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Abstract

A non-replicating form of pseudotyped influenza virus, inactivated by suppression of the haemagglutinin signal sequence (S-FLU), can act as a broadly protective vaccine. S-FLU can infect for a single round only, and induces heterotypic protection predominantly through activation of cross-reactive T cells in the lung. Unlike the licensed live attenuated virus, it cannot reassort a pandemic haemagglutinin (HA) into seasonal influenza. Here we present data on four new forms of S-FLU coated with H7 HAs from either A/Anhui/1/2013, A/Shanghai/1/2013, A/Netherlands/219/2003 or A/New York/107/2003 strains of H7 virus. We show that intranasal vaccination induced a strong local CD8 T cell response and protected against heterosubtypic X31 (H3N2) virus and highly virulent PR8 (H1N1), but not influenza B virus. Intranasal vaccination also induced a strong neutralizing antibody response to the encoded neuraminidase. If given at higher dose in the periphery with intraperitoneal administration, H7 S-FLU induced a specific neutralizing antibody response to H7 HA coating the particle. Polyvalent intraperitoneal vaccination with mixed H7 S-FLU induced a broadly neutralizing antibody response to all four H7 strains. S-FLU is a versatile vaccine candidate that could be rapidly mobilized ahead of a new pandemic threat.

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/content/journal/jgv/10.1099/jgv.0.001228
2019-02-04
2019-08-22
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References

  1. Medina RA, García-Sastre A. Influenza A viruses: new research developments. Nat Rev Microbiol 2011;9:590–603 [CrossRef][PubMed]
    [Google Scholar]
  2. Paules CI, Marston HD, Eisinger RW, Baltimore D, Fauci AS. The pathway to a universal influenza vaccine. Immunity 2017;47:599–603 [CrossRef][PubMed]
    [Google Scholar]
  3. Gao R, Cao B, Hu Y, Feng Z, Wang D et al. Human infection with a novel avian-origin influenza A (H7N9) virus. N Engl J Med 2013;368:1888–1897 [CrossRef][PubMed]
    [Google Scholar]
  4. Xiong X, Martin SR, Haire LF, Wharton SA, Daniels RS et al. Receptor binding by an H7N9 influenza virus from humans. Nature 2013;499:496–499 [CrossRef][PubMed]
    [Google Scholar]
  5. Smith W, Andrewes CH, Laidlaw PP. A virus obtained from influenza patients. The Lancet 1933;222:66–68 [CrossRef]
    [Google Scholar]
  6. Schulman JL, Kilbourne ED. Induction of partial specific heterotypic immunity in mice by a single infection with influenza a virus. J Bacteriol 1965;89:170–174[PubMed]
    [Google Scholar]
  7. Doherty PC, Kelso A. Toward a broadly protective influenza vaccine. J Clin Invest 2008;118:3273–3275 [CrossRef][PubMed]
    [Google Scholar]
  8. Epstein SL, Price GE. Cross-protective immunity to influenza A viruses. Expert Rev Vaccines 2010;9:1325–1341 [CrossRef][PubMed]
    [Google Scholar]
  9. Schulman JL. Experimental transmission of influenza virus infection in mice. 3. Differing effects of immunity induced by infection and by inactivated influenza virus vaccine on transmission of infection. J Exp Med 1967;125:467–478 [CrossRef][PubMed]
    [Google Scholar]
  10. Steel J, Staeheli P, Mubareka S, García-Sastre A, Palese P et al. Transmission of pandemic H1N1 influenza virus and impact of prior exposure to seasonal strains or interferon treatment. J Virol 2010;84:21–26 [CrossRef][PubMed]
    [Google Scholar]
  11. Fazekas de St Groth S, Donnelley M. Studies in experimental immunology of influenza. IV. The protective value of active immunization. Aust J Exp Biol Med Sci 1950;28:61–75[PubMed]
    [Google Scholar]
  12. Nguyen HH, Moldoveanu Z, Novak MJ, van Ginkel FW, Ban E et al. Heterosubtypic immunity to lethal influenza A virus infection is associated with virus-specific CD8(+) cytotoxic T lymphocyte responses induced in mucosa-associated tissues. Virology 1999;254:50–60 [CrossRef][PubMed]
    [Google Scholar]
  13. Perrone LA, Ahmad A, Veguilla V, Lu X, Smith G et al. Intranasal vaccination with 1918 influenza virus-like particles protects mice and ferrets from lethal 1918 and H5N1 influenza virus challenge. J Virol 2009;83:5726–5734 [CrossRef][PubMed]
    [Google Scholar]
  14. Lau YF, Wright AR, Subbarao K. The contribution of systemic and pulmonary immune effectors to vaccine-induced protection from H5N1 influenza virus infection. J Virol 2012;86:5089–5098 [CrossRef][PubMed]
    [Google Scholar]
  15. Wu T, Hu Y, Lee YT, Bouchard KR, Benechet A et al. Lung-resident memory CD8 T cells (TRM) are indispensable for optimal cross-protection against pulmonary virus infection. J Leukoc Biol 2014;95:215–224 [CrossRef][PubMed]
    [Google Scholar]
  16. Uddback IE, Pedersen LM, Pedersen SR, Steffensen MA, Holst PJ et al. Combined local and systemic immunization is essential for durable T-cell mediated heterosubtypic immunity against influenza A virus. Sci Rep 2016;6:20137 [CrossRef][PubMed]
    [Google Scholar]
  17. Townsend AR, Skehel JJ. The influenza A virus nucleoprotein gene controls the induction of both subtype specific and cross-reactive cytotoxic T cells. J Exp Med 1984;160:552–563 [CrossRef][PubMed]
    [Google Scholar]
  18. Taylor PM, Askonas BA. Influenza nucleoprotein-specific cytotoxic T-cell clones are protective in vivo. Immunology 1986;58:417–420[PubMed]
    [Google Scholar]
  19. Liang S, Mozdzanowska K, Palladino G, Gerhard W. Heterosubtypic immunity to influenza type A virus in mice. Effector mechanisms and their longevity. J Immunol 1994;152:1653–1661[PubMed]
    [Google Scholar]
  20. Epstein SL, Lo CY, Misplon JA, Lawson CM, Hendrickson BA et al. Mechanisms of heterosubtypic immunity to lethal influenza A virus infection in fully immunocompetent, T cell-depleted, beta2-microglobulin-deficient, and J chain-deficient mice. J Immunol 1997;158:1222–1230[PubMed]
    [Google Scholar]
  21. Laidlaw BJ, Decman V, Ali MA, Abt MC, Wolf AI et al. Cooperativity between CD8+ T cells, non-neutralizing antibodies, and alveolar macrophages is important for heterosubtypic influenza virus immunity. PLoS Pathog 2013;9:e1003207 [CrossRef][PubMed]
    [Google Scholar]
  22. McMichael AJ, Gotch FM, Dongworth DW, Clark A, Potter CW. Declining T-cell immunity to influenza, 1977-82. Lancet 1983;2:762–764 [CrossRef][PubMed]
    [Google Scholar]
  23. Sridhar S, Begom S, Bermingham A, Hoschler K, Adamson W et al. Cellular immune correlates of protection against symptomatic pandemic influenza. Nat Med 2013;19:1305–1312 [CrossRef][PubMed]
    [Google Scholar]
  24. Hayward AC, Wang L, Goonetilleke N, Fragaszy EB, Bermingham A et al. Natural T cell-mediated protection against seasonal and pandemic influenza: results of the flu watch cohort study. Am J Respir Crit Care Med 2015;191:1422–1431 [CrossRef][PubMed]
    [Google Scholar]
  25. Wang Z, Wan Y, Qiu C, Quiñones-Parra S, Zhu Z et al. Recovery from severe H7N9 disease is associated with diverse response mechanisms dominated by CD8+ T cells. Nat Commun 2015;6:6833 [CrossRef][PubMed]
    [Google Scholar]
  26. van de Sandt CE, Kreijtz JH, de Mutsert G, Geelhoed-Mieras MM, Hillaire ML et al. Human cytotoxic T lymphocytes directed to seasonal influenza A viruses cross-react with the newly emerging H7N9 virus. J Virol 2014;88:1684–1693 [CrossRef][PubMed]
    [Google Scholar]
  27. Lee LY, Ha Dola, Simmons C, de Jong MD, Chau NV et al. Memory T cells established by seasonal human influenza A infection cross-react with avian influenza A (H5N1) in healthy individuals. J Clin Invest 2008;118:3478–3490 [CrossRef][PubMed]
    [Google Scholar]
  28. McMichael AJ, Gotch FM, Noble GR, Beare PA. Cytotoxic T-cell immunity to influenza. N Engl J Med 1983;309:13–17 [CrossRef][PubMed]
    [Google Scholar]
  29. Wilkinson TM, Li CK, Chui CS, Huang AK, Perkins M et al. Preexisting influenza-specific CD4+ T cells correlate with disease protection against influenza challenge in humans. Nat Med 2012;18:274–280 [CrossRef][PubMed]
    [Google Scholar]
  30. Powell TJ, Silk JD, Sharps J, Fodor E, Townsend AR. Pseudotyped influenza A virus as a vaccine for the induction of heterotypic immunity. J Virol 2012;86:13397–13406 [CrossRef][PubMed]
    [Google Scholar]
  31. Baz M, Boonnak K, Paskel M, Santos C, Powell T et al. Nonreplicating influenza A virus vaccines confer broad protection against lethal challenge. mBio 2015;6:e0148701415 [CrossRef][PubMed]
    [Google Scholar]
  32. Morgan SB, Hemmink JD, Porter E, Harley R, Shelton H et al. Aerosol delivery of a candidate universal influenza vaccine reduces viral load in pigs challenged with pandemic H1N1 virus. J Immunol 2016;196:5014–5023 [CrossRef][PubMed]
    [Google Scholar]
  33. Nogales A, Baker SF, Domm W, Martínez-Sobrido L. Development and applications of single-cycle infectious influenza A virus (sciIAV). Virus Res 2016;216:26–40 [CrossRef][PubMed]
    [Google Scholar]
  34. Reed LJ, Muench H. A simple method of estimating fifty per cent endpoints. Am J Hyg 1938;27:493–497
    [Google Scholar]
  35. Brooke CB, Ince WL, Wrammert J, Ahmed R, Wilson PC et al. Most influenza a virions fail to express at least one essential viral protein. J Virol 2013;87:3155–3162 [CrossRef][PubMed]
    [Google Scholar]
  36. Southam DS, Dolovich M, O'Byrne PM, Inman MD. Distribution of intranasal instillations in mice: effects of volume, time, body position, and anesthesia. Am J Physiol Lung Cell Mol Physiol 2002;282:L833–L839 [CrossRef][PubMed]
    [Google Scholar]
  37. Lambré CR, Terzidis H, Greffard A, Webster RG. An enzyme-linked lectin assay for sialidase. Clin Chim Acta 1991;198:183–193 [CrossRef][PubMed]
    [Google Scholar]
  38. Couzens L, Gao J, Westgeest K, Sandbulte M, Lugovtsev V et al. An optimized enzyme-linked lectin assay to measure influenza A virus neuraminidase inhibition antibody titers in human sera. J Virol Methods 2014;210:7–14 [CrossRef][PubMed]
    [Google Scholar]
  39. Wan H, Yang H, Shore DA, Garten RJ, Couzens L et al. Structural characterization of a protective epitope spanning A(H1N1)pdm09 influenza virus neuraminidase monomers. Nat Commun 2015;6:6114 [CrossRef][PubMed]
    [Google Scholar]
  40. Chen Z, Baz M, Lu J, Paskel M, Santos C et al. Development of a high-yield live attenuated H7N9 influenza virus vaccine that provides protection against homologous and heterologous H7 wild-type viruses in ferrets. J Virol 2014;88:7016–7023 [CrossRef][PubMed]
    [Google Scholar]
  41. Jin H, Subbarao K. Live attenuated influenza vaccine. Curr Top Microbiol Immunol 2015;386:181–204 [CrossRef][PubMed]
    [Google Scholar]
  42. Mallory RM, Yi T, Ambrose CS. Shedding of Ann Arbor strain live attenuated influenza vaccine virus in children 6-59 months of age. Vaccine 2011;29:4322–4327 [CrossRef][PubMed]
    [Google Scholar]
  43. Joseph T, McAuliffe J, Lu B, Jin H, Kemble G et al. Evaluation of replication and pathogenicity of avian influenza a H7 subtype viruses in a mouse model. J Virol 2007;81:10558–10566 [CrossRef][PubMed]
    [Google Scholar]
  44. Hatta Y, Boltz D, Sarawar S, Kawaoka Y, Neumann G et al. M2SR, a novel live influenza vaccine, protects mice and ferrets against highly pathogenic avian influenza. Vaccine 2017;35:4177–4183 [CrossRef][PubMed]
    [Google Scholar]
  45. Hatta Y, Boltz D, Sarawar S, Kawaoka Y, Neumann G et al. Novel influenza vaccine M2SR protects against drifted H1N1 and H3N2 influenza virus challenge in ferrets with pre-existing immunity. Vaccine 2018;36:5097–5103 [CrossRef][PubMed]
    [Google Scholar]
  46. Air GM. Influenza neuraminidase. Influenza Other Respir Viruses 2012;6:245–256 [CrossRef][PubMed]
    [Google Scholar]
  47. Wohlbold TJ, Nachbagauer R, Xu H, Tan GS, Hirsh A et al. Vaccination with adjuvanted recombinant neuraminidase induces broad heterologous, but not heterosubtypic, cross-protection against influenza virus infection in mice. mBio 2015;6:e02556 [CrossRef][PubMed]
    [Google Scholar]
  48. Monto AS, Petrie JG, Cross RT, Johnson E, Liu M et al. Antibody to influenza virus neuraminidase: an independent correlate of protection. J Infect Dis 2015;212:1191–1199 [CrossRef][PubMed]
    [Google Scholar]
  49. Memoli MJ, Shaw PA, Han A, Czajkowski L, Reed S et al. Evaluation of antihemagglutinin and antineuraminidase antibodies as correlates of protection in an influenza A/H1N1 virus healthy human challenge model. mBio 2016;7:e0041700416 [CrossRef][PubMed]
    [Google Scholar]
  50. Webster RG, Laver WG. Preparation and properties of antibody directed specifically against the neuraminidase of influenza virus. J Immunol 1967;99:49–55[PubMed]
    [Google Scholar]
  51. Lin YP, Gregory V, Collins P, Kloess J, Wharton S et al. Neuraminidase receptor binding variants of human influenza A(H3N2) viruses resulting from substitution of aspartic acid 151 in the catalytic site: a role in virus attachment?. J Virol 2010;84:6769–6781 [CrossRef][PubMed]
    [Google Scholar]
  52. Hooper KA, Bloom JD. A mutant influenza virus that uses an N1 neuraminidase as the receptor-binding protein. J Virol 2013;87:12531–12540 [CrossRef][PubMed]
    [Google Scholar]
  53. Chen Z, Kim L, Subbarao K, Jin H. The 2009 pandemic H1N1 virus induces anti-neuraminidase (NA) antibodies that cross-react with the NA of H5N1 viruses in ferrets. Vaccine 2012;30:2516–2522 [CrossRef][PubMed]
    [Google Scholar]
  54. Easterbrook JD, Schwartzman LM, Gao J, Kash JC, Morens DM et al. Protection against a lethal H5N1 influenza challenge by intranasal immunization with virus-like particles containing 2009 pandemic H1N1 neuraminidase in mice. Virology 2012;432:39–44 [CrossRef][PubMed]
    [Google Scholar]
  55. Wan H, Gao J, Xu K, Chen H, Couzens LK et al. Molecular basis for broad neuraminidase immunity: conserved epitopes in seasonal and pandemic H1N1 as well as H5N1 influenza viruses. J Virol 2013;87:9290–9300 [CrossRef][PubMed]
    [Google Scholar]
  56. Zhou F, Wang G, Buchy P, Cai Z, Chen H et al. A triclade DNA vaccine designed on the basis of a comprehensive serologic study elicits neutralizing antibody responses against all clades and subclades of highly pathogenic avian influenza H5N1 viruses. J Virol 2012;86:6970–6978 [CrossRef][PubMed]
    [Google Scholar]
  57. Schwartzman LM, Cathcart AL, Pujanauski LM, Qi L, Kash JC et al. An intranasal virus-like particle vaccine broadly protects mice from multiple subtypes of influenza A virus. mBio 2015;6:e01044 [CrossRef][PubMed]
    [Google Scholar]
  58. Harris K, Ream R, Gao J, Eichelberger MC. Intramuscular immunization of mice with live influenza virus is more immunogenic and offers greater protection than immunization with inactivated virus. Virol J 2011;8:251 [CrossRef][PubMed]
    [Google Scholar]
  59. Matrosovich M, Matrosovich T, Carr J, Roberts NA, Klenk HD. Overexpression of the alpha-2,6-sialyltransferase in MDCK cells increases influenza virus sensitivity to neuraminidase inhibitors. J Virol 2003;77:8418–8425 [CrossRef][PubMed]
    [Google Scholar]
  60. Kilbourne ED. Future influenza vaccines and the use of genetic recombinants. Bull World Health Organ 1969;41:643–645[PubMed]
    [Google Scholar]
  61. Huang KY, Rijal P, Schimanski L, Powell TJ, Lin TY et al. Focused antibody response to influenza linked to antigenic drift. J Clin Invest 2015;125:2631–2645 [CrossRef][PubMed]
    [Google Scholar]
  62. Smith K, Garman L, Wrammert J, Zheng NY, Capra JD et al. Rapid generation of fully human monoclonal antibodies specific to a vaccinating antigen. Nat Protoc 2009;4:372–384 [CrossRef][PubMed]
    [Google Scholar]
  63. Demaison C, Parsley K, Brouns G, Scherr M, Battmer K et al. High-level transduction and gene expression in hematopoietic repopulating cells using a human immunodeficiency [correction of imunodeficiency] virus type 1-based lentiviral vector containing an internal spleen focus forming virus promoter. Hum Gene Ther 2002;13:803–813 [CrossRef][PubMed]
    [Google Scholar]
  64. Chen Z, Wang W, Zhou H, Suguitan AL, Shambaugh C et al. Generation of live attenuated novel influenza virus A/California/7/09 (H1N1) vaccines with high yield in embryonated chicken eggs. J Virol 2010;84:44–51 [CrossRef][PubMed]
    [Google Scholar]
  65. Martínez-Sobrido L, Cadagan R, Steel J, Basler CF, Palese P et al. Hemagglutinin-pseudotyped green fluorescent protein-expressing influenza viruses for the detection of influenza virus neutralizing antibodies. J Virol 2010;84:2157–2163 [CrossRef][PubMed]
    [Google Scholar]
  66. Puleston DJ, Zhang H, Powell TJ, Lipina E, Sims S et al. Autophagy is a critical regulator of memory CD8(+) T cell formation. Elife 2014;3:e03706 [CrossRef][PubMed]
    [Google Scholar]
  67. Rowe T, Abernathy RA, Hu-Primmer J, Thompson WW, Lu X et al. Detection of antibody to avian influenza A (H5N1) virus in human serum by using a combination of serologic assays. J Clin Microbiol 1999;37:937–943[PubMed]
    [Google Scholar]
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