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WO2018045029A1 - Vaccin vivant atténué à arénavirus d'amérique du sud - Google Patents

Vaccin vivant atténué à arénavirus d'amérique du sud Download PDF

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Publication number
WO2018045029A1
WO2018045029A1 PCT/US2017/049371 US2017049371W WO2018045029A1 WO 2018045029 A1 WO2018045029 A1 WO 2018045029A1 US 2017049371 W US2017049371 W US 2017049371W WO 2018045029 A1 WO2018045029 A1 WO 2018045029A1
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Prior art keywords
arenavirus
virus
igr
deletion
car
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Joseph W. Golden
Jay W. Hooper
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United States Department of the Army
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United States Department of the Army
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/76—Viruses; Subviral particles; Bacteriophages
    • A61K35/761—Adenovirus
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    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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    • C12N7/00—Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof
    • 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
    • C12N2760/10011—Arenaviridae
    • C12N2760/10021—Viruses as such, e.g. new isolates, mutants or their genomic sequences
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    • 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
    • C12N2760/10011—Arenaviridae
    • C12N2760/10034—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
    • C12N2760/10011—Arenaviridae
    • C12N2760/10061—Methods of inactivation or attenuation
    • C12N2760/10062—Methods of inactivation or attenuation by genetic engineering
    • 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
    • C12N2760/10011—Arenaviridae
    • C12N2760/10061—Methods of inactivation or attenuation
    • C12N2760/10064—Methods of inactivation or attenuation by serial passage
    • 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
    • C12N2760/10011—Arenaviridae
    • C12N2760/10071—Demonstrated in vivo effect

Definitions

  • the present invention generally relates to Arenaviruses and vaccines.
  • Arenaviridae Members of the Arenaviridae (Arenaviruses) are enveloped ambisense single- stranded RNA viruses with two segments, small (S) and large (L), encoding a 10.7 kb genome expressing five distinct proteins.
  • the L-segment encodes the matrix ring finger Z protein4 and the polymerase L protein.
  • the S-segment encodes the nucleoprotein (NP) and the glycoprotein precursor (GPC). GPC is cleaved into two glycoproteins, GP1 and GP2 by the cellular protease S IP.
  • Each RNA segment encodes two ORFs and contains noncoding regions including 5' and 3' untranslated regions (UTRs) and a non-coding intergenic region (IGR).
  • Mammalian Arenaviruses (genus mammarenavirus) are divided into the Old World Complex Arenaviruses (OW Arenaviruses) and New World Complex Arenaviruses (NW Arenaviruses)
  • Machupo virus is a member of the NW Arenaviruses and is the causative agent of Venezuelan hemorrhagic fever [1]. Human infections result from exposure to chronically infected rodents (Calomys callosus) [2], but human-to-human spread has been reported [3]. Venezuelan hemorrhagic fever is a febrile illness often associated with vascular leakage and occasional concomitant neurological manifestations [3, 4]. Infection can result in a systemic inflammatory response syndrome leading to multiple organ failure and death.
  • Arenaviruses that cause hemorrhagic fever (HF) in humans include the Junin virus (IUNV) the causative agent of Argentine hemorrhagic fever and the Guanarito virus (GTOV) the causative agent of Venezuelan hemorrhagic fever [5].
  • IUNV Junin virus
  • GTOV Guanarito virus
  • Candid#l An attenuated live- virus vaccine derived from JU V, termed Candid#l, is currently used in populations at high risk to JUNV infection [12-15]. Implementation of Candid#l in the endemic region of Argentina reduced fatality rates substantially.
  • Candid#l was produced by passage of the virulent strain XJ twice in guinea pigs, 44 times in mouse brains, and finally several passages in fetal rhesus lung diploid cells (FRhL-2) [15, 17-19].
  • This process produced a strain that is attenuated in humans, non-human primates, guinea pigs, and mice and also lacks neurotropism in animal models. The exact nature of the attenuation is enigmatic and recent evidence indicates that single amino acid changes in the glycoprotein 2 transmembrane region restores virulence in neonatal mice [17].
  • TACV Tacaribe virus
  • MACV MACV
  • Glycoprotein-targeting subunit vaccines based on modified vaccine Ankara or Venezuelan equine encephalitis replicon vectored systems protect against lethal infection by JUNV in guinea pig models [22, 23].
  • heterogeneity in the glycoproteins [20, 24, 25] it is unlikely these vaccines will provide sufficient cross-protection against heterologous Arenaviruses.
  • alternative strategies aimed at producing safe and broadly protective Arenavirus vaccines are needed.
  • the present invention provides a method of making an IGR
  • Deletion Arenavirus which comprises deleting at least a portion of an intergenic region (IGR) of one or both genome segments of an Arenavirus
  • the portion of the IGR is deleted using recombinant DNA methods known in the art.
  • the genome segment is the L-segment.
  • the genome segment is the S-segment.
  • at least about 15-50 nucleotide bases of the IGR are deleted.
  • at least about 20-45 nucleotide bases of the IGR are deleted.
  • at least about 25-40 nucleotide bases of the IGR are deleted.
  • at least about 30-35 nucleotide bases of the IGR are deleted.
  • at least about 20%, preferably at least about 30%, more preferably at least about 40%, even more preferably at least about 50%, and most preferably about 60% of the nucleotide bases of the IGR are deleted.
  • the native structure of the hairpin loop formed by the nucleotide sequence of the IGR of the Arenavirus is altered by the deletion of the nucleotide bases.
  • the Arenavirus is an OW Arenavirus. In some embodiments, the
  • Arenavirus is a NW Arenavirus.
  • the Arenavirus is a Lassa virus, a Lujo virus, a Lymphocytic choriomeningitis virus, a Chapare virus, a Guanarito virus, a Junin virus, a Machupo virus, a Sabia virus, a Tacaribe virus, or a Whitewater Arroyo virus.
  • the Arenavirus is a Junin virus, a Machupo virus, a Sabia virus, or a Tacaribe virus.
  • the Arenavirus is JUNV strain
  • the Arenavirus is MACV strain Carvallo. In some embodiments, the Arenavirus is MACV strain Chicava.
  • the present invention provides a composition comprising, consisting essentially of, or consisting of one or more IGR Deletion Arenaviruses, which have at least a portion of an intergenic region (IGR) of one or both genome segments of an Arenavirus.
  • the portion of the IGR is deleted using recombinant DNA methods known in the art.
  • the genome segment is the L- segment.
  • the genome segment is the S-segment.
  • at least about 15-50 nucleotide bases of the IGR are deleted.
  • at least about 20-45 nucleotide bases of the IGR are deleted.
  • at least about 25-40 nucleotide bases of the IGR are deleted.
  • At least about 30-35 nucleotide bases of the IGR are deleted. In some embodiments, at least about 20%, preferably at least about 30%, more preferably at least about 40%, even more preferably at least about 50%, and most preferably about 60% of the nucleotide bases of the IGR are deleted. In some embodiments, the native structure of the hairpin loop formed by the nucleotide sequence of the IGR of the Arenavirus is altered by the deletion of the nucleotide bases. In some embodiments, the Arenavirus is an OW Arenavirus. In some embodiments, the Arenavirus is a NW Arenavirus.
  • the Arenavirus is a Lassa virus, a Lujo virus, a Lymphocytic choriomeningitis virus, a Chapare virus, a Guanarito virus, a Junin virus, a Machupo virus, a Sabia virus, a Tacaribe virus, or a Whitewater Arroyo virus.
  • the Arenavirus is a Junin virus, a Machupo virus, a Sabia virus, or a Tacaribe virus. In some embodiments, the Arenavirus is JUNV strain Candid#l . In some embodiments, the Arenavirus is MACV strain Carvallo. In some embodiments, the Arenavirus is MACV strain Chicava. In some embodiments, the composition comprises a pharmaceutically acceptable carrier. In some embodiments, the composition comprises an adjuvant.
  • the present invention provides a method of treating, inhibiting, or reducing an Arenavirus infection or a disease caused by an Arenavirus in a subject, which comprises administering to the subject an effective amount of one or more IGR Deletion Arenaviruses, which have at least a portion of an intergenic region (IGR) of one or both genome segments of an Arenavirus.
  • IGR intergenic region
  • the portion of the IGR is deleted using recombinant DNA methods known in the art.
  • the genome segment is the L-segment.
  • the genome segment is the S-segment.
  • at least about 15-50 nucleotide bases of the IGR are deleted.
  • At least about 20-45 nucleotide bases of the IGR are deleted. In some embodiments, at least about 25-40 nucleotide bases of the IGR are deleted. In some embodiments, at least about 30-35 nucleotide bases of the IGR are deleted. In some embodiments, at least about 20%, preferably at least about 30%, more preferably at least about 40%, even more preferably at least about 50%, and most preferably about 60% of the nucleotide bases of the IGR are deleted. In some
  • the native structure of the hairpin loop formed by the nucleotide sequence of the IGR of the Arenavirus is altered by the deletion of the nucleotide bases.
  • the Arenavirus is an OW Arenavirus. In some embodiments, the
  • Arenavirus is a NW Arenavirus.
  • the Arenavirus is a Lassa virus, a Lujo virus, a Lymphocytic choriomeningitis virus, a Chapare virus, a Guanarito virus, a Junin virus, a Machupo virus, a Sabia virus, a Tacaribe virus, or a Whitewater Arroyo virus.
  • the Arenavirus is a Junin virus, a Machupo virus, a Sabia virus, or a Tacaribe virus.
  • the Arenavirus is JUNV strain
  • the Arenavirus is MACV strain Carvallo. In some embodiments, the Arenavirus is MACV strain Chicava. In some embodiments, the Arenavirus and the IGR Deletion Arenavirus are of the same viral species. In some embodiments, the Arenavirus and the IGR Deletion Arenavirus are of different viral species. In some embodiments, the Arenavirus is an OW Arenavirus and the IGR
  • the Deletion Arenavirus is a NW Arenavirus.
  • the Arenavirus is a NW Arenavirus and the IGR Deletion Arenavirus is an OW Arenavirus.
  • Arenavirus and the IGR Deletion Arenavirus are each independently selected from the group consisting of Lassa virus, Lujo virus, Lymphocytic
  • the Arenavirus is a Lassa virus, a, Lujo virus, a.
  • the Lymphocytic choriomeningitis virus a Chapare virus, a Guanarito virus, a Junin virus, a Machupo virus, a Sabia virus, a Tacaribe virus, or a Whitewater Arroyo virus and the IGR Deletion Arenavirus is JUNV strain Candid#l, MACV strain Carvallo, or MACV strain Chicava, and has a portion of its intragenic region (IGR) of the L-segment deleted.
  • the Arenavirus is a Guanarito virus or a Junin virus and the IGR Deletion Arenavirus is a Machupo virus.
  • the one or more IGR Deletion Arenaviruses are administered in the form of a composition as described herein.
  • the present invention provides a method of immunizing a subject against an Arenavirus, which comprises administering to the subject an immunogenic amount of one or more IGR Deletion Arenaviruses, which have at least a portion of an intergenic region (IGR) of one or both genome segments of an Arenavirus.
  • the portion of the IGR is deleted using recombinant DNA methods known in the art.
  • the genome segment is the L-segment.
  • the genome segment is the S-segment.
  • at least about 15-50 nucleotide bases of the IGR are deleted.
  • at least about 20-45 nucleotide bases of the IGR are deleted.
  • At least about 25-40 nucleotide bases of the IGR are deleted. In some embodiments, at least about 30-35 nucleotide bases of the IGR are deleted. In some embodiments, at least about 20%, preferably at least about 30%, more preferably at least about 40%, even more preferably at least about 50%, and most preferably about 60% of the nucleotide bases of the IGR are deleted. In some embodiments, the native structure of the hairpin loop formed by the nucleotide sequence of the IGR of the Arenavirus is altered by the deletion of the nucleotide bases. In some embodiments, the Arenavirus is an OW Arenavirus. In some embodiments, the Arenavirus is a NW Arenavirus.
  • the Arenavirus is a Lassa virus, a Lujo virus, a Lymphocytic choriomeningitis virus, a Chapare virus, a Guanarito virus, a Junin virus, a Machupo virus, a Sabia virus, a Tacaribe virus, or a Whitewater Arroyo virus.
  • the Arenavirus is a Junin virus, a Machupo virus, a Sabia virus, or a Tacaribe virus.
  • the Arenavirus is JUNV strain Candid#l .
  • the Arenavirus is MACV strain
  • the Arenavirus is MACV strain Chicava.
  • the Arenavirus and the IGR Deletion Arenavirus are of the same viral species.
  • the Arenavirus and the IGR Deletion Arenavirus are of different viral species.
  • the Arenavirus is an OW Arenavirus and the IGR Deletion Arenavirus is a NW Arenavirus.
  • the Arenavirus is a NW Arenavirus and the IGR Deletion Arenavirus is an OW Arenavirus.
  • the Arenavirus and the IGR Deletion Arenavirus are each independently selected from the group consisting of Lassa virus, Lujo virus, Lymphocytic
  • the Arenavirus is a Lassa virus, a. Lujo virus, a.
  • Lymphocytic choriomeningitis virus a Chapare virus, a Guanarito virus, a Junin virus, a Machupo virus, a Sabia virus, a Tacaribe virus, or a Whitewater Arroyo virus and the IGR Deletion Arenavirus is JUNV strain Candid#l, MACV strain Carvallo, or MACV strain Chicava, and has a portion of its intragenic region (IGR) of the L-segment deleted.
  • the Arenavirus is a Guanarito virus or a Junin virus and the IGR Deletion Arenavirus is a Machupo virus.
  • the one or more IGR Deletion Arenaviruses are administered in the form of a composition as described herein. In some embodiments, the administration is before, during, and/or after exposure to the Arenavirus. In some embodiments, the Arenavirus and the IGR Deletion Arenavirus are of different viral species. In some embodiments, the Arenavirus is a Guanarito virus or a Junin virus and the IGR Deletion Arenavirus is a Machupo virus. In some embodiments, the one or more IGR Deletion Arenaviruses elicits a protective immune response against the Arenavirus when administered to the subject.
  • the present invention provides a method of eliciting an immunogenic response in a subject, which comprises administering to the subject an immunogenic amount of one or more IGR Deletion Arenaviruses, which have at least a portion of an intergenic region (IGR) of one or both genome segments of an Arenavirus.
  • the portion of the IGR is deleted using recombinant DNA methods known in the art.
  • the genome segment is the L-segment.
  • the genome segment is the S-segment.
  • at least about 15-50 nucleotide bases of the IGR are deleted.
  • at least about 20-45 nucleotide bases of the IGR are deleted.
  • At least about 25-40 nucleotide bases of the IGR are deleted. In some embodiments, at least about 30-35 nucleotide bases of the IGR are deleted. In some embodiments, at least about 20%, preferably at least about 30%, more preferably at least about 40%, even more preferably at least about 50%, and most preferably about 60% of the nucleotide bases of the IGR are deleted. In some embodiments, the native structure of the hairpin loop formed by the nucleotide sequence of the IGR of the Arenavirus is altered by the deletion of the nucleotide bases. In some embodiments, the Arenavirus is an OW Arenavirus. In some embodiments, the Arenavirus is a NW Arenavirus.
  • the Arenavirus is a Lassa virus, a Lujo virus, a Lymphocytic choriomeningitis virus, a Chapare virus, a Guanarito virus, a Junin virus, a Machupo virus, a Sabia virus, a Tacaribe virus, or a Whitewater Arroyo virus.
  • the Arenavirus is & Junin virus, a Machupo virus, a Sabia virus, or a Tacaribe virus.
  • the Arenavirus is JUNV strain Candid#l .
  • the Arenavirus is MACV strain Carvallo.
  • the Arenavirus is MACV strain Chicava.
  • the one or more IGR Deletion Arenaviruses are administered in the form of a composition as described herein. In some embodiments, the administration is before, during, and/or after exposure to an Arenavirus. In some embodiments, the Arenavirus and the IGR Deletion Arenavirus are of the same viral species. In some embodiments, the Arenavirus and the IGR Deletion Arenavirus are of different viral species. In some embodiments, the Arenavirus is an OW Arenavirus and the IGR Deletion Arenavirus is a NW Arenavirus. In some embodiments, the Arenavirus is a NW Arenavirus and the IGR Deletion Arenavirus is an OW Arenavirus.
  • the Arenavirus and the IGR Deletion Arenavirus are each independently selected from the group consisting of Lassa virus, Lujo virus, Lymphocytic choriomeningitis virus, Chapare virus, Guanarito virus, Junin virus, Machupo virus, Sabia virus, Tacaribe virus, and Whitewater Arroyo virus.
  • the Arenavirus is a Lassa virus, a Lujo virus, a Lymphocytic choriomeningitis virus, a Chapare virus, a Guanarito virus, a Junin virus, a Machupo virus, a Sabia virus, a Tacaribe virus, or a Whitewater Arroyo virus and the IGR Deletion Arenavirus is JUNV strain Candid#l, MACV strain Carvallo, or MACV strain Chicava, and has a portion of its intragenic region (IGR) of the L-segment deleted.
  • the Arenavirus is a Guanarito virus or a Junin virus and the IGR Deletion Arenavirus is a Machupo virus.
  • the one or more IGR Deletion Arenaviruses elicits an immune response against the Arenavirus when challenged therewith.
  • the present invention is directed to the use of at least one
  • IGR Deletion Arenavirus in the manufacture of a medicament for preventing, inhibiting, reducing, or treating an Arenavirus infection in a subject.
  • the present invention is directed to the use of at least one IGR Deletion Arenavirus for the manufacture of a medicament for preventing, inhibiting, reducing, or treating an
  • the medicament is prepared to be administered in accordance with one or more of the dosage regimens as described herein.
  • the medicament comprises a therapeutically effective amount of the at least one IGR Deletion Arenavirus as described herein.
  • the medicament comprises a pharmaceutically acceptable carrier.
  • the medicament comprises an adjuvant.
  • the subject of the methods of the present invention is a mammalian subject. In some embodiments, the subject is a human subject. In some embodiments, the subject is one who is in need of treatment with at least one IGR Deletion Arenavirus. As used herein, a subject who is in need of treatment with at least one IGR Deletion Arenavirus is one who has, will, or will likely be exposed to an Arenavirus.
  • the IGR Deletion Arenavirus is an Arenavirus that is
  • the IGR Deletion Arenavirus is not Car 91 .
  • Figure 1 Figure 1 : Guinea pigs were infected with 2000 pfu MACV strains Car 91 and weights based on Day 0 starting weight were graphed.
  • Figure 2 Percent change in temperature relative to Day 0 was plotted.
  • Figure 3 Serum from guinea pigs was incubated with VSVAG particles pseudotyped with MACV strain Carvallo glycoprotein and the PsVNA80 titers were graphed.
  • Figure 4, Figure 5, and Figure 6 are graphs summarizing the results of in vitro characterization assays of Car 91 , Car 68 , and Chic.
  • Figure 4 Parti cle-to-pfu ratios for each of the indicated MACV strains were determined using a ViroCyte system. Four virus preparations for each virus were tested in triplicate. The GMTs are indicated by the solid line.
  • Figure 5 Indicated cells were infected with Car 91 (circles), Car 68 (squares) or Chic (triangles) and replication quantitated at 24, 48, and 72 hpi by plaque assay. All samples were titered in duplicate and the mean +/- SD were graphed.
  • Figure 6 Anti-glycoprotein antisera from four rabbits vaccinated with MACV strain Carvallo GPc [29] was serially diluted and incubated with Car 68 , Car 91 , and Chic. PRNT50 and PRNT80 titers were plotted.
  • Figure 7, Figure 8, and Figure 9 summarize the sequence analyses of MACV strain
  • Figure 7 Predicted L-segment amino acid changes between Car 91 and Car 68 .
  • Figure 8 Nucleotide line up of Car 91 (SEQ ID NO: 1) and Car 68 (SEQ ID NO: 2). The underlined region denotes the deleted region. Also underlined is the single nucleotide change at position 399.
  • Figure 9 schematically shows the predicted hairpin tertiary structure of the Car 91 (SEQ ID NO: 3) and Car 68 (SEQ ID NO: 4) L-segment IGRs.
  • Figure 10 Figure 11, Figure 12, Figure 13, Figure 14 and Figure 15 summarize infection of Hartley guinea pigs with MACV strain Car 68 , Car 91 , and Chic.
  • Figure 10 Guinea pigs were i.p. infected with 1000 pfu of MACV strains Car 91 , Car 68 , and Chic. Survival was monitored for 30 days post-infection. Percent weight loss for each group (Figure 11) and individual guinea pigs ( Figure 12, Figure 13, and Figure 14) were plotted based on Day 0 starting weight. Animals succumbing to infection are shown in solid points in Figure 13, and all points in Figure 14.
  • Figure 15 Group temperatures were plotted. Normal temperature values are shown as a solid grey area.
  • Figure 16, Figure 17, and Figure 18 are graphs summarizing the results of viremia and antibody assays on serum from infected guinea pigs.
  • Figure 16 Serum viremia from animals succumbing to disease was determined on Vero cell monolayers. The solid line represents the GMT values.
  • Figure 17 Antibody binding titers were determined by incubating sera from Car 91 infected animals with PsVs pseudotyped with GPc from strain Carvallo. Antiserum samples were serially diluted prior to incubation. The dashed line denotes the limit of detection. The solid line represents the GMT values.
  • Figure 18 Titers of neutralizing antibody in Car 91 infected animals was determined and PR T50 and PRNT80 titers were plotted. The dashed line denotes the limit of detection. The solid line represents the GMT values.
  • Figure 19 Figure 20, and Figure 21 are graphs showing the protective efficacy of
  • FIG. 19 Survival plot of guinea pigs were infected by the i.p. route with 2000 pfu GTOV. Survival was plotted for 30 day post-infection.
  • Figure 20 Percent loss from starting weight was plotted for each group as described above.
  • Figure 21 Temperature was monitored as in Figure 16 to Figure 18.
  • FIG. 22 Antibody binding titers were determined by coating 96-well plates with the indicated PsVs and incubating them with serially diluted antiserum samples from before GTOV challenge (circles/PRE) or after GTOV challenge (squares/POST). The dashed line denotes the limits of detection. The red circle (on the horizontal line, the first dot in the first graph, the second dot in the second graph, and the only dot in the third graph) denotes the single animal (Animal #4) that died from infection.
  • Figure 23 PRNT80 titers against MACV prior to and after challenge with GTOV. PRNT50 titers were determined as above.
  • Figure 24 PRNT50 titers against JUNV, MACV, and GTOV were determined as in Figure 4 to Figure 6. Titers were determined as described above. The dashed line indicates the limits of detection.
  • MACV strain Carvallo is the prototypical MACV strain first isolated in 1963 [26,
  • Car 91 was discovered to have a deletion of 35 nucleotides in the intragenic region (IGR) of the L-segment of the bisegmented genome. This mutation, which appears to have occurred during passage in culture cells as the originally isolated virus taken from an infected person in the 1960s does not contain this mutation, impacts replication kinetics. Contrary to the wildtype (natural) strain of Carvallo, Car 91 does not cause a lethal infection in infected guinea pigs. Also, as disclosed herein, Car 91 produces antibodies, including neutralizing antibodies that do not cross-neutralize other related NW Arenaviruses, in animals.
  • IGR intragenic region
  • guinea pigs initially challenged with Car 91 are protected against infection by the Guanarito virus, a distantly related NW Arenavirus. That is, a deletion in the L-segment IGR of a given Arenavirus results in an attenuated virus that provides protective immunity against other Arenaviruses that are distantly related to the given Arenavirus.
  • the present invention provides a method of
  • the genome segment is the L-segment. In some embodiments, the genome segment is the S-segment. In some embodiments, at least about 15-50 nucleotide bases of the IGR are deleted. In some embodiments, at least about 20-45 nucleotide bases of the IGR are deleted. In some embodiments, at least about 25-40 nucleotide bases of the IGR are deleted. In some embodiments, at least about 30-35 nucleotide bases of the IGR are deleted. In some embodiments, at least about 20%, preferably at least about 30%, more preferably at least about 40%, even more preferably at least about 50%, and most preferably about 60% of the nucleotide bases of the IGR are deleted. In some embodiments,
  • all the nucleotide bases of the IGR are deleted.
  • the native structure of the hairpin loop formed by the nucleotide sequence of the IGR of the Arenavirus is altered by the deletion of the nucleotide bases.
  • the Arenavirus is an OW Arenavirus. In some embodiments, the Arenavirus is a NW
  • the Arenavirus is a Lassa virus, a Lujo virus, a Lymphocytic choriomeningitis virus, a Chapare virus, a Guanarito virus, a Junin virus, a Machupo virus, a Sabia virus, a Tacaribe virus, or a Whitewater Arroyo virus.
  • the Arenavirus is a Junin virus, ⁇ Machupo virus, a Sabia virus, or a Tacaribe virus.
  • the Arenavirus is JU V strain Candid#l .
  • the Arenavirus is MACV strain Carvallo.
  • the Arenavirus is MACV strain Chicava.
  • the present invention provides IGR Deletion Arenaviruses and compositions comprising one or more IGR Deletion Arenaviruses.
  • a "IGR Deletion Arenavirus” refers to an Arenavirus that has been attenuated by using recombinant DNA techniques to delete at least a portion of an IGR of one or both genome segments of the native form of the Arenavirus.
  • the genome segment is the L-segment.
  • the genome segment is the S-segment.
  • at least about 15-50 nucleotide bases of the IGR are deleted.
  • at least about 20-45 nucleotide bases of the IGR are deleted.
  • At least about 25-40 nucleotide bases of the IGR are deleted. In some embodiments, at least about 30-35 nucleotide bases of the IGR are deleted. In some embodiments, at least about 20%, preferably at least about 30%, more preferably at least about 40%, even more preferably at least about 50%, and most preferably about 60% of the nucleotide bases of the IGR are deleted. In some embodiments, the native structure of the hairpin loop formed by the nucleotide sequence of the IGR of the Arenavirus is altered by the deletion of the nucleotide bases. In some embodiments, the Arenavirus is an OW Arenavirus. In some embodiments, the Arenavirus is a NW Arenavirus. In some embodiments, the Arenavirus is a Lassa virus, a Lujo virus, a Lymphocytic
  • choriomeningitis virus a Chopore virus, a Guonorito virus, a Junin virus, a Machupo virus, a Sabia virus, a Tacaribe virus, or a Whitewater Arroyo virus.
  • the Arenavirus is a Junin virus, a Machupo virus, a Sabia virus, or a Tacaribe virus.
  • the Arenavirus is JUNV strain Candid#l .
  • the Arenavirus is MACV strain Carvallo.
  • the Arenavirus is MACV strain Chicava.
  • the present invention provides a method of treating
  • an "Arenavirus infection” refers to an infection by one or more viruses belonging to the family Arenaviridae .
  • Diseases caused by Arenavirus infections include hemorrhagic fevers, Lassa fever, Lymphocytic choriomeningitis, and Influenza-like illness.
  • Hemorrhagic fevers include Argentine hemorrhagic fever, Venezuelan hemorrhagic fever, and Brazilian hemorrhagic fever.
  • the effective amount is a
  • the effective amount is an immunogenic amount.
  • the one or more IGR Deletion Arenaviruses is administered before, during, and/or after exposure to the Arenavirus.
  • the Arenavirus and the IGR Deletion Arenavirus are of the same viral species.
  • the Arenavirus and the IGR Deletion Arenavirus are of different viral species.
  • the Arenavirus is an OW Arenavirus and the IGR Deletion Arenavirus is a W Arenavirus.
  • the Arenavirus is a NW Arenavirus and the IGR Deletion Arenavirus is an OW Arenavirus.
  • the Arenavirus and the IGR Deletion Arenavirus are each independently selected from the group consisting of Lassa virus, Lujo virus, Lymphocytic
  • the Arenavirus is a Lassa virus, a Lujo virus, a Lymphocytic choriomeningitis virus, a Chapare virus, a Guanarito virus, a Junin virus, a Machupo virus, a Sabia virus, a Tacaribe virus, or a Whitewater Arroyo virus and the IGR Deletion Arenavirus is JUNV strain Candid#l, MACV strain Carvallo, or MACV strain Chicava, and has a portion of its intragenic region (IGR) of the L-segment deleted.
  • the Arenavirus is a Guanarito virus or a Junin virus and the IGR Deletion Arenavirus is & Machupo virus.
  • the present invention provides a method of immunizing a subject against an Arenavirus, which comprises administering to the subject an immunogenic amount of one or more IGR Deletion Arenaviruses.
  • the one or more IGR Deletion Arenaviruses is administered before, during, and/or after exposure to the Arenavirus.
  • the Arenavirus and the IGR Deletion Arenavirus are of the same viral species.
  • the Arenavirus and the IGR Deletion Arenavirus are of different viral species.
  • the Arenavirus is an OW Arenavirus and the IGR Deletion Arenavirus is a NW Arenavirus.
  • the Arenavirus is a NW Arenavirus and the IGR Deletion
  • Arenavirus is an OW Arenavirus.
  • the Arenavirus and the IGR Deletion Arenavirus are each independently selected from the group consisting of Lassa virus, Lujo virus, Lymphocytic choriomeningitis virus, Chapare virus, Guanarito virus, Junin virus, Machupo virus, Sabia virus, Tacaribe virus, and Whitewater Arroyo virus.
  • the Arenavirus is a Lassa virus, a Lujo virus, a Lymphocytic choriomeningitis virus, a Chapare virus, a Guanarito virus, a Junin virus, a Machupo virus, a Sabia virus, a Tacaribe virus, or a Whitewater Arroyo virus and the IGR Deletion Arenavirus is JUNV strain Candid#l, MACV strain Carvallo, or MACV strain Chicava, and has a portion of its intragenic region (IGR) of the L-segment deleted.
  • the Arenavirus is a Guanarito virus or a Junin virus and the IGR Deletion Arenavirus is a Machupo virus.
  • the immunogenic amount results in a protective immune response against the Arenavirus.
  • compositions of the present invention include one or more IGR Deletion Arenaviruses as described herein.
  • pharmaceutical composition refers to a composition suitable for pharmaceutical use in a subject.
  • a pharmaceutical composition generally comprises an effective amount of an active agent, e.g., one or more IGR Deletion Arenaviruses according to the present invention, and a pharmaceutically acceptable carrier.
  • effective amount refers to a dosage or amount sufficient to produce a desired result.
  • the desired result may comprise an objective or subjective improvement in the recipient of the dosage or amount, e.g., long-term survival, effective prevention of a disease state, and the like.
  • compositions according to the present invention may further include one or more supplementary agents.
  • suitable supplementary agents include ribavirin, antivirals, and the like.
  • IGR Deletion Arenaviruses may be administered, preferably in the form of pharmaceutical compositions, to a subject.
  • the subject is mammalian, more preferably, the subject is human.
  • Preferred pharmaceutical compositions are those comprising, consisting essentially of, or consisting of at least one IGR Deletion Arenavirus in a therapeutically effective amount or an immunogenic amount, and a pharmaceutically acceptable vehicle.
  • Vaccines according to the present invention provide a protective immune response when administered to a subject.
  • a "vaccine” according to the present invention is a pharmaceutical composition that comprises an immunogenic amount of at least one IGR Deletion Arenavirus and provides a protective immune response when administered to a subject.
  • the protective immune response may be complete or partial, e.g., a reduction in symptoms as compared with an unvaccinated subject.
  • an "immunogenic amount” is an amount that is sufficient to elicit an immune response in a subject and depends on a variety of factors such as the immunogenicity of the given IGR Deletion Arenavirus, the degree of infection by or exposure to an Arenavirus, the manner of administration, the general state of health of the subject, and the like.
  • the typical immunogenic amounts for initial and boosting immunizations for therapeutic or prophylactic administration may range from about 10 1 to about 10 7 plaque forming units (pfu) or equivalent TCID50. In some embodiments, the immunogenic amount is about 10 2 to about 10 7 plaque forming units (pfu) or equivalent TCID50.
  • the immunogenic amount is about 10 3 to about 10 7 plaque forming units (pfu) or equivalent TCID50.
  • the vaccine initial vaccine and booster vaccination may be the same dosage or different.
  • the amount of attenuated virus used may be different.
  • a therapeutic dose of a given IGR Deletion Arenavirus may be 10 7 pfu or equivalent TCID50, while the therapeutic dose of a different IGR Deletion Arenavirus may be 1000 pfu or equivalent TCID50.
  • suitable immunization protocols include an initial immunization injection (time 0), followed by booster injections (if needed) at 4, and/or 8 weeks, which these initial immunization injections may be followed by further booster injections at 1 or 2 years if needed.
  • a "therapeutically effective amount” refers to an amount that may be used to treat, prevent, or inhibit an Arenavirus infection in a subject as compared to a control. Again, the skilled artisan will appreciate that certain factors may influence the amount required to effectively treat a subject, including the degree of infection by or exposure to an Arenavirus, previous treatments, the general health and age of the subject, and the like. Nevertheless, therapeutically effective amounts may be readily determined by methods in the art. It should be noted that treatment of a subject with a therapeutically effective amount or an immunogenic amount may be administered as a single dose or as a series of several doses. The dosages used for treatment may increase or decrease over the course of a given treatment.
  • Optimal dosages for a given set of conditions may be ascertained by those skilled in the art using dosage-determination tests and/or diagnostic assays in the art. Dosage-determination tests and/or diagnostic assays may be used to monitor and adjust dosages over the course of treatment.
  • compositions of the present invention may include an adjuvant. As used herein,
  • an “adjuvant” refers to any substance which, when administered in conjunction with (e.g., before, during, or after) a pharmaceutically active agent, such as a IGR Deletion Arenavirus according to the present invention, aids the pharmaceutically active agent in its mechanism of action.
  • a pharmaceutically active agent such as a IGR Deletion Arenavirus according to the present invention
  • an adjuvant in a vaccine according to the present invention is a substance that aids the at least one IGR Deletion Arenavirus in eliciting an immune response.
  • Suitable adjuvant include incomplete Freund' s adjuvant, alum, aluminum phosphate, aluminum hydroxide, N-acetyl-muramyl-L-threonyl-D-isoglutamine (thr- MDP), N-acetyl-nor-muramyl-L-alanyl-D-isoglutamine (CGP 11637, nor-MDP), N- acetylmuramyl-Lalanyl-D-isoglutaminyl-L-alanine-2-( -2'-dipa-lmitoyl-sn-glycero-3- hydroxyphosphoryloxy)-ethylamine (CGP 19835A, MTP-PE), and RIBI, which comprise three components extracted from bacteria, monophosphoryl lipid A, trehalose dimycolate and cell wall skeleton (NPL+TDM+CWS) in a 2% squalene/Tween 80 emulsion.
  • compositions of the present invention may be formulated for the intended route of delivery, including intravenous, intramuscular, intra peritoneal, subcutaneous, intraocular, intrathecal, intraarticular, intrasynovial, cisternal, intrahepatic, intralesional injection, intracranial injection, infusion, and/or inhaled routes of administration using methods known in the art.
  • compositions according to the present invention may include one or more of the following: pH buffered solutions, adjuvants (e.g., preservatives, wetting agents, emulsifying agents, and dispersing agents), liposomal formulations, nanoparticles, dispersions, suspensions, or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • adjuvants e.g., preservatives, wetting agents, emulsifying agents, and dispersing agents
  • liposomal formulations e.g., nanoparticles, dispersions, suspensions, or emulsions
  • sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • compositions of the present invention may be administered to a subject by any suitable route including oral, transdermal, subcutaneous, intranasal, inhalation, intramuscular, and intravascular administration. It will be appreciated that the preferred route of administration and pharmaceutical formulation will vary with the condition and age of the subject, the nature of the condition to be treated, the therapeutic effect desired, and the particular IGR Deletion Arenavirus used.
  • pharmaceutically acceptable carrier and “pharmaceutically acceptable excipient” are used interchangeably and refer to solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, that are compatible with
  • pharmaceutically acceptable vehicles, carriers, and excipients refer to a human-made substance that is of a purity level that is acceptable for administration to humans, e.g., sterile water that is acceptable for intravenous administration.
  • Pharmaceutically acceptable vehicles include those known in the art. See, e.g. , Remington: The Science and Practice of Pharmacy. 20 th ed. (2000) Lippincott Williams & Wilkins. Baltimore, MD, which is herein incorporated by reference.
  • compositions of the present invention may be provided in dosage unit forms.
  • dosage unit form refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a
  • predetermined quantity of the one or more IGR Deletion Arenavirus calculated to produce the desired therapeutic effect in association with the required pharmaceutically acceptable carrier.
  • the specification for the dosage unit forms of the invention are dictated by and directly dependent on the unique characteristics of the given IGR Deletion Arenavirus and desired therapeutic effect to be achieved, and the limitations inherent in the art of compounding such an active compound for the treatment of individuals.
  • Toxicity and therapeutic efficacy of IGR Deletion Arenaviruses according to the instant invention and compositions thereof can be determined using cell cultures and/or experimental animals and pharmaceutical procedures in the art. For example, one may determine the lethal dose, LC50 (the dose expressed as concentration x exposure time that is lethal to 50% of the population) or the LD50 (the dose lethal to 50% of the population), and the ED50 (the dose therapeutically effective in 50% of the population) by methods in the art. The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD50/ED50.
  • IGR Deletion Arenaviruses which exhibit large therapeutic indices are preferred. While IGR Deletion Arenaviruses that result in toxic side-effects may be used, care should be taken to design a delivery system that targets such compounds to the site of treatment to minimize potential damage to uninfected cells and, thereby, reduce side-effects.
  • the data obtained from the cell culture assays and animal studies can be used in formulating a range of dosages for use in humans.
  • Preferred dosages provide a range of circulating concentrations that include the ED50 with little or no toxicity.
  • the dosage may vary depending upon the dosage form employed and the route of administration utilized.
  • Therapeutically effective amounts and dosages of one or more IGR Deletion Arenaviruses according to the present invention can be estimated initially from cell culture assays.
  • a dose may be formulated in animal models to achieve a circulating plasma concentration range that includes the IC50 (i.e., the concentration of the test compound which achieves a half-maximal inhibition of symptoms) as determined in cell culture.
  • IC50 i.e., the concentration of the test compound which achieves a half-maximal inhibition of symptoms
  • levels in plasma may be measured, for example, by high performance liquid chromatography.
  • a dosage suitable for a given subject can be determined by an attending physician or qualified medical practitioner, based on various clinical factors.
  • kits which comprise one or more IGR Deletion Arenaviruses, optionally in a composition or in combination with one or more supplementary agents, packaged together with one or more reagents or drug delivery devices for preventing, inhibiting, reducing, or treating Arenavirus infection in a subject.
  • kits include a carrier, package, or container that may be compartmentalized to receive one or more containers, such as vials, tubes, and the like.
  • kits optionally include an identifying description or label or instructions relating to its use.
  • the kits comprise the one or more IGR Deletion Arenaviruses, optionally in one or more unit dosage forms, packaged together as a pack and/or in drug delivery device, e.g., a pre-filled syringe.
  • the kits include information prescribed by a governmental agency that regulates the manufacture, use, or sale of compounds and compositions according to the present invention.
  • GTOV strain INH95551, MACV strain Chic, and two MACV strains of Carvallo from passages dated 1968 (Car 68 ) and 1991 (Car 91 ) were propagated in Vero cell monolayers (ATCC CRL-1587) as previously reported [29]. All work with the viruses was performed in registered and certified biological safety level 4 (BSL4) containment environments.
  • 239T cells, 104CL guinea pig fibroblasts (ATCC) were maintained in MEM or RPMI containing 10% heat-inactivated fetal bovine serum (FBS), 1% antibiotics (100 U/ml penicillin, 100 ⁇ g/ml of streptomycin, respectively.
  • Human umbilical vein cells (HUVECs) (Lonza) were maintained in manufacture's medium.
  • Vero, 104CL, and HUVECs were seeded at a density of 1 x 10 5 cells per well in
  • Particle counts were determined with a Virocyt machine (Virocyt, Boulder, CO) using the manufacture's protocol.
  • the parti cle-to-pfu ratios were determined by dividing particle counts by the amount of infectious virus. Four virus preparations per strain were used in the calculations.
  • SISPA sequence-independent, single primer amplification
  • Pseudovirion neutralization assay (PsVNA) and ELISA
  • PsVNA pseudovirion neutralization assay
  • a vesicular stomatitis virus backbone with a luciferase reporter gene was used to produce particles decorated with glycoproteins from MACV, JUNV, and GTOV. These particles were subsequently incubated with the indicated serially diluted sera in triplicate and the geometric mean titers (GMT) of PsVNA50 plotted.
  • GTT geometric mean titers
  • BMDS INC Seaford, DE
  • Animals were challenged with the indicated MACV strains (1,000 pfu) or GTOV (2000 pfu) diluted in a total volume of 0.5 ml PBS by intraperitoneal (i.p.) injection. Animals were weighed and monitored for fever. All animal studies were conducted in compliance with the Animal Welfare Act and other federal statutes and regulations relating to animals and experiments involving animals and adheres to principles state in the Guide for the Care and Use of Laboratory Animals, National Research Council, 1996. The facilities where this research was conducted are fully accredited by the Association for Assessment and Accreditation of Laboratory Animal Care International. Animals meeting criteria were humanly euthanized.
  • MACV strain Car 91 was tested for its ability to produce an acute infection in
  • guinea pig fibroblasts were infected with Car 91 , Car 68 , or Chic and replication was assayed at 24, 48, and 72 hours post-infection (hpi) ( Figure 5). After 24 hours, Car 68 grew to the highest levels in both Vero and HUVEC. The 24 hour growth in 104CL cells was markedly lower than Vero and HUVECs with values for all three viruses ⁇ lxlO 3 pfu/ml, however growth of Car 91 was the lowest. At 48 hpi, Car 91 replication was still reduced compared to the other viruses in 104C1 and Vero cells, however in HUVECs Car 91 and Car 68 had similar titers.
  • MACV strain Car 91 protects guinea pigs against lethal infection by GTOV
  • strain Car 91 was highly attenuated in guinea pigs but produced detectable immune responses, it was hypothesized that it might function as a live-attenuated vaccine. To this end, the ability of Car 91 to protect guinea pigs against GTOV, a distantly related NW Arenavirus [35]. Guinea pigs were challenged with GTOV 45 days after exposure to MACV ( Figure 19, Figure 20, and Figure 21). As a control for acute infection, a group of six weight-matched naive guinea pigs were also infected. Animals were monitored for survival, weight loss, and fever over 25 days ( Figure 19, Figure 20, and Figure 21).
  • Knipe DM Knipe DM
  • Howley PM eds. Fields Virology. 5th ed. Vol. 2.
  • Arenavirus-California 1999-2000. MMWR Morbidity and mortality weekly report 2000; 49:709-11.
  • tributylribavirin on argentine hemorrhagic fever (Junin virus) in guinea pigs.
  • Enria DA Barrera Oro JG. Junin virus vaccines. Current topics in microbiology and immunology 2002; 263 :239-61.
  • Weissenbacher MC Coto CE, Calello MA.
  • Cross-protection between Tacaribe complex viruses Presence of neutralizing antibodies against Junin virus (Argentine hemorrhagic fever) in guinea pigs infected with Tacaribe virus Intervirology 1975; 6:42- 9.
  • choriomeningitis virus identification of the virus structural and cell associated polypeptides. Virology 1978; 89: 133-45.
  • DNA vaccine delivered using a spring-powered jet injector elicits a potent neutralizing antibody response in rabbits and nonhuman primates.
  • lymphocytic choriomeningitis virus WE and ARM
  • Pichinde Arenavirus Virus research 1985; 2:35-51.
  • non-human animal includes all vertebrates, e.g., mammals and non-mammals, such as non-human primates, horses, sheep, dogs, cows, pigs, chickens, and other veterinary subjects and test animals.
  • the subject is a mammal. In some embodiments of the present invention, the subject is a human.
  • the term “comprising” is used in its conventional sense to indicate that the given composition (or method) may include other ingredients (or steps).
  • the term “consisting of is used in its conventional sense to indicate that the given composition (or method) may not include any additional ingredients (or steps).
  • the phrase “consists essentially of indicates that the given composition (or method) may include other ingredients (or steps) so long as the additional ingredients (or steps) do not materially change the biological and/or chemical activity (or results) of the specified ingredients (or steps).
  • the phrase "comprises, consists essentially of, or consists of is used as a tool to avoid excess page and translation fees and means that in some embodiments the given thing at issue comprises something, and in some embodiments the given thing at issue consists of something.
  • the sentence "In some embodiments, the composition comprises, consists essentially of, or consists of A” is to be interpreted as if written as the following two separate sentences: "In some embodiments, the composition comprises A. In some embodiments, the composition consists essentially of A. In some embodiments, the composition consists of A.”
  • a sentence reciting a string of alternates is to be interpreted as if a string of sentences were provided such that each given alternate was provided in a sentence by itself.
  • the sentence "In some embodiments, the composition comprises A, B, or C" is to be interpreted as if written as the following three separate sentences: "In some embodiments, the composition comprises A. In some embodiments, the composition comprises B. In some embodiments, the composition comprises C.”

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Abstract

L'invention concerne des procédés de génération d'arénavirus atténués, des compositions comprenant les arénavirus atténués, et des procédés d'utilisation des arénavirus atténués. Selon l'invention, les arénavirus atténués présentent une délétion d'au moins une partie de la région intergénique (IGR) d'un ou des deux segments génomiques.
PCT/US2017/049371 2015-08-28 2017-08-30 Vaccin vivant atténué à arénavirus d'amérique du sud Ceased WO2018045029A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100297172A1 (en) * 2007-12-27 2010-11-25 Pinschewer Daniel D Replication-defective arenavirus vectors
WO2014140301A1 (fr) * 2013-03-15 2014-09-18 Université De Genève Vaccins anti-mycobactériens
WO2016075250A1 (fr) * 2014-11-13 2016-05-19 Université De Genève Arénavirus tri-segmentés en tant que vecteurs de vaccins
US20160206724A1 (en) * 2014-07-30 2016-07-21 University Of Rochester Methods and Compositions Related to Reorganization of Arenavirus Genome for Development of Novel Arenavirus Live-Attenuated Vaccines (LAV)
WO2017080920A1 (fr) * 2015-11-12 2017-05-18 Hookipa Biotech Ag Particules d'arénavirus utilisées comme vaccins contre le cancer

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100297172A1 (en) * 2007-12-27 2010-11-25 Pinschewer Daniel D Replication-defective arenavirus vectors
EP2604695A1 (fr) * 2007-12-27 2013-06-19 Universität Zürich Vecteurs d'arénavirus à réplication défectueuse
WO2014140301A1 (fr) * 2013-03-15 2014-09-18 Université De Genève Vaccins anti-mycobactériens
US20160206724A1 (en) * 2014-07-30 2016-07-21 University Of Rochester Methods and Compositions Related to Reorganization of Arenavirus Genome for Development of Novel Arenavirus Live-Attenuated Vaccines (LAV)
WO2016075250A1 (fr) * 2014-11-13 2016-05-19 Université De Genève Arénavirus tri-segmentés en tant que vecteurs de vaccins
WO2017080920A1 (fr) * 2015-11-12 2017-05-18 Hookipa Biotech Ag Particules d'arénavirus utilisées comme vaccins contre le cancer

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