenza A virus A/Puerto Rico/8/1934.

35. The method according to any one of claims 30 to 34, wherein the method further comprises administering to the subject a third immunogenic composition a certain time after the administration of the second immunogenic composition to the subject, wherein the third immunogenic composition comprises a third inactivated influenza virus and a CpG oligonucleotide adjuvant, wherein the third inactivated influenza virus comprises a third chimeric HA, wherein the third chimeric HA comprises a third influenza virus HA globular head domain and a third influenza virus HA stalk domain, wherein the third HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA of interest, wherein the third HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest, and wherein the third HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the first HA globular head domain and the second HA globular head domain.

36. A method of preventing influenza virus disease in a subject, comprising: a) administering to the subject a first immunogenic composition comprising a first inactivated split influenza virus and a CpG oligonucleotide adjuvant, wherein the first inactivated split influenza virus comprises a first chimeric HA, wherein the first chimeric HA comprises a first influenza virus HA globular head domain and a first influenza virus HA stalk domain, wherein the first HA stalk domain comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second inactivated split influenza virus and a CpG oligonucleotide adjuvant, wherein the second inactivated split influenza virus comprises a second chimeric HA, and wherein the second chimeric HA comprises a second influenza virus HA globular head domain and a second influenza virus HA stalk domain, wherein the second HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA of interest, and wherein the second HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the second HA globular head domain, and wherein each CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID N0:3).

37. A method of immunizing a subject against influenza virus disease, comprising: a) administering to the subject a first immunogenic composition comprising a first inactivated split influenza virus and a CpG oligonucleotide adjuvant, wherein the first inactivated split influenza virus comprises a first chimeric HA, wherein the first chimeric HA comprises a first influenza virus HA globular head domain and a first influenza virus HA stalk domain, wherein the first HA stalk domain comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second inactivated split influenza virus and a CpG oligonucleotide adjuvant, wherein the second inactivated split influenza virus comprises a second chimeric HA, wherein the second chimeric HA comprises a second influenza virus HA globular head domain and a second influenza virus HA stalk domain, wherein the second HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA of interest, and wherein the second HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the second HA globular head domain, and wherein each CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

38. A method of inducing a cross-reactive immune response to at least two group 2 influenza A viruses in a subject, comprising: a) administering to the subject a first immunogenic composition comprising a first inactivated split influenza virus and a CpG oligonucleotide adjuvant, wherein the first inactivated split influenza virus comprises a first chimeric HA, wherein the first chimeric HA comprises a first influenza virus HA globular head domain and a first influenza virus HA stalk domain, wherein the first HA stalk domain comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second inactivated split influenza virus and a CpG oligonucleotide adjuvant, wherein the second inactivated split influenza virus comprises a second chimeric HA, wherein the second chimeric HA comprises a second influenza virus HA globular head domain and a second influenza virus HA stalk domain, wherein the second HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA of interest, and wherein the second HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the second HA globular head domain, and wherein each CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

39. The method according to any one of claims 36 to 38, wherein the first inactivated split influenza virus and the second inactivated split influenza virus each comprise neuraminidase of the group 2 influenza A virus.

40. The method according to any one of claims 36 to 39, the first inactivated split influenza virus and the second inactivated split influenza virus each comprise one or more proteins encoded by one or more genes of influenza A virus A/Puerto Rico/8/1934.

41. The method according to any one of claims 36 to 40, wherein the method further comprises administering to the subject a third immunogenic composition a certain time after the administration of the second immunogenic composition to the subject, wherein the third immunogenic composition comprises a third inactivated split influenza virus and a CpG oligonucleotide adjuvant, wherein the third inactivated split influenza virus comprises a third chimeric HA, and wherein the third chimeric HA comprises a third influenza virus HA globular head domain and a third influenza virus HA stalk domain, wherein the third HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA of interest, wherein the third HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest, and wherein the third HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the first HA globular head domain and the second HA globular head domain.

42. A method of preventing influenza virus disease in a subject, comprising: a) administering to the subject a first immunogenic composition comprising a first chimeric hemagglutinin (HA) and a CpG oligonucleotide adjuvant, wherein the first chimeric HA comprises a first influenza virus HA globular head domain and a first influenza virus HA stalk domain, wherein the first HA stalk domain comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second chimeric HA and a CpG oligonucleotide adjuvant, wherein the second chimeric HA comprises a second influenza virus HA globular head domain and a second influenza virus HA stalk domain, wherein the second HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA of interest, and wherein the second HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest, and wherein the first globular head comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the second HA globular head domain, and wherein each CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID N0:3).

43. A method of immunizing a subject against influenza virus disease, comprising: a) administering to the subject a first immunogenic composition comprising a first chimeric hemagglutinin (HA) and a CpG oligonucleotide adjuvant, wherein the first chimeric HA comprises a first influenza virus HA globular head domain and a first influenza virus HA stalk domain, wherein the first HA stalk domain comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second chimeric HA and a CpG oligonucleotide adjuvant, wherein the second chimeric HA comprises a second influenza virus HA globular head domain and a second influenza virus HA stalk domain, wherein the second HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA of interest, and wherein the second HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the second HA globular head domain, and wherein each CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

44. A method of inducing a cross-reactive immune response to at least two group

2 influenza A viruses in a subject, comprising: a) administering to the subject a first immunogenic composition comprising a first chimeric hemagglutinin (HA) and a CpG oligonucleotide adjuvant, wherein the first chimeric HA comprises a first influenza virus HA globular head domain and a first influenza virus HA stalk domain, wherein the first HA stalk domain comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second chimeric HA and a CpG oligonucleotide adjuvant, wherein the second chimeric HA comprises a second influenza virus HA globular head domain and a second influenza virus HA stalk domain, wherein the second HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA of interest, and wherein the second HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest, and wherein the first globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the second HA globular head domain, and wherein each CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

45. The method according to any one of claims 30 to 44, wherein the group 2 influenza A virus HA of interest is of subtype H3.

46. The method according to any one of claims 30 to 45, wherein the group 2 influenza A virus HA of interest is A/Hong Kong/4801/2014, NYMC X-263 HA, or A/Hong Kong/4801/2014-like HA.

47. The method according to any one of claims 30 to 46, wherein the first HA globular head domain or the second HA globular head domain is the HA globular head domain of a group 1 influenza A virus HA.

48. The method according to any one of claims 30 to 46, wherein the first HA globular head domain and the second HA globular head domain are the HA globular head domain of group 1 influenza A virus HAs.

49. The method according to any one of claims 30 to 46, wherein the first HA globular head domain or the second HA globular head domain is the HA globular head domain of an HA of subtype H2, H5, H6, H8, H9, Hl 1, H12, H13, H16, H17, or H18.

50. The method according to any one of claims 30 to 46, wherein the first HA globular head domain and the second HA globular head domain are the HA globular head domain of an HA of subtype H2, H5, H6, H8, H9, Hl 1, H12, H13, H16, H17, or H18.

51. The method according to claim 45 or 46, wherein the first HA globular head domain and the second HA globular head domain are the HA globular head domain of subtype H4, H7, H10, H14, or H15.

52. The method according to claim 45 or 46, wherein the first HA globular head domain is the HA globular head domain of A/wedge-tailed shearwater/Westem Australia/2576/1979 HA or A/wedge-tailed shearwater/Western Australia/2576/1979-like HA.

53. The method according to claim 45 or 46, wherein the second HA globular head domain is the HA globular head domain of A/Duck/Czechoslovakia/1956 HA or A/Duck/Czechoslovakia/1956-like HA.

54. A method of preventing influenza virus disease in a subject, comprising: a) administering to the subject a first immunogenic composition comprising a first inactivated influenza virus and a CpG oligonucleotide adjuvant, wherein the first inactivated influenza virus comprises a first chimeric HA, and wherein the first chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8; and b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second inactivated influenza virus and a CpG oligonucleotide adjuvant, wherein the second inactivated influenza virus comprises a second chimeric HA, and wherein the second chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8, wherein

55. A method of immunizing a subject against influenza virus disease, comprising: a) administering to the subject a first immunogenic composition comprising a first inactivated influenza virus and a CpG oligonucleotide adjuvant, wherein the first inactivated influenza virus comprises a first chimeric HA, and wherein the first chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8; and b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition, wherein the second immunogenic composition comprises a second inactivated influenza virus and a CpG oligonucleotide adjuvant, wherein the second inactivated influenza virus comprises a second chimeric HA, and wherein the second chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8, wherein

56. A method of inducing a cross-reactive immune response to at least two group 2 influenza A viruses in a subject, comprising: a) administering to the subject a first immunogenic composition comprising a first inactivated influenza virus and a CpG oligonucleotide adjuvant, wherein the first inactivated influenza virus comprises a first chimeric HA, and wherein the first chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8; and b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition, wherein the second immunogenic composition comprises a second inactivated split influenza virus and a CpG oligonucleotide adjuvant, wherein the second inactivated split influenza virus comprises a second chimeric HA, and wherein the second chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8, wherein

57. A method of preventing influenza virus disease in a subject, comprising: a) administering to the subject a first immunogenic composition comprising a first inactivated split influenza virus and a CpG oligonucleotide adjuvant, wherein the first inactivated split influenza virus comprises a first chimeric HA, and wherein the first chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8; and b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second inactivated split influenza virus and a CpG oligonucleotide adjuvant, wherein the second inactivated split influenza virus comprises a second chimeric HA, and wherein the second chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8, wherein

58. A method of immunizing a subject against influenza virus disease, comprising: a) administering to the subject a first immunogenic composition comprising a first inactivated split influenza virus and a CpG oligonucleotide adjuvant, wherein the first inactivated split influenza virus comprises a first chimeric HA, and wherein the first chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8; and b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second inactivated split influenza virus and a CpG oligonucleotide adjuvant, wherein the second inactivated split influenza virus comprises a second chimeric HA, and wherein the second chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8, wherein

59. A method of inducing a cross-reactive immune response to at least two group 2 influenza A viruses in a subject, comprising: a) administering to the subject a first immunogenic composition comprising a first inactivated split influenza virus and a CpG oligonucleotide adjuvant, wherein the first inactivated split influenza virus comprises a first chimeric HA, and wherein the first chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8; and b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second inactivated split influenza virus and a CpG oligonucleotide adjuvant, wherein the second inactivated split influenza virus comprises a second chimeric HA, and wherein the second chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8, wherein

60. A method of preventing influenza virus disease in a subject, comprising: a) administering to the subject a first immunogenic composition comprising a first chimeric HA and a CpG oligonucleotide adjuvant, wherein the first chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8; and b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second chimeric HA and a CpG oligonucleotide adjuvant, wherein the second chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8, wherein

(i) the second chimeric HA comprises the amino acid sequence of SEQ ID

61. A method of immunizing a subject against influenza virus disease, comprising: a) administering to the subject a first immunogenic composition comprising a first chimeric HA and a CpG oligonucleotide adjuvant, wherein the first chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8; and b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second chimeric HA and a CpG oligonucleotide adjuvant, wherein the second chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8, wherein

(i) the second chimeric HA comprises the amino acid sequence of SEQ ID

62. A method of inducing a cross-reactive immune response to at least two group 2 influenza A viruses in a subject, comprising: a) administering to the subject a first immunogenic composition comprising a first chimeric HA and a CpG oligonucleotide adjuvant, wherein the first chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8; and b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second chimeric HA and a CpG oligonucleotide adjuvant, wherein the second chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8, wherein

63. The method according to any one of claims 30 to 62, wherein the second immunogenic composition is administered to the subject about 21 to about 6 months after the administration of the first immunogenic composition to the subject.

64. The method according to any one of claims 30 to 63, wherein the oligonucleotide comprises the nucleotide sequence of 5’-TGACTGTGAACGTTCGAGATGA-3’

(SEQ ID NO:4).

65. The method according to any one according to claims 30 to 64, wherein the oligonucleotide is 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 nucleotides in length.

66. The method according to any one of claims 30 to 65, wherein the oligonucleotide is a single stranded oligodeoxynucleotide.

67. The method according to any one of claims 30 to 66, wherein the oligonucleotide comprises only phosphorothioate linkages, or a combination of one or more phosphodiester linkages and one or more phosphorothioate linkages.

68. The method according to any one of claims 30 to 67, wherein the oligonucleotide is fully RNA or is an RNA/DNA chimera.

69. The method according to any one of claims 30 to 68, wherein the composition further comprises an aluminum salt.

70. The method according to claim 69, wherein the aluminum salt comprises one or more selected from the group consisting of amorphous aluminum hydroxyphosphate sulfate, aluminum hydroxide, aluminum phosphate, and potassium aluminum sulfate.

71. The method according to claim 69, wherein the aluminum salt comprises aluminum hydroxide or aluminum phosphate.

72. The method according to any one of claims 30 to 71, wherein the first immunogenic composition or second immunogenic is administered to the subject intramuscularly or intranasally.

73. The method according to any one of claims 30 to 71, wherein the first immunogenic composition and second immunogenic are administered to the subject intramuscularly or intranasally.

74. The method according to any one of claims 26 to 73, wherein the subject is human.

75. A method of preventing an influenza virus disease in a subject, comprising: a) administering to the subject an immunogenic composition comprising a chimeric hemagglutinin (HA), wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises an amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, wherein the HA globular head domain of the chimeric HA is heterologous to the HA stalk domain of the group 2 influenza A virus HA of interest, and wherein the HA globular head domain of the chimeric HA is from an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and b) administering to the subject a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

76. A method of immunizing a subject against influenza virus disease, comprising: a) administering to the subject an immunogenic composition comprising a chimeric hemagglutinin (HA), wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises an amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, wherein the HA globular head domain of the chimeric HA is heterologous to the HA stalk domain of the group 2 influenza A virus HA of interest, and wherein the HA globular head domain of the chimeric HA is from an influenza A virus HA of a different strain, subtype, or group than the globular head domain of the group 2 influenza A virus HA of interest; and b) administering to the subject a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

77. A method of inducing a cross-reactive immune response to at least two group 2 influenza A viruses in a subject, comprising: a) administering to the subject an immunogenic composition comprising a chimeric hemagglutinin (HA), wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises an amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, wherein the HA globular head domain of the chimeric HA is heterologous to the HA stalk domain of the group 2 influenza A virus HA of interest, and wherein the HA globular head domain of the chimeric HA is from an influenza A virus HA of a different strain, subtype, or group than the globular head domain of the group 2 influenza A virus HA of interest; and b) administering to the subject a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

78. A method of preventing an influenza virus disease in a subject, comprising: a) administering to the subject an immunogenic composition comprising an inactivated influenza virus in an admixture with a pharmaceutically acceptable carrier, wherein the inactivated influenza virus comprises a chimeric hemagglutinin (HA), wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises an amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the HA globular head domain of the chimeric HA comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and b) administering to the subject a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

79. A method of immunizing a subject against influenza virus disease, comprising: a) administering to the subject an immunogenic composition comprising an inactivated influenza virus in an admixture with a pharmaceutically acceptable carrier, wherein the inactivated influenza virus comprises a chimeric hemagglutinin (HA), wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises an amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and the HA globular head domain of the chimeric HA comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and b) administering to the subject a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

80. A method of inducing a cross-reactive immune response to at least two group 2 influenza A viruses in a subject, comprising: a) administering to the subject an immunogenic composition comprising an inactivated influenza virus in an admixture with a pharmaceutically acceptable carrier, wherein the inactivated influenza virus comprises a chimeric hemagglutinin (HA), wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises an amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the HA globular head domain of the chimeric HA comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and b) administering to the subject a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

81. The method according to any one of claims 78 to 80, wherein the inactivated influenza virus comprises neuraminidase of the group 2 influenza A virus.

82. The method according to any one of claims 78 to 81, wherein the inactivated influenza virus comprises one or more proteins encoded by one or more genes of influenza A virus A/Puerto Rico/8/1934.

83. A method of preventing an influenza virus disease in a subject, comprising: a) administering to the subject an immunogenic composition comprising an inactivated split influenza virus in an admixture with a pharmaceutically acceptable carrier, wherein the inactivated split influenza virus comprises a chimeric hemagglutinin (HA), wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises an amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the HA globular head domain of the chimeric HA comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and b) administering to the subject a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

84. A method of immunizing a subject against influenza virus disease, comprising: a) administering to the subject an immunogenic composition comprising an inactivated split influenza virus in an admixture with a pharmaceutically acceptable carrier, wherein the inactivated split influenza virus comprises a chimeric hemagglutinin (HA), wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises an amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the HA globular head domain of the chimeric HA comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and b) administering to the subject a CpG oligonucleotide adjuvant, wherein the CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

85. A method of inducing a cross-reactive immune response to at least two group 2 influenza A viruses in a subject, comprising: a) administering to the subject an immunogenic composition comprising an inactivated split influenza virus in an admixture with a pharmaceutically acceptable carrier, wherein the inactivated split influenza virus comprises a chimeric hemagglutinin (HA), wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises an amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the HA globular head domain of the chimeric HA comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and b) administering to the subject a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

86. The method according to any one of claims 83 to 85, wherein the inactivated split influenza virus comprises neuraminidase of the group 2 influenza A virus.

87. The method according to any one of claims 83 to 86, wherein the inactivated split influenza virus comprises one or more proteins encoded by one or more genes of influenza A virus A/Puerto Rico/8/1934.

88. The method according to any one of claims 75 to 87, wherein the group 2 influenza A virus HA of interest is of subtype H3.

89. The method according to any one of claims 75 to 87, wherein the group 2 influenza A virus HA of interest is A/Hong Kong/4801/2014, NYMC X-263 HA or A/Hong Kong/4801/2014-like HA.

90. The method according to any one of claims 75 to 89, wherein the influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest is a group 1 influenza A virus HA.

91. The method according to any one of claims 75 to 89, wherein the influenza A virus HA of a different strain, subtype, or group is subtype than the group 2 influenza A virus HA of interest is HA of subtype H2, H5, H6, H8, H9, Hl l, H12, H13, H16, H17, or H18.

92. The method according to claim 75 or 89, wherein the influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest is HA of subtype H4, H7, H10, H14, or H15.

93. The method according to claim 88 or 89, wherein the influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest is A/wedge-tailed shearwater/We stern Australia/2576/1979 HA or A/wedge-tailed shearwater/Western Australia/2576/1979-like HA.

94. The method according to claim 88 or 89, wherein the influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest is A/Duck/Czechoslovakia/1956 HA or A/Duck/Czechoslovakia/1956-like HA.

95. The method according to any one of claims 75 to 94, wherein the oligonucleotide comprises the nucleotide sequence of 5’-TGACTGTGAACGTTCGAGATGA-3’ (SEQ ID NO:4).

96. The method according to any one of claims 75 to 95, wherein the oligonucleotide is 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 nucleotides in length.

97. The method according to any one of claims 75 to 96, wherein the oligonucleotide is a single stranded oligodeoxynucleotide.

98. The method according to any one of claims 75 to 97, wherein the oligonucleotide comprises only phosphorothioate linkages, or a combination of one or more phosphodiester linkages and one or more phosphorothioate linkages.

99. The method according to any one of claims 75 to 98, wherein the oligonucleotide is fully RNA or is an RNA/DNA chimera.

100. The method according to any one of method 75 to 99, wherein the immunogenic composition, the CpG oligonucleotide adjuvant, or both are administered intramuscularly to the subject.

101. The method according to any one of claims 75 to 100, wherein the composition further comprises an aluminum salt.

102. The method according to claim 101, wherein the aluminum salt comprises one or more selected from the group consisting of amorphous aluminum hydroxyphosphate sulfate, aluminum hydroxide, aluminum phosphate, and potassium aluminum sulfate.

103. The method according to claim 101, wherein the aluminum salt comprises aluminum hydroxide or aluminum phosphate.

104. The method according to any one of claims 75 to 103, wherein the subject is human.

105. The method according to any one of claims 75 and 104, wherein the immunogenic composition and CpG oligonucleotide adjuvant are administered concurrently to the subject.

106. The method according to any one of claims 75 and 104, wherein the immunogenic composition and CpG oligonucleotide adjuvant are administered to the subject within 30 minutes of each other.

107. The method according to any one of claims 75 and 104, wherein the immunogenic composition and CpG oligonucleotide adjuvant are administered to the subject within 15 minutes of each other.

108. A kit comprising a container containing an immunogenic composition comprising a chimeric hemagglutinin (HA) and a CpG oligonucleotide adjuvant, wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises an amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, wherein the HA globular head domain of the chimeric HA is heterologous to the HA stalk domain of the group 2 influenza A virus HA of interest, wherein the HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest, and wherein the CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

109. A kit comprising a container containing an immunogenic composition comprising an inactivated influenza virus and a CpG oligonucleotide adjuvant, wherein the inactivated influenza virus comprises a first chimeric HA, and wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, wherein the HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest, and wherein the CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

110. A kit comprising a container containing an immunogenic composition comprising an inactivated split influenza virus and a CpG oligonucleotide adjuvant, wherein the inactivated split influenza virus comprises a first chimeric HA, and wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, wherein the HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest, and wherein the CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

111. A kit comprising: a) a first container containing an immunogenic composition comprising a chimeric HA, wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises an amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, wherein the HA globular head domain of the chimeric HA is heterologous to the HA stalk domain of the group 2 influenza A virus HA of interest, wherein the HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and b) a second container containing a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

112. A kit compri sing : a) a first container containing an immunogenic composition comprising a first inactivated influenza virus, wherein the first inactivated influenza virus comprises a first chimeric HA, wherein the first chimeric HA comprises a first influenza virus HA globular head domain and a first influenza virus HA stalk domain, wherein the first HA stalk domain comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and b) a second container containing a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

113. A kit compri sing : a) a first container containing an immunogenic composition comprising a first inactivated split influenza virus, wherein the first inactivated split influenza virus comprises a first chimeric HA, and wherein the first chimeric HA comprises a first influenza virus HA globular head domain and a first influenza virus HA stalk domain, wherein the first HA stalk domain comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and b) a second container containing a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

114. A kit compri sing : a) a first container containing a first immunogenic composition comprising a first inactivated influenza virus and a CpG oligonucleotide adjuvant, wherein the first inactivated influenza virus comprises a first chimeric HA, and wherein the first chimeric HA comprises a first influenza virus HA globular head domain and a first influenza virus HA stalk domain, wherein the first HA stalk domain comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and b) a second container containing a second immunogenic composition comprising a second inactivated influenza virus and a CpG oligonucleotide adjuvant, wherein the second inactivated influenza virus comprises a second chimeric HA, and wherein the second chimeric HA comprises a second influenza virus HA globular head domain and a second influenza virus HA stalk domain, wherein the second HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA of interest, and wherein the second HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest, wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the second HA globular head domain, and wherein the CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

115. A kit compri sing : a) a first container containing a first immunogenic composition comprising a first inactivated split influenza virus and a CpG oligonucleotide adjuvant, wherein the first inactivated split influenza virus comprises a first chimeric HA, and wherein the first chimeric HA comprises a first influenza virus HA globular head domain and a first influenza virus HA stalk domain, wherein the first HA stalk domain comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and b) a second container containing a second immunogenic composition comprising a second inactivated split influenza virus and a CpG oligonucleotide adjuvant, wherein the second inactivated split influenza virus comprises a second chimeric HA, and wherein the second chimeric HA comprises a second influenza virus HA globular head domain and a second influenza virus HA stalk domain, wherein the second HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA of interest, and the second HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest, wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the second HA globular head domain, and wherein the CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).