1887

Abstract

The potential of RNA-based vaccines was evaluated for the generation of a protective immune response in the mouse model of influenza type A virus infection using the internal nucleoprotein (NP) as antigen. This antigen is of particular interest, since it has the potential to elicit protective cytotoxic T lymphocytes (CTL) against heterologous strains of influenza A virus. In view of the short half-life of RNA, self-replicating RNAs or replicons of the positive-stranded genomes of Semliki Forest virus (SFV) and poliovirus were engineered to synthesize the influenza A virus NP in place of their structural proteins. NP expression was demonstrated by immunoprecipitation after transfection of cells with RNA from the SFV (rSFV-NP) and poliovirus (rΔP1-E-NP) genome-derived replicons transcribed . C57BL/6 mice were injected intramuscularly with these synthetic RNAs in naked form. Both replicons, rSFV-NP and rΔP1-E-NP, induced antibodies against the influenza virus NP, but only mice immunized with the rSFV-NP replicon developed a CTL response against the immunodominant H-2D epitope NP366. Finally, the protective potential of the CTL response induced by immunization of mice with rSFV-NP RNA was demonstrated by the reduction of virus load in the lungs after challenge infection with mouse-adapted influenza A/PR/8/34 virus and was comparable to the protective potential of the response induced by plasmid DNA immunization. These results demonstrate that naked RNA immunization with self-replicating molecules can effectively induce both humoral and cellular immune responses and constitutes an alternative strategy to DNA immunization.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/0022-1317-82-7-1737
2001-07-01
2024-03-28
Loading full text...

Full text loading...

/deliver/fulltext/jgv/82/7/0821737a.html?itemId=/content/journal/jgv/10.1099/0022-1317-82-7-1737&mimeType=html&fmt=ahah

References

  1. Allan W., Tabi Z., Cleary A., Doherty P. C. 1990; Cellular events in the lymph node and lung of mice with influenza. Consequences of depleting CD4+ T cells. Journal of Immunology 144:3980–3986
    [Google Scholar]
  2. Ansardi D. C., Moldoveanu Z., Porter D. C., Walker D. E., Conry R. M., LoBuglio A. F., McPherson S., Morrow C. D. 1994; Characterization of poliovirus replicons encoding carcinoembryonic antigen. Cancer Research 54:6359–6364
    [Google Scholar]
  3. Bot A., Bot S., Garcia-Sastre A., Bona C. 1996; DNA immunization of newborn mice with a plasmid-expressing nucleoprotein of influenza virus. Viral Immunology 9:207–210
    [Google Scholar]
  4. Choi W. S., Pal-Ghosh R., Morrow C. D. 1991; Expression of human immunodeficiency virus type 1 (HIV-1) Gag, Pol, and Env proteins from chimeric HIV-1–poliovirus minireplicons. Journal of Virology 65:2875–2883
    [Google Scholar]
  5. Conry R. M., LoBuglio A. F., Wright M., Sumerel L., Pike M. J., Johanning F., Benjamin R., Lu D., Curiel D. T. 1995; Characterization of a messenger RNA polynucleotide vaccine vector. Cancer Research 55:1397–1400
    [Google Scholar]
  6. Corr M., von Damm A., Lee D. J., Tighe H. 1999; In vivo priming by DNA injection occurs predominantly by antigen transfer. Journal of Immunology 163:4721–4727
    [Google Scholar]
  7. Crotty S., Lohman B. L., Lu F. X., Tang S., Miller C. J., Andino R. 1999; Mucosal immunization of cynomolgus macaques with two serotypes of live poliovirus vectors expressing simian immunodeficiency virus antigens: stimulation of humoral, mucosal, and cellular immunity. Journal of Virology 73:9485–9495
    [Google Scholar]
  8. Dalemans W., Delers A., Delmelle C., Denamur F., Meykens R., Thiriart C., Veenstra S., Francotte M., Bruck C., Cohen J. 1995; Protection against homologous influenza challenge by genetic immunization with SFV RNA encoding Flu HA. Annals of the New York Academy of Sciences 772:255–256
    [Google Scholar]
  9. Deitz S., Dodd D., Cooper S., Parham P., Kirkegaard K. 2000; MHC I-dependent antigen presentation is inhibited by poliovirus protein 3A. Proceedings of the National Academy of Sciences, USA 97:13790–13795
    [Google Scholar]
  10. Doedens J. R., Kirkegaard K. 1995; Inhibition of cellular protein secretion by poliovirus proteins 2B and 3A. EMBO Journal 14:894–907
    [Google Scholar]
  11. Endo A., Itamura S., Iinuma H., Funahashi S., Shida H., Koide F., Nerome K., Oya A. 1991; Homotypic and heterotypic protection against influenza virus infection in mice by recombinant vaccinia virus expressing the haemagglutinin or nucleoprotein of influenza virus. Journal of General Virology 72:699–703
    [Google Scholar]
  12. Escriou N., Leclerc C., Gerbaud S., Girard M., van der Werf S. 1995; Cytotoxic T cell response to Mengo virus in mice: effector cell phenotype and target proteins. Journal of General Virology 76:1999–2007
    [Google Scholar]
  13. Frolov I., Hoffman T. A., Pragai B. M., Dryga S. A., Huang H. V., Schlesinger S., Rice C. M. 1996; Alphavirus-based expression vectors: strategies and applications. Proceedings of the National Academy of Sciences, USA 93:11371–11377
    [Google Scholar]
  14. Graham M. B., Braciale T. J. 1997; Resistance to and recovery from lethal influenza virus infection in B lymphocyte-deficient mice. Journal of Experimental Medicine 186:2063–2068
    [Google Scholar]
  15. Hellen C. U., Lee C. K., Wimmer E. 1992; Determinants of substrate recognition by poliovirus 2A proteinase. Journal of Virology 66:3330–3338
    [Google Scholar]
  16. Kees U., Krammer P. H. 1984; Most influenza A virus-specific memory cytotoxic T lymphocytes react with antigenic epitopes associated with internal virus determinants. Journal of Experimental Medicine 159:365–377
    [Google Scholar]
  17. Kieny M. P., Rautmann G., Schmitt D., Dott K., Wain-Hobson S., Alizon M., Girard M., Chamaret S., Laurent A., Montagnier L., Lecocq J. P. 1986; AIDS virus Env protein expressed from a recombinant vaccinia virus. Biotechnology 4:790–795
    [Google Scholar]
  18. Kingsbury D. W., Jones I. M., Murti K. G. 1987; Assembly of influenza ribonucleoprotein in vitro using recombinant nucleoprotein. Virology 156:396–403
    [Google Scholar]
  19. Lawson C. M., Bennink J. R., Restifo N. P., Yewdell J. W., Murphy B. R. 1994; Primary pulmonary cytotoxic T lymphocytes induced by immunization with a vaccinia virus recombinant expressing influenza A virus nucleoprotein peptide do not protect mice against challenge. Journal of Virology 68:3505–3511
    [Google Scholar]
  20. Leitner W. W., Ying H., Restifo N. P. 1999; DNA and RNA-based vaccines: principles, progress and prospects. Vaccine 18:765–777
    [Google Scholar]
  21. Liljeström P., Garoff H. 1991; A new generation of animal cell expression vectors based on the Semliki Forest virus replicon. Biotechnology 9:1356–1361
    [Google Scholar]
  22. McMichael A. J., Gotch F. M., Noble G. R., Beare P. A. 1983; Cytotoxic T-cell immunity to influenza. New England Journal of Medicine 309:13–17
    [Google Scholar]
  23. McMinn P., Carrello A., Cole C., Baker D., Hampson A. 1999; Antigenic drift of influenza A (H3N2) virus in a persistently infected immunocompromised host is similar to that occurring in the community. Clinical Infectious Diseases 29:456–458
    [Google Scholar]
  24. Mandl S., Sigal L. J., Rock K. L., Andino R. 1998; Poliovirus vaccine vectors elicit antigen-specific cytotoxic T cells and protect mice against lethal challenge with malignant melanoma cells expressing a model antigen. Proceedings of the National Academy of Sciences, USA 95:8216–8221
    [Google Scholar]
  25. Marc D., Drugeon G., Haenni A. L., Girard M., van der Werf S. 1989; Role of myristoylation of poliovirus capsid protein VP4 as determined by site-directed mutagenesis of its N-terminal sequence. EMBO Journal 8:2661–2668
    [Google Scholar]
  26. Martinon F., Krishnan S., Lenzen G., Magne R., Gomard E., Guillet J. G., Levy J. P., Meulien P. 1993; Induction of virus-specific cytotoxic T lymphocytes in vivo by liposome-entrapped mRNA. European Journal of Immunology 23:1719–1722
    [Google Scholar]
  27. Moldoveanu Z., Porter D. C., Lu A., McPherson S., Morrow C. D. 1995; Immune responses induced by administration of encapsidated poliovirus replicons which express HIV-1 gag and envelope proteins. Vaccine 13:1013–1022
    [Google Scholar]
  28. Nichols W. W., Ledwith B. J., Manam S. V., Troilo P. J. 1995; Potential DNA vaccine integration into host cell genome. Annals of the New York Academy of Sciences 772:30–39
    [Google Scholar]
  29. Oukka M., Manuguerra J. C., Livaditis N., Tourdot S., Riche N., Vergnon I., Cordopatis P., Kosmatopoulos K. 1996; Protection against lethal viral infection by vaccination with nonimmunodominant peptides. Journal of Immunology 157:3039–3045
    [Google Scholar]
  30. Parker C. E., Gould K. G. 1996; Influenza A virus – a model for viral antigen presentation to cytotoxic T lymphocytes. Seminars in Virology 7:61–73
    [Google Scholar]
  31. Percy N., Barclay W. S., Sullivan M., Almond J. W. 1992; A poliovirus replicon containing the chloramphenicol acetyltransferase gene can be used to study the replication and encapsidation of poliovirus RNA. Journal of Virology 66:5040–5046
    [Google Scholar]
  32. Porter D. C., Wang J., Moldoveanu Z., McPherson S., Morrow C. D. 1997; Immunization of mice with poliovirus replicons expressing the C-fragment of tetanus toxin protects against lethal challenge with tetanus toxin. Vaccine 15:257–264
    [Google Scholar]
  33. Qiu P., Ziegelhoffer P., Sun J., Yang N. S. 1996; Gene gun delivery of mRNA in situ results in efficient transgene expression and genetic immunization. Gene Therapy 3:262–268
    [Google Scholar]
  34. Rocha E., Cox N. J., Black R. A., Harmon M. W., Harrison C. J., Kendal A. P. 1991; Antigenic and genetic variation in influenza A (H1N1) virus isolates recovered from a persistently infected immunodeficient child. Journal of Virology 65:2340–2350
    [Google Scholar]
  35. Sambrook J., Fritsch E. F., Maniatis T. 1989 Molecular Cloning: A Laboratory Manual. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory;
    [Google Scholar]
  36. Sato Y., Roman M., Tighe H., Lee D., Corr M., Nguyen M. D., Silverman G. J., Lotz M., Carson D. A., Raz E. 1996; Immunostimulatory DNA sequences necessary for effective intradermal gene immunization. Science 273:352–354
    [Google Scholar]
  37. Stitz L., Schmitz C., Binder D., Zinkernagel R., Paoletti E., Becht H. 1990; Characterization and immunological properties of influenza A virus nucleoprotein (NP): cell-associated NP isolated from infected cells or viral NP expressed by vaccinia recombinant virus do not confer protection. Journal of General Virology 71:1169–1179
    [Google Scholar]
  38. Taylor P. M., Askonas B. A. 1986; Influenza nucleoprotein-specific cytotoxic T-cell clones are protective in vivo. Immunology 58:417–420
    [Google Scholar]
  39. 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]
  40. Tsuji M., Bergmann C. C., Takita-Sonoda Y., Murata K., Rodrigues E. G., Nussenzweig R. S., Zavala F. 1998; Recombinant Sindbis viruses expressing a cytotoxic T-lymphocyte epitope of a malaria parasite or of influenza virus elicit protection against the corresponding pathogen in mice. Journal of Virology 72:6907–6910
    [Google Scholar]
  41. Ulmer J. B., Donnelly J. J., Parker S. E., Rhodes G. H., Felgner P. L., Dwarki V. J., Gromkowski S. H., Deck R. R., DeWitt C. M., Friedman A. and others 1993; Heterologous protection against influenza by injection of DNA encoding a viral protein. Science 259:1745–1749
    [Google Scholar]
  42. 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]
  43. Voeten J. T., Bestebroer T. M., Nieuwkoop N. J., Fouchier R. A., Osterhaus A. D., Rimmelzwaan G. F. 2000; Antigenic drift in the influenza A virus (H3N2) nucleoprotein and escape from recognition by cytotoxic T lymphocytes. Journal of Virology 74:6800–6807
    [Google Scholar]
  44. Webster R. G., Kawaoka Y., Taylor J., Weinberg R., Paoletti E. 1991; Efficacy of nucleoprotein and haemagglutinin antigens expressed in fowlpox virus as vaccine for influenza in chickens. Vaccine 9:303–308
    [Google Scholar]
  45. Wolff J. A., Ludtke J. J., Acsadi G., Williams P., Jani A. 1992; Long-term persistence of plasmid DNA and foreign gene expression in mouse muscle. Human Molecular Genetics 1:363–369
    [Google Scholar]
  46. Yamanaka K., Ishihama A., Nagata K. 1990; Reconstitution of influenza virus RNA–nucleoprotein complexes structurally resembling native viral ribonucleoprotein cores. Journal of Biological Chemistry 265:11151–11155
    [Google Scholar]
  47. Yewdell J. W., Bennink J. R., Smith G. L., Moss B. 1985; Influenza A virus nucleoprotein is a major target antigen for cross-reactive anti-influenza A virus cytotoxic T lymphocytes. Proceedings of the National Academy of Sciences, USA 82:1785–1789
    [Google Scholar]
  48. Ying H., Zaks T. Z., Wang R. F., Irvine K. R., Kammula U. S., Marincola F. M., Leitner W. W., Restifo N. P. 1999; Cancer therapy using a self-replicating RNA vaccine. Nature Medicine 5:823–827
    [Google Scholar]
  49. Zhou X., Berglund P., Rhodes G., Parker S. E., Jondal M., Liljeström P. 1994; Self-replicating Semliki Forest virus RNA as recombinant vaccine. Vaccine 12:1510–1514
    [Google Scholar]
  50. Zhou X., Berglund P., Zhao H., Liljeström P., Jondal M. 1995; Generation of cytotoxic and humoral immune responses by nonreplicative recombinant Semliki Forest virus. Proceedings of the National Academy of Sciences, USA 92:3009–3013
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/0022-1317-82-7-1737
Loading
/content/journal/jgv/10.1099/0022-1317-82-7-1737
Loading

Data & Media loading...

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error