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WO2025073874A1 - Composition de vaccin comprenant des nanoparticules m2e et une protéine ha1 - Google Patents

Composition de vaccin comprenant des nanoparticules m2e et une protéine ha1 Download PDF

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Publication number
WO2025073874A1
WO2025073874A1 PCT/EP2024/077908 EP2024077908W WO2025073874A1 WO 2025073874 A1 WO2025073874 A1 WO 2025073874A1 EP 2024077908 W EP2024077908 W EP 2024077908W WO 2025073874 A1 WO2025073874 A1 WO 2025073874A1
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Prior art keywords
protein
seq
virus
influenza
abs
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Inventor
Christophe Chevalier
Denis Archambault
Steve BOURGAULT
Ronan Le Goffic
Cynthia Calzas
Yohannes BERHANE
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Agence Canadienne D'inspection Des Aliments Acia
Transfert Plus SC
Universite de Versailles Saint Quentin en Yvelines
Institut National de Recherche pour lAgriculture lAlimentation et lEnvironnement
Original Assignee
Agence Canadienne D'inspection Des Aliments Acia
Transfert Plus SC
Universite de Versailles Saint Quentin en Yvelines
Institut National de Recherche pour lAgriculture lAlimentation et lEnvironnement
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Publication of WO2025073874A1 publication Critical patent/WO2025073874A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/12—Viral antigens
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/55—Medicinal preparations containing antigens or antibodies characterised by the host/recipient, e.g. newborn with maternal antibodies
    • A61K2039/552—Veterinary vaccine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/55566—Emulsions, e.g. Freund's adjuvant, MF59
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/58—Medicinal preparations containing antigens or antibodies raising an immune response against a target which is not the antigen used for immunisation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/60—Medicinal preparations containing antigens or antibodies characteristics by the carrier linked to the antigen
    • A61K2039/6031—Proteins
    • A61K2039/6068—Other bacterial proteins, e.g. OMP
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/60—Medicinal preparations containing antigens or antibodies characteristics by the carrier linked to the antigen
    • A61K2039/6031—Proteins
    • A61K2039/6075—Viral proteins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/64—Medicinal preparations containing antigens or antibodies characterised by the architecture of the carrier-antigen complex, e.g. repetition of carrier-antigen units
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/64—Medicinal preparations containing antigens or antibodies characterised by the architecture of the carrier-antigen complex, e.g. repetition of carrier-antigen units
    • A61K2039/645—Dendrimers; Multiple antigen peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/70—Multivalent vaccine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2760/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses negative-sense
    • C12N2760/00011—Details
    • C12N2760/16011—Orthomyxoviridae
    • C12N2760/16111—Influenzavirus A, i.e. influenza A virus
    • C12N2760/16122—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2760/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses negative-sense
    • C12N2760/00011—Details
    • C12N2760/16011—Orthomyxoviridae
    • C12N2760/16111—Influenzavirus A, i.e. influenza A virus
    • C12N2760/16134—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2760/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses negative-sense
    • C12N2760/00011—Details
    • C12N2760/18011—Paramyxoviridae
    • C12N2760/18511—Pneumovirus, e.g. human respiratory syncytial virus
    • C12N2760/18522—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes

Definitions

  • Influenza A viruses whose natural reservoirs are wild aquatic birds, infect a wide range of species including domestic birds and mammals such as pigs and humans. Based on genetic and antigenic characterization of the two surface glycoproteins, namely the hemagglutinin (HA) and neuraminidase (NA), avian IAV are categorized into 16 HA and 9 NA subtypes. Generally, avian IAV are classified into low pathogenicity avian influenza (LPAI) or high pathogenic avian influenza (HPAI) viruses on the basis of their pathobiological effects in gallinaceous species. In chickens, infections with LPAI viruses are usually asymptomatic or cause low to mild clinical signs associated with limited viral replication in the respiratory, digestive, and/or reproductive systems.
  • LPAI low pathogenicity avian influenza
  • HPAI high pathogenic avian influenza
  • HPAI viruses replicate in multiple tissues causing systemic infections manifested by a complex set of clinical diseases such as central nervous system as well as respiratory involvements, leading to significant mortality.
  • HPAI H5 viruses derived from the Gs/GD lineage which has evolved worldwide into diverse clades, subclades and reassortants (“H5Nx viruses”), cause not only important economic problems to the poultry industry, but also serious threat to public health worldwide through their zoonotic and pandemic potential.
  • Vaccination when implemented with good farm biosecurity measures, can be an effective approach to control IAV infections in poultry and reduce the economic impacts.
  • licensed vaccines include whole inactivated viruses (WIV) emulsified in oil adjuvants and live recombinant viral vectors with HA-encoding gene inserts. These vaccines generate variable levels of neutralizing antibodies directed towards the globular head domain of HA (HA1), which can block viral entry into permissive host cells and subsequent virus replication.
  • WIV whole inactivated viruses
  • HA1 globular head domain of HA
  • antigenically updated vaccines can provide improved protection against the clinical disease and virus shedding.
  • antigenic drifts that result from mutations, mostly in the HA gene and virus reassortment events occurring periodically in circulating IAV, impact vaccine efficacy in the field.
  • M2e matrix protein
  • NR nanorings
  • NF nanofilaments
  • NF are composed of recombinant curli-specific gene A (CsgA) protein, a major extracellular matrix component contributing to biofilm formation in numerous enteric bacteria.
  • CsgA curli-specific gene A
  • Recombinant CsgA monomers spontaneously self-assemble in vitro into cross-p-sheet quaternary structures forming long and unbranched fibrils with similar structural and mechanical properties to the in vivo assemblies (Wang et al. J Biol Chem (2008) 283(31):21530-9. Epub 2008/01/30.
  • NR- 3M2e Recombinant chimeric NR bearing M2e antigens
  • NF-3M2e Recombinant chimeric NR bearing M2e antigens
  • the protein carrier is selected from the group consisting of CRM197 (nontoxic variant of diphtheria toxin isolated from Corynebacterium diphtheriae C7 (P197), tetanus toxoid (TT), a Pseudomonas aeruginosa protein, human serum albumin (HSA), bovine serum albumin (BSA), keyhole limpet hemocyanin (KLH), diphtheria toxin fragment B (DTFB), DTFB C8, diphtheria toxoid (DT), fragment C of TT, pertussis toxoid, cholera toxoid, E. coli heat-labile toxin, E. coli heatstable toxin, meningococcal outer membrane protein complex (OMPC), Haemophilus influenzae protein D (HiD), and exotoxin A from Pseudomonas aeruginosa.
  • CRM197 nontoxic variant of diphtheria toxin isolated from Cory
  • the protein carrier is a self-assembling protein able to form a nanoparticle, optionally selected from the group consisting of a nucleoprotein N of respiratory syncytial virus (RSV), CsgA (Curli-specific gene A), an amyloid protein such as CspA (E. coli cold shock protein A), ferritin, Soc (Small Outer Capsid protein) of phage T4, hepatitis B virus core antigen (HBc), bacteriophage AP205 coat protein, coat protein of bacteriophage QP, a dodecameric DNA binding protein from starved cells (Dps) of bacteria or archaea such as Dsp of E.
  • RSV respiratory syncytial virus
  • CsgA Curli-specific gene A
  • an amyloid protein such as CspA (E. coli cold shock protein A), ferritin, Soc (Small Outer Capsid protein) of phage T4, hepatitis B virus
  • coli Brucella outer membrane protein BP26, capsid protein of PCV2 (porcine circovirus type 2), protrusion domain of the capsid protein of norovirus, a self-assembling an amyloid protein p-peptide such as a ten-mer self-assembling sequence (110) derived from an amyloidogenic peptide (SNNFGAILSS, SEQ ID NO: 36), an antibody such as anti-Clec9A monoclonal antibody, CTA1-DD (ADP-ribosylating Al subunit of cholera toxin CT linked to a dimer of the D-fragment of Staphylococcus aureus protein A), bacterial flagellin such as flagellin of Bacillus subtilis or Salmonella serovar enterica typhimurium (S.
  • Qll peptide QQKFQFQFEQQ, SEQ ID NO: 37
  • lumazine synthase especially Aguifex aelocus (A. aelocus) lumazine synthase
  • encapsulin especially from T maritime/, and small Heat shock protein (sHsp) 16.5, especially from Methanocaldoccus jannaschii, a superfolder green fluorescent protein (sfGFP), bacteriophage P22, E2p, especially from Bacillus stearothermophilus (B.
  • stearothermophilus 13-01 derived from Thermotoga maritima's 2-keto-3-deoxy-6- phosphogluconate (KDPG) aldolase, especially from T. maritima, 153-50, IMX313, SAP, E2, Coil29, FliC, latency-associated nuclear antigen (LANA) from the Kaposi's sarcoma-associated herpesvirus (KSHV), coat of a plant virus such as nepovirus coat virus, in particular GFLV (Grapevine fanleaf virus), hydrophobin, bacteriophage T7 endonuclease, A beta 1-40, Sup35p of Saccharomyces cerevisiae, human Pmell7, Agfa Tafi protein, a Chaplin protein, a peptide derived from islet amyloid polypeptide (IAPP), in particular SNNFGAILSS (SEQ ID NO: 36), and a combination thereof. .
  • KSHV Kaposi's sarcoma-
  • the protein carrier is a N protein of Respiratory syncytial virus (RSV) and the M2e domain or a tandem repeat thereof is fused to the C-terminal end of the N protein.
  • the protein carrier is fused to a tandem repeat of 2 to 4 M2e domains, especially of 3 M2e domains. Accordingly, a tandem repeat of 2 to 4 M2e domains, preferably of 3 M2e domains, can be fused to the C-terminal end of the N protein.
  • the protein carrier is curli specific gene A (CsgA) or a fragment thereof and the M2e domain or a tandem repeat thereof is fused to the N-terminal end of CsgA.
  • the protein carrier is fused to a tandem repeat of 2 to 4 M2e domains, especially of 3 M2e domains. Accordingly, a tandem repeat of 2 to 4 M2e domains, preferably of 3 M2e domains, is fused to the N-terminal end of CsgA.
  • the protein carrier is CsgA.
  • the protein carrier is a fragment of CsgA comprising R2, R3, R4 and R5 repeat units, or R3, R4 and R5 repeat units, or R4 and R5 repeat units, or R5 repeat unit.
  • the recombinant hemagglutinin HA1 is from an influenza A virus selected from any of the following groups
  • H5N4 H5N5, H5N6, H5N7, H5N8, H5N9, H6N1, H6N2, H6N3, H6N4, H6N5, H6N6, H6N7,
  • the M2e domain can comprise a sequence selected in the group consisting of: (M/abs) S L L T E V E T (P/L) T (K/R) (T/N/K/S) (E/G) W (E/G)
  • composition further comprises an adjuvant.
  • the present invention further relates to a vaccine composition as disclosed herein for use against influenza A infection, especially by reducing or preventing the effects of an infection by influenza A virus, the effects being selected in the group consisting of mortality, clinical disease associated with infection by influenza A virus, histopathological lesions associated with infection by influenza A, and influenza A virus shedding. It also relates to the use of a vaccine composition as disclosed herein for the manufacture of a vaccine against influenza A infection, especially by reducing or preventing the effects of an infection by influenza A virus, the effects being selected in the group consisting of mortality, clinical disease associated with infection by influenza A virus, histopathological lesions associated with infection by influenza A, and influenza A virus shedding.
  • the subject is a poultry and the influenza A virus is selected from the group consisting of H5N1, H5N2, H5N6, H5N8, H5N9, H7N1, H7N3, H7N4, H7N6, H7N7, and H7N9.
  • influenza A virus is selected from the group consisting of H5N1, H5N2, H5N6, H5N8, H5N9, H7N1, H7N3, H7N4, H7N6, H7N7, and H7N9.
  • A Histological and (B) immunohistochemical analyses of the heart tissue of the PBS group at 3 dpc.
  • C Histological and (D) immunohistochemical analyses of the heart tissue of the NR-3M2e group at 3 dpc.
  • E Histological and (F) immunohistochemical analyses of the heart tissue of the NF-3M2e group at 3 dpc.
  • G Histological and (H) immunohistochemical analyses of the heart tissue of the HA1 group at 19 dpc.
  • I Histological and (J) immunohistochemical analyses of the heart tissue of the [NR-3M2e + HA1] group at 21 dpc.
  • K Histological and (L) immunohistochemical analyses of the heart tissue of the [NF- 3M2e + HA1] group at 21 dpc.
  • the inventors evaluated the benefits of supplementing nanoparticles bearing three tandem repeats of M2e, e.g., in the forms of nanorings (NR-3M2e) or nanofilaments (NF-3M2e), with an HA1 subunit vaccine, in the protection against a heterologous HPAI H5N1 virus challenge in specific pathogen-free chickens.
  • Birds immunized with NR-3M2e or NF-3M2e admixed with HA1 protein developed M2e and HAl-specific antibodies, at levels which were similar to chickens given HA1 protein alone or each of the M2e-containing nanoparticles.
  • 3M2e nanoparticles and HA1 protein provided full cross-protection against HPAI H5N1 heterologous virus and prevented virus shedding in the environment.
  • the present invention relates to a vaccine or immunogenic composition
  • a vaccine or immunogenic composition comprising: a recombinant hemagglutinin HA1 from an influenza A virus; and a protein carrier fused with an ectodomain of a matrix protein 2 (M2e domain) from an influenza A virus or a tandem repeat thereof, optionally through a peptide linker.
  • M2e domain matrix protein 2
  • influenza A virus is any subtype selected from the group consisting of H1N1, H1N2, H2N2, H2N3, H3N2, H3N8, H5N1, H5N2, H5N3, H5N4, H5N5, H5N6, H5N8, H5N9, H7N1, H7N2, H7N3, H7N4, H7N6, H7N7, H7N9, H9N2, H9N6, H9N7, H10N3, and H10N7.
  • influenza A virus is an avian influenza A virus.
  • it is a highly pathogenic avian influenza A virus (HPAI).
  • HPAI highly pathogenic avian influenza A virus
  • the avian influenza A virus is a virus subtype A(H5), A(H6), A(H7), A(H9), or A(H10), especially A(H5) virus subtype, A(H7) virus subtype, or A(H9) virus subtype.
  • the avian influenza A virus is any subtype selected from the group consisting of H5N1, H5N2, H5N3, H5N4, H5N5, H5N6, H5N7, H5N8, H5N9, H6N1, H6N2, H6N3, H6N4, H6N5, H6N6, H6N7, H6N8, H6N9, H7N1, H7N2, H7N3, H7N4, H7N5, H7N6, H7N7, H7N8, H7N9, H9N1, H9N2, H9N3, H9N4, H9N5, H9N6, H9N7, H9N8, H9N9, H10N1, H10N2, H10N3, H10N4, H10N5, H10N6, H10N7, H10N8, and H10N9.
  • the avian influenza A virus is any subtype selected from the group consisting of H5N1, H5N2, H5N3, H5N4, H5N5, H5N6, H5N7, H5N8, H5N9, H7N1, H7N2, H7N3, H7N4, H7N5, H7N6, H7N7, H7N8, and H7N9.
  • the avian influenza A virus is any subtype selected from the group consisting of H5N1, H5N6, H6N1, H7N2, H7N6, H7N9, H9N2, H10N3, H10N7, and H10N8.
  • the avian influenza A virus is any subtype selected from the group consisting of H5N1, H5N2, H5N3, H5N4, H5N5, H5N6, H5N7, H5N8, and H5N9, preferably H5N1, H5N6, and H5N8.
  • the highly pathogenic influenza A virus is an avian highly pathogenic influenza A virus selected from the group consisting of H5N1, H5N2, H5N6, H5N8, H5N9, H7N1, H7N3, H7N4, H7N7, and H7N9.
  • influenza A virus can be a mammal influenza A virus.
  • it is an equine influenza A virus. It can also be a canine, swine, or human influenza A virus.
  • influenza A virus is an equine influenza A virus such as H3N8 and H7N7, preferably H3N8.
  • influenza A virus is a swine influenza A virus such as H1N1, H1N2, H2N3, H3N1, H3N2, and H7N9.
  • influenza A virus is a canine influenza A virus such as H3N2.
  • influenza A virus is a human influenza A virus such as H1N1 and H3N2.
  • the highly pathogenic influenza A virus is a H5 virus, especially H5N1.
  • the vaccine or immunogenic composition does not comprise any additional influenza protein or part thereof, for instance Ml (matrix protein 1) or a fragment thereof, full- length M2 (matrix protein 2), neuraminidase NA, or a fragment thereof, full-length hemagglutinin HA or hemagglutinin HA2 region or a fragment thereof.
  • the vaccine or immunogenic composition does not comprise live-attenuated influenza A virus, inactivated influenza A virus such as WIV or split virus.
  • the recombinant hemagglutinin HA1 is from a virus selected from the group consisting of H5N1, H5N2, H5N3, H5N4, H5N5, H5N6, H5N7, H5N8, and H5N9, preferably H5N1, H5N2, H5N6, H5N8, and H5N9.
  • the recombinant hemagglutinin HA1 is from a H5N1 virus.
  • the recombinant hemagglutinin HA1 is from H9 subtype, in particular a virus selected from the group consisting of H9N1, H9N2, H9N3, H9N4, H9N5, H9N6, H9N7, H9N8, and H9N9, preferably H9N2, H9N6, H9N6, and H9N7.
  • the recombinant hemagglutinin HA1 is from H10 subtype, in particular a virus selected from the group consisting of H10N1, H10N2, H10N3, H10N4, H10N5, H10N6, H10N7, H10N8, and H10N9, preferably H10N3, H10N7, and H10N8.
  • the protein carrier is not a protein from influenza A virus, such as nucleoprotein (NP) or hemagglutinin (HA) or a part thereof such as a truncated NP or HA1 or HA2.
  • NP nucleoprotein
  • HA hemagglutinin
  • Protein carriers that self-assemble in nanoparticles are well-known in the art (see non-exhaustively, Lamontagne et al, Vaccines 2022, 10(11), 1920; https://doi.org/10.3390/vaccinesl0111920; Zottig et al, Nanomaterials 2020, 10(5), 1008; https://doi.org/10.3390/nanol0051008; W02020220044, WO2015104352).
  • the self-assembling protein refers to individual units or building blocks made of amino acids capable of spontaneous association into highly arranged/ordered structures/patterns. Such highly arranged/ordered structures/patterns are nanoparticles.
  • Virus-like particles are nanoparticles made in vitro by the capsid structural proteins of a virus, especially a non-enveloped which are able to self-assemble into symmetric supramolecular architectures.
  • the nanoparticle can non-exhaustively be a nanoring, an icosahedral nanoparticle, an octahedral cage, a dodecahedral cage, fibrils, nanorods, or nanofilaments.
  • the nanoparticle is a nanoring or a nanofilament.
  • the size of VLP or SAPN generally ranges between 5 and 900 nm.
  • the protein carrier can be selected in the non-exhaustive list comprising a nucleoprotein N of respiratory syncytial virus (RSV) (Herve et al, J Virol. (2014) 88:325-38. doi: 10.1128/JVI.01141-13), CsgA (Curli-specific gene A) (WO2008/124646), an amyloid protein such as CspA (E. coli cold shock protein A), ferritin, Soc (Small Outer Capsid protein) of phage T4, hepatitis B virus core antigen (HBc) (De Filette et al. Vaccine. (2006) 24:544-51. doi: 10.1016/j.vaccine.2005.08.061; Chen et al.
  • RSV respiratory syncytial virus
  • a self-assembling an amyloid protein p-peptide such as a ten-mer self-assembling sequence (110) derived from an amyloidogenic peptide (SNNFGAILSS, SEQ ID NO: 36) (Al Halifa et al, Nanomaterials 2020, 10(10), 1981; https://doi.org/10.3390/nanol0101981), an antibody such as anti-Clec9A monoclonal antibody, CTA1-DD (ADP-ribosylating Al subunit of cholera toxin CT linked to a dimer of the D-fragment of Staphylococcus aureus protein A), bacterial flagel lin such as flagellin of Bacillus subtilis or Salmonella serovar enterica typhimurium (S.
  • stearothermophilusj 13-01 derived from Thermotoga maritima's 2-Keto-3-deoxy-6-phosphogluconate (KDPG) aldolase, especially from T maritima, 153- 50, IMX313, SAP, E2, Coil29, FliC, latency-associated nuclear antigen (LANA) from the Kaposi's sarcoma-associated herpesvirus (KSHV) (WQ2023170068), coat of a plant virus such as nepovirus coat virus, in particular GFLV (Grapevine fanleaf virus) (WO 2017/042367), hydrophobin, bacteriophage T7 endonuclease, A beta 1-40, Sup35p of S.
  • KSHV Kaposi's sarcoma-associated herpesvirus
  • GFLV Grampevine fanleaf virus
  • hydrophobin bacteriophage T7 endonuclease, A beta 1-40, Sup35p of S.
  • the protein carrier can be phage T4 Soc.
  • the Soc proteins self-assemble into a nanoparticle (Li et al, 2023, https://doi.Org/10.1016/j.antiviral.2023.105688).
  • the M2e or tandem repeat thereof is fused the Soc protein.
  • the protein carrier can also be a combination of proteins.
  • the combination can be a combination of ferritin, MsDps2 and Encapsulin (Kar et al, Front. Immunol., 26 May 2022, https://doi.org/10.3389/fimmu.2022.890622).
  • the M2e or tandem repeat thereof can be fused to C terminal end of MsDps2, and/or to the N-terminal end of ferritin and/or to the C-terminal end of encapsulin, optionally through a peptide linker.
  • the carrier protein can be Brucella outer membrane protein BP26, which self-assemble to form a nanobarrel displaying M2e or tandem repeat thereof (Kang et al, ACS Nano 2021, 15, 6, 10722- 10732).
  • the M2e or tandem repeat thereof can be fused to BP26, preferably to the N-terminal end of BP26, optionally through a linker.
  • the carrier protein can be a capsid protein of PCV2, which self-assemble to form a VLP displaying M2e or tandem repeat thereof (Ding et al, Int J Biol Macromol. 2021 Mar 15;173:244-250. doi: 10.1016/j.ijbiomac.2021.01.132).
  • the M2e or tandem repeat thereof can be fused to the C-terminal end of Cap of PCV2, optionally through a linker.
  • the carrier protein can be a self-assembling p-peptide such 110, forming cross-p fibrils displaying The M2e or tandem repeat thereof.
  • the M2e or tandem repeat thereof can be fused to the N- terminal end of the peptide, preferably through a peptide linker.
  • carrier proteins are not fused or covalently linked to any other influenza protein or part thereof, for instance NP, NA, HA1, HA2, or Ml.
  • the carrier protein is not fused or covalently linked to full- length M2.
  • the self-assembling protein is a N protein of a virus of the Paramyxoviridae family, such as the mumps virus, measles virus, human metapneumovirus, parainfluenza virus, and respiratory syncytial virus (see W02007/119011).
  • the N protein can be modified, for instance in the region defined by the last 25 C-terminal amino acids.
  • the N proteins are fused at their C-terminal end to the M2e domain or a tandem repeat thereof, optionally through a peptide linked.
  • Rl, R3, and R5 are repeat units capable of assembling into amyloid fibers (Wang et al, J Biol Chem, 2007, 282, 3713-3719. Accordingly, truncated forms of CsgA can be used instead of the full length protein.
  • the selfassembling protein can be selected from the following truncated forms: a fragment of CsgA comprising R2, R3, R4, and R5 repeat units; a fragment of CsgA comprising R3, R4, and R5 repeat units; a fragment of CsgA comprising R4 and R5 repeat units; and a fragment of CsgA comprising R5 repeat unit.
  • the carrier protein, in particular the self-assembling protein is fused to one M2e domain.
  • the carrier protein, in particular the self-assembling protein is fused to a repeat of 2 to 10 M2e sequences, for instance 2, 3, 4, 5, 6, 7, 8, 9, or 10 M2e sequences.
  • the tandem repeat of M2e domains comprises from 2 to 5 M2e sequences or from 2 to 4 M2e sequences.
  • the tandem repeat comprises 2, 3, 4, or 5 M2e sequences.
  • the tandem repeat has 3 M2e sequences.
  • sequence of M2e domain is highly conserved among the influenza A viruses. Accordingly, it is possible to define consensus sequences for these viruses, especially the HPAI viruses.
  • sequence of M2e domain comprises, essentially consists of or consists of a sequence of SEQ ID NO: 12:
  • sequence of M2e domain comprises, essentially consists of or consists of a sequence of SEQ ID NO: 13:
  • sequence of M2e domain comprises, essentially consists of or consists of a sequence selected in the group consisting of:
  • M/abs means a methionine or no amino acid.
  • P/L means proline or leucine.
  • K/R means lysine or arginine.
  • T/N/K/S means threonine, asparagine, lysine, or serine.
  • T/N means threonine or asparagine.
  • E/G means glutamic acid or glycine.
  • C/S means cysteine or serine.
  • R/N/K means arginine, asparagine, or lysine.
  • K/R means lysine or arginine.
  • S/N means serine or asparagine.
  • D/V/G means aspartic acid, valine, or glycine.
  • the M2e sequence of SEQ ID NO: 12 is a consensus sequence of M2e of influenza A viruses.
  • the M2e sequence of SEQ ID NOs: 13 and 14-16 are consensus sequences from influenza viruses of H3, H5, and H7 subtypes.
  • the M2e sequence of SEQID NO: 17 is more specific to H5 subtype of influenza virus.
  • the M2e sequence of SEQ ID NO: 18 is more specific to H7 subtype of influenza virus.
  • the M2e sequence of SEQ ID NO: 19 is more specific to H3 subtype of influenza virus.
  • the M2e sequence comprises the M2e sequence comprises, essentially consists of or consists of a sequence selected in the group consisting of:
  • the tandem repeat includes 3 M2e sequences and the M2e sequence is (M/abs ) S L L T E V E T P T R T E W E S R S S D S S D (SEQ ID NO: 23).
  • the M2e sequence can be shorter and may have a deletion of 1, 2, or 3 amino acid(s) at the C-terminal end.
  • the M2e sequence can be longer and include 1, 2, or 3 additional amino acid(s) at the C-terminal end, for instance the addition of P, PV, or PVL.
  • the M2e sequences are the same in the tandem repeat.
  • the M2e sequences in the tandem repeat can be different.
  • the tandem repeat may comprise a M2e sequence from influenza A H5 subtype, a M2e sequence from influenza A H7 subtype, a M2e sequence from influenza A H9 subtype, and a M2e sequence from influenza A H10 subtype, or any combination of 2, 3 or 4 different subtypes.
  • the first M2e sequence includes a M residue at the N terminal end whereas the other M2e sequences are devoid of the N-terminal M residue.
  • the M2e sequences do not include a M residue at the N-terminal end of the M2e sequence.
  • the M2e sequences include a M residue at the N-terminal end of the M2e sequence.
  • the vaccine or immunogenic composition comprises:
  • hemagglutinin HA1 from H5 virus comprising a sequence of SEQ ID NO: 3 or 38 or a sequence having at least 80, 85, 90, or 95% identity with SEQ ID NO: 3 or SEQ ID NO: 38;
  • a nanoparticle made of a self-assembling protein being selected from the group consisting of nucleocapsid protein (N) of respiratory syncytial virus (RSV) and curli specific gene A (CsgA) or a fragment thereof, the self-assembling protein being fused with a tandem repeat of 3 M2e sequences and the M2e sequence comprises, essentially consists of or consists of a sequence (M/abs ) S L L T E V E T P T R T E W E S R S S D S S D (SEQ ID NO: 23).
  • the self-assembling protein is N protein of SEQ ID NO: 5 and the tandem repeat of M2e is fused to the C-terminal end of the N protein.
  • the N protein of RSV fused with a tandem repeat of 3 M2e sequences comprises or consists in the sequence as shown in SEQ ID NO: 6 and the coding sequence can be for instance the nucleic acid sequence of SEQ ID NO: 9.
  • the self-assembling protein is CsgA protein of SEQ ID NO: 7 or a fragment thereof and the tandem repeat of M2e is fused to the N-terminal end of the CsgA protein of the fragment thereof.
  • the CsgA fused with a tandem repeat of 3 M2e sequences comprises or consists in the sequence as shown in SEQ ID NO: 8 and the coding sequence can be for instance the nucleic acid sequence of SEQ ID NO: 10.
  • hemagglutinin HA1 from H3N8 virus comprising a sequence of SEQ ID NO: 39 or 40 or a sequence having at least 80, 85, 90, or 95% identity with SEQ ID NO: 39 or 40;
  • a nanoparticle made of a carrier protein being selected from the group consisting of nucleocapsid protein (N) of respiratory syncytial virus (RSV) and curli specific gene A (CsgA) or a fragment thereof, the carrier protein being fused with a tandem repeat of 3 M2e sequences and the M2e sequence comprises, essentially consists of or consists of a sequence (M/abs) S L L T E V E T P T R N (E/G) W E (C/S) K (C/S) S D S D (SEQ ID NO: 19), preferably (M/abs) S L L T E V E T P T R N G W E C K C S D S S D (SEQ ID NO: 32) or (M/abs) S L L T E V E T P T R N G W E S K S S D S D (SEQ ID NO: 35).
  • the avian influenza A virus is any subtype selected from the group consisting of H5N1, H5N2, H5N3, H5N4, H5N5, H5N6, H5N7, H5N8, H5N9, H6N1, H6N2, H6N3, H6N4, H6N5, H6N6, H6N7, H6N8, H6N9, H7N1, H7N2, H7N3, H7N4, H7N5, H7N6, H7N7, H7N8, H7N9, H9N1, H9N2, H9N3, H9N4, H9N5, H9N6, H9N7, H9N8, H9N9, H10N1, H10N2, H10N3, H10N4, H10N5, H10N6, H10N7, H10N8, and H10N9.
  • influenza A virus is selected from the group consisting of H5N1, H5N2, H5N3, H5N4, H5N5, H5N6, H5N8, H5N9, H7N1, H7N3, H7N4, H7N7, H7N9, H9N2, H9N6, H9N6, and H9N7.
  • influenza A virus is an avian highly pathogenic influenza A virus, such as H5N1, H5N2, H5N6, H5N8, H5N9, H7N1, H7N3, H7N4, H7N7, and H7N9. More specifically, the influenza A virus is H5N1 virus.
  • the vaccine or immunogenic composition comprises a recombinant HA1 from a A(H9) virus subtype and a selfassembling protein being fused with a tandem repeat of M2e sequences from a A(H9) virus subtype or a consensus sequence thereof.
  • the recombinant HA1 and the tandem repeat of M2e sequences can be as detailed above.
  • the vaccine or immunogenic composition as disclosed herein is for use for immunizing horse against an equine influenza A, especially H3N8.
  • the vaccine or immunogenic composition comprises a recombinant HA1 from an equine H3N8 virus and a selfassembling protein being fused with a tandem repeat of M2e sequences from a H3N8 virus or a consensus sequence thereof, in particular as detailed above.
  • the vaccine or immunogenic composition against an influenza virus is selected for having a recombinant HA1 having at least 80, 85, 90, or 95% identity with the sequence of the HA1 domain of the target virus.
  • the contiguous segment of the variant amino acid sequence may have additional amino acid residues or deleted amino acid residues with respect to the reference amino acid sequence.
  • the contiguous segment used for comparison to the reference nucleotide sequence or reference amino acid sequence will comprise at least 20 contiguous nucleotides, or amino acid residues, and may be 30, 40, 50, 100, or more nucleotides or amino acid residues. Corrections for increased sequence identity associated with inclusion of gaps in the variant's nucleotide sequence or amino acid sequence can be made by assigning gap penalties. Methods of sequence alignment are well known in the art. The determination of percent identity between two sequences can be accomplished using a mathematical algorithm.
  • an "immunological response” includes but is not limited to one or more of the following effects: the production or activation of antibodies, B cells, helper T cells, suppressor T cells, and/or cytotoxic T cells and/or gamma-delta T cells, directed specifically to an antigen or antigens included in the immunogenic composition of the invention.
  • the host will display either a protective immunological response or a therapeutically response.
  • the inventors evaluated the effect of the supplementation of nanoparticles incorporating M2e antigens with an HA1 subunit vaccine in the cross-protection against HPAI H5N1 virus challenge in chickens.
  • chimeric NR-3M2e and NF-3M2e were produced and their physicochemical characteristics were evaluated using previous protocols (Herve et al. J Virol (2014) 88(l):325-38. Epub 2013/10/25. doi: 10.1128/JVI.01141-13; Tran et al. J Gen Virol (2007) 88(Pt l):196-206. Epub 2006/12/16. doi: 10.1099/vir.0.82282-0; Calzas et al.
  • NF-3M2e The self-assembly and morphology of the purified NF-3M2e were analyzed by CD spectroscopy, ThT and ANS fluorescence spectroscopy, AFM, and TEM.
  • CD spectroscopy indicated NF-3M2e being largely unstructured immediately after its purification (0 h spectrum). However, after sufficient assembly time (24 h and 48 h), NF-3M2e adopted structural conformations and displayed a characteristic minimum at ⁇ 218 nm and maximum at ⁇ 197 nm, corresponding to a p-sheet-rich secondary structure.
  • the NF-3M2e structural morphology was also probed by measuring the fluorescence intensity of ThT, a dye commonly used to probe cross- -sheet quaternary structure (Groenning et al. J Chem Biol (2010) 3(1):1-18. Epub 2009/08/21. doi: 10.1007/sl2154-009-0027- 5).
  • ThT a dye commonly used to probe cross- -sheet quaternary structure
  • the inventors evaluated the immunogenicity of the vaccine formulations.
  • Chickens received three intramuscular administrations, at 2-week intervals, of NR-3M2e or NF-3M2e admixed with HA1 protein, or each single component alone.
  • Vaccine antigens were emulsified with Emulsigen’-P, an oil-in-water adjuvant used in veterinary vaccination.
  • the HAl-specific antibody responses were assessed by an HI assay ( Figure 2) and competitive ELISA ( Figure 3).
  • Viral RNA was detected in the swabs of all dead chickens and all surviving chickens with the exception of three surviving chickens in the HA1 group. By severe contrast, no viral RNA was detected in both cloacal and oropharyngeal swabs of birds immunized with [NR-3M2e + HA1] or [NF-3M2e + HA1] during the course of the experiment (Table 2). Thus, the supplementation of NR-3M2e or NF-3M2e with HA1 protein was essential to completely prevent chickens from clinical disease, mortality, and virus shedding after a challenge with heterologous
  • the virus antigen load was scanty detected in PBS and HA1 groups ( Figures 6B and 6H), whereas it presented an unusual extensive spread in the lungs of chickens vaccinated with NR-3M2e or NF-3M2e ( Figures 6D and 6F). No virus antigen was visible in the lungs of chickens immunized with the supplemented vaccine formulations ( Figures 6J and 6L).
  • the virus was inoculated via the allantoic route in 9- day-old specific pathogen free (SPF) embryonated chicken eggs (Canadian Food Inspection Agency [CFIA] Fallowfield Laboratory, Ottawa, Canada) and incubated at 37°C.
  • SPF 9- day-old specific pathogen free
  • the vector was purified and co-transfected with linearized baculovirus vector DNA and ProFoldTM-ERl (AB Vector) into Spodoptera frugiperda (Sf9) insect cells to generate recombinant baculovirus containing the HA1 gene.
  • the baculovirus was plaque-purified and sequenced for HA1 gene validation.
  • Sf9 cells were infected with the baculovirus and incubated for 72 h at 27°C under agitation. Cells were pelleted and lysed with l-PER insect cell protein extraction reagent (Pierce Biotechnology, Rockford, IL). The supernatant was purified using Ni-NTA bead resin and the expression of the recombinant protein was confirmed via Western blotting using a 6x histidine-specific monoclonal antibody (Novagen, Billerica, MA).
  • the synthesized pUC57-3M2e plasmid (ProteoGenix, Schiltigheim, France) was used as a template to amplify the 3M2e sequence by PCR using the Phusion high-fidelity DNA polymerase (Thermo Fisher Scientific, Waltham, MA, USA) with gene-specific primers flanked with Sacl/Sacl (forward primer/reverse primer) sites.
  • the PCR-amplified 3M2e sequence was then digested by Sad and inserted into the pET-N-Sac plasmid using the same restriction site.
  • Thioflavin T (ThT; 1 mM) was added to NF-3M2e sample to reach a final ThT concentration of 40 pM, and fluorescence emission was recorded by a PTI QuantaMasterTM (Horiba Ltd., Kyoto, Japan) spectrofluorometer from 450 nm to 550 nm at an excitation wavelength of 440 nm.
  • PTI QuantaMasterTM Horiba Ltd., Kyoto, Japan
  • the final concentration of ANS was 450 pM and the fluorescence emission was measured between 385 and 550 nm with a constant excitation at 370 nm. Fluorescence was measured in ultramicro 10 mm length quartz cells. Data are expressed as arithmetic means with the standard error of the mean ( ⁇ SEM) of at least three individual experiments performed in triplicate.
  • Electron micrographs of NR-3M2e were acquired using a CM12 TEM (Royal Philips Electronics, Amsterdam, Netherlands) at 80 kV excitation voltage. Samples at 0.05-1 mg/mL were applied onto an airglow- discharged carbon-coated 200-mesh copper grid and stained with a 2% uranyl acetate aqueous solution. Animal experiments
  • the vaccine formulations consisted of HA1 protein (15 pg) admixed with NF-3M2e (50 pg) or with NR-3M2e (50 pg), or each single component administered alone. The last group served as unvaccinated PBS group. Before administration, vaccine antigens were mixed with Emulsigen’-P (MVP Adjuvants, Phibro Animal Health, NJ) for 2 h under gentle agitation. Three vaccinations were applied via the intramuscular route. The two booster vaccinations were applied two weeks apart. On days 14, 28, and 42 post-primary vaccination, sera were collected from each bird.
  • Emulsigen’-P MVP Adjuvants
  • Chickens were challenged at day 42 post-primary vaccination with 2.3 x 10 2 PFU of heterologous A/chicken/BC/FAV-002/2015 virus in 100 pL endotoxin-free PBS via the intranasal route (50 pL/nostril).
  • HAl-specific antibody response in serum samples was evaluated by competitive ELISA as described previously (Yang et al. J Virol Methods (2009) 162(l-2):194-202. Epub 2009/08/25. doi: 10.1016/j.jviromet.2009.08.006) with modifications. Briefly, 96-well flat-bottom polystyrene plates (Nunc MaxiSorpTM; Nunc, Roskilde, Denmark) were coated with recombinant HA1 protein in carbonate-bicarbonate buffer 0.1 M (pH 9.6).
  • Tissues fixed in 10% neutral phosphate buffered formalin were sectioned at 5 pm and stained with haematoxylin and eosin (HE) for histopathologic analysis.
  • HE haematoxylin and eosin
  • IHC immunohistochemistry
  • paraffin tissue sections were quenched for 10 min in aqueous 3% H 2 O 2 and then pretreated with proteinase K for 15 min for epitope retrieval.
  • a mouse monoclonal antibody specific for influenza A nucleoprotein (F26NP9) (43) was applied on the sections at a dilution of 1:10,000 for 1 h.
  • the microscopic sections were then visualized using a horseradish peroxidase labelled polymer, Envision® + system (anti-mouse) (Dako, USA), and reacted with the chromogen diaminobenzidine (DAB). The sections were then counter stained with Gill's hematoxylin. The virus antigen load and distribution in the tissue section were visualized under the microscope and the intensity of coloration (brown) in the tissues of the different groups were qualitatively evaluated.
  • Envision® + system anti-mouse
  • DAB chromogen diaminobenzidine

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Abstract

La présente invention concerne un vaccin contre les virus de la grippe A, ledit vaccin comprenant une protéine HA et des nanostructures portant M2e, et son utilisation pour la vaccination contre la grippe aviaire, en particulier dans le domaine vétérinaire.
PCT/EP2024/077908 2023-10-05 2024-10-04 Composition de vaccin comprenant des nanoparticules m2e et une protéine ha1 Pending WO2025073874A1 (fr)

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