1887

Abstract

In mice, vaccines inducing antibodies to the extracellular domain of the M2 protein (M2e) can confer protection to influenza A virus infection. Unlike the surface glycoproteins, haemagglutinin and neuraminidase, this domain of M2 is highly conserved and is therefore a potential broad-spectrum immunogen. In this study, the protection conferred by vaccines inducing antibodies to M2e was evaluated in a challenge model for swine influenza in pigs. A protein resulting from the fusion between M2e and the hepatitis B virus core protein (M2eHBc), with or without adjuvant, was evaluated. In addition, a DNA construct expressing a fusion protein between M2e and influenza virus nucleoprotein (M2eNP) was evaluated to see if the broad-spectrum protection conferred by antibodies could be further enhanced by T helper cells and cytotoxic T cells. All vaccines induced an antibody response against M2e, and the M2eNP DNA vaccine additionally induced an influenza virus-specific lymphoproliferation response. However, after challenge with a swine influenza virus (H1N1), no protection was observed in the vaccinated groups compared with the non-vaccinated control group. On the contrary, vaccinated pigs showed more severe clinical signs than the control pigs. The M2eNP DNA-vaccinated pigs showed the most severe clinical signs and three out of six pigs died on days 1 and 2 post-challenge. These results indicate that antibodies to M2e, especially in combination with cell-mediated immune responses, exacerbate disease. Thus, clinical signs after infection should be observed closely in further studies using M2e as an immunogen and caution should be exercised in using M2e in humans.

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2002-08-01
2019-10-18
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References

  1. Castrucci, M. R., Donatelli, I., Sidoli, L., Barigazzi, G., Kawaoka, Y. & Webster, R. G. ( 1993; ). Genetic reassortment between avian and human influenza A viruses in Italian pigs. Virology 193, 503-506.[CrossRef]
    [Google Scholar]
  2. Chen, R. F., Yeh, W. T., Yang, M. Y. & Yang, K. D. ( 2001; ). A model of the real-time correlation of viral titers with immune reactions in antibody-dependent enhancement of dengue-2 infections. FEMS Immunology and Medical Microbiology 30, 1-7.[CrossRef]
    [Google Scholar]
  3. Doherty, P. C. & Christensen, J. P. ( 2000; ). Accessing complexity: the dynamics of virus-specific T cell responses. Annual Review of Immunology 18, 561-592.[CrossRef]
    [Google Scholar]
  4. Epstein, S. L., Stack, A., Misplon, J. A., Lo, C. Y., Mostowski, H., Bennink, J. & Subbarao, K. ( 2000; ). Vaccination with DNA encoding internal proteins of influenza virus does not require CD8+ cytotoxic T lymphocytes: either CD4+ or CD8+ T cells can promote survival and recovery after challenge. International Immunology 12, 91-101.[CrossRef]
    [Google Scholar]
  5. Flynn, K. J., Belz, G. T., Altman, J. D., Ahmed, R., Woodland, D. L. & Doherty, P. C. ( 1998; ). Virus-specific CD8+ T cells in primary and secondary influenza pneumonia. Immunity 8, 683-691.[CrossRef]
    [Google Scholar]
  6. Flynn, K. J., Riberdy, J. M., Christensen, J. P., Altman, J. D. & Doherty, P. C. ( 1999; ). In vivo proliferation of naive and memory influenza-specific CD8+ T cells. Proceedings of the National Academy of Sciences, USA 96, 8597-8602.[CrossRef]
    [Google Scholar]
  7. Frace, A. M., Klimov, A. I., Rowe, T., Black, R. A. & Katz, J. M. ( 1999; ). Modified M2 proteins produce heterotypic immunity against influenza A virus. Vaccine 17, 2237-2244.[CrossRef]
    [Google Scholar]
  8. Heinen, P. P., de Boer-Luijtze, E. A. & Bianchi, A. T. J. ( 2001; ). Respiratory and systemic humoral and cellular immune response of pigs to a heterosubtypic influenza A virus infection. Journal of General Virology 82, 2697-2707.
    [Google Scholar]
  9. Kasza, L., Shadduck, J. A. & Christofinis, G. J. ( 1972; ). Establishment, viral susceptibility and biological characteristics of a swine kidney cell line SK-6. Research in Veterinary Science 13, 46-51.
    [Google Scholar]
  10. Kendal, A. P., Pereira, M. S. & Skehel, J. J. (1982). Concepts and Procedures for Laboratory-based Influenza Surveillance. Washington, DC: Department of Health and Human Services, Centers for Disease Control.
  11. Kimman, T. G., de Bruin, T. M., Voermans, J. J., Peeters, B. P. & Bianchi, A. T. ( 1995; ). Development and antigen specificity of the lymphoproliferation responses of pigs to pseudorabies virus: dichotomy between secondary B- and T-cell responses. Immunology 86, 372-378.
    [Google Scholar]
  12. Kozak, M. ( 1987; ). At least six nucleotides preceding the AUG initiator codon enhance translation in mammalian cells. Journal of Molecular Biology 196, 947-950.[CrossRef]
    [Google Scholar]
  13. Loeffen, W. L., Kamp, E. M., Stockhofe-Zurwieden, N., van Nieuwstadt, A. P., Bongers, J. H., Hunneman, W. A., Elbers, A. R., Baars, J., Nell, T. & van Zijderveld, F. G. ( 1999; ). Survey of infectious agents involved in acute respiratory disease in finishing pigs. Veterinary Record 145, 123-129.[CrossRef]
    [Google Scholar]
  14. Macklin, M. D., McCabe, D., McGregor, M. W., Neumann, V., Meyer, T., Callan, R., Hinshaw, V. S. & Swain, W. F. ( 1998; ). Immunization of pigs with a particle-mediated DNA vaccine to influenza A virus protects against challenge with homologous virus. Journal of Virology 72, 1491-1496.
    [Google Scholar]
  15. Morens, D. M. ( 1994; ). Antibody-dependent enhancement of infection and the pathogenesis of viral disease. Clinical Infectious Diseases 19, 500-512.[CrossRef]
    [Google Scholar]
  16. Mozdzanowska, K., Furchner, M., Maiese, K. & Gerhard, W. ( 1997; ). CD4+ T cells are ineffective in clearing a pulmonary infection with influenza type A virus in the absence of B cells. Virology 239, 217-225.[CrossRef]
    [Google Scholar]
  17. Mozdzanowska, K., Maiese, K., Furchner, M. & Gerhard, W. ( 1999; ). Treatment of influenza virus-infected SCID mice with nonneutralizing antibodies specific for the transmembrane proteins matrix 2 and neuraminidase reduces the pulmonary virus titer but fails to clear the infection. Virology 254, 138-146.[CrossRef]
    [Google Scholar]
  18. Mozdzanowska, K., Maiese, K. & Gerhard, W. ( 2000; ). Th cell-deficient mice control influenza virus infection more effectively than Th- and B cell-deficient mice: evidence for a Th-independent contribution by B cells to virus clearance. Journal of Immunology 164, 2635-2643.[CrossRef]
    [Google Scholar]
  19. Neirynck, S., Deroo, T., Saelens, X., Vanlandschoot, P., Jou, W. M. & Fiers, W. ( 1999; ). A universal influenza A vaccine based on the extracellular domain of the M2 protein. Nature Medicine 5, 1157-1163.[CrossRef]
    [Google Scholar]
  20. Riberdy, J. M., Christensen, J. P., Branum, K. & Doherty, P. C. ( 2000; ). Diminished primary and secondary influenza virus-specific CD8+ T-cell responses in CD4-depleted Ig(−/−) mice. Journal of Virology 74, 9762-9765.[CrossRef]
    [Google Scholar]
  21. Scholtissek, C. ( 1995; ). Molecular evolution of influenza viruses. Virus Genes 11, 209-215.[CrossRef]
    [Google Scholar]
  22. Slepushkin, V. A., Katz, J. M., Black, R. A., Gamble, W. C., Rota, P. A. & Cox, N. J. ( 1995; ). Protection of mice against influenza A virus challenge by vaccination with baculovirus-expressed M2 protein. Vaccine 13, 1399-1402.[CrossRef]
    [Google Scholar]
  23. Topham, D. J. & Doherty, P. C. ( 1998; ). Clearance of an influenza A virus by CD4+ T cells is inefficient in the absence of B cells. Journal of Virology 72, 882-885.
    [Google Scholar]
  24. Treanor, J. J., Tierney, E. L., Zebedee, S. L., Lamb, R. A. & Murphy, B. R. ( 1990; ). Passively transferred monoclonal antibody to the M2 protein inhibits influenza A virus replication in mice. Journal of Virology 64, 1375-1377.
    [Google Scholar]
  25. Ulmer, J. B., Fu, T. M., Deck, R. R., Friedman, A., Guan, L., DeWitt, C., Liu, X., Wang, S., Liu, M. A., Donnelly, J. J. & Caulfield, M. J. ( 1998; ). Protective CD4+ and CD8+ T cells against influenza virus induced by vaccination with nucleoprotein DNA. Journal of Virology 72, 5648-5653.
    [Google Scholar]
  26. van Leengoed, L. A. & Kamp, E. M. ( 1989; ). A method for bronchoalveolar lavage in live pigs. Veterinary Quarterly 11, 65-72.[CrossRef]
    [Google Scholar]
  27. Yang, K. D., Yeh, W. T., Yang, M. Y., Chen, R. F. & Shaio, M. F. ( 2001; ). Antibody-dependent enhancement of heterotypic dengue infections involved in suppression of IFNgamma production. Journal of Medical Virology 63, 150-157.[CrossRef]
    [Google Scholar]
  28. Zebedee, S. L. & Lamb, R. A. ( 1989; ). Growth restriction of influenza A virus by M2 protein antibody is genetically linked to the M1 protein. Proceedings of the National Academy of Sciences, USA 86, 1061-1065.[CrossRef]
    [Google Scholar]
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