1887

Abstract

Although approximately 3 % of the world's population is infected with (HCV), there is no prophylactic vaccine available. This study reports the design, cloning and purification of a single polyprotein comprising the HCV core protein and non-structural proteins NS3, NS4a, NS4b, NS5a and NS5b. The immunogenicity of this polyprotein, which was formulated in alum, oil-in-water emulsion MF59 or poly(-lactide co-glycolide) in the presence or absence of CpG adjuvant, was then determined in a murine model for induction of B- and T-cell responses. The addition of adjuvants or a delivery system to the HCV polyprotein enhanced serum antibody and T-cell proliferative responses, as well as IFN- responses, by CD4 T cells. The antibody responses were mainly against the NS3 and NS5 components of the polyprotein and relatively poor responses were elicited against NS4 and the core components. IFN- responses, however, were induced against all of the individual components of the polyprotein. These data suggest that the HCV polyprotein delivered with adjuvants induces broad B- and T-cell responses and could be a vaccine candidate against HCV.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.81849-0
2006-08-01
2021-03-09
Loading full text...

Full text loading...

/deliver/fulltext/jgv/87/8/2253.html?itemId=/content/journal/jgv/10.1099/vir.0.81849-0&mimeType=html&fmt=ahah

References

  1. Alter M. J. 1993; The detection, transmission, and outcome of hepatitis C virus infection. Infect Agents Dis 2:155–166
    [Google Scholar]
  2. Armstrong G. L., Alter M. J., McQuillan G. M., Margolis H. S. 2000; The past incidence of hepatitis C virus infection: implications for the future burden of chronic liver disease in the United States. Hepatology 31:777–782 [CrossRef]
    [Google Scholar]
  3. Bird A. P. 1987; CpG islands as gene markers in the vertebrate nucleus. Trends Genet 3:342–347 [CrossRef]
    [Google Scholar]
  4. Cataldo D. M., Van Nest G. 1997; The adjuvant MF59 increases the immunogenicity and protective efficacy of subunit influenza vaccine in mice. Vaccine 15:1710–1715 [CrossRef]
    [Google Scholar]
  5. Choo Q.-L., Kuo G., Weiner A. J., Overby L. R., Bradley D. W., Houghton M. 1989; Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science 244:359–362 [CrossRef]
    [Google Scholar]
  6. Choo Q.-L., Richman K. H., Han J. H. & 11 other authors 1991; Genetic organization and diversity of the hepatitis C virus. Proc Natl Acad Sci U S A 88:2451–2455 [CrossRef]
    [Google Scholar]
  7. Choo Q. L., Kuo G., Ralston R. & 15 other authors 1994; Vaccination of chimpanzees against infection by the hepatitis C virus. Proc Natl Acad Sci U S A 91:1294–1298 [CrossRef]
    [Google Scholar]
  8. Coates S., Choo Q. L., Kuo G. & 16 other authors 2004; Protection of chimpanzees against heterologous 1a viral challenge using a gpE1/gpE2 heterodimer vaccine. In Proceedings of the 11th International Symposium on Viral Hepatitis and Liver Disease Edited by Jilbert A. R., Grgacic E. V. L., Vickery K., Burrell C., Cossart Y. E. Melbourne: Australian Centre for Hepatitis Virology;
    [Google Scholar]
  9. Cohen J. 1999; The scientific challenge of hepatitis C. Science 285:26–30 [CrossRef]
    [Google Scholar]
  10. Cooper S., Erickson A. L., Adams E. J., Kansopon J., Weiner A. J., Chien D. Y., Houghton M., Parham P., Walker C. M. 1999; Analysis of a successful immune response against hepatitis C virus. Immunity 10:439–449 [CrossRef]
    [Google Scholar]
  11. Diepolder H. M., Zachoval R., Hoffmann R. M., Wierenga E. A., Santantonio T., Jung M. C., Eichenlaub D., Pape G. R. 1995; Possible mechanism involving T-lymphocyte response to non-structural protein 3 in viral clearance in acute hepatitis C virus infection. Lancet 346:1006–1007 [CrossRef]
    [Google Scholar]
  12. Eyles J. E., Carpenter Z. C., Alpar H. O., Williamson E. D. 2003; Immunological aspects of polymer microsphere vaccine delivery systems. J Drug Target 11:509–514 [CrossRef]
    [Google Scholar]
  13. Ferrari G., Humphrey W., McElrath M. J., Excler J.-L., Duliege A.-M., Clements M. L., Corey L. C., Bolognesi D. P., Weinhold K. J. 1997; Clade B-based HIV-1 vaccines elicit cross-clade cytotoxic T lymphocyte reactivities in uninfected volunteers. Proc Natl Acad Sci U S A 94:1396–1401 [CrossRef]
    [Google Scholar]
  14. Gerlach J. T., Diepolder H. M., Jung M.-C. & 7 other authors 1999; Recurrence of hepatitis C virus after loss of virus-specific CD4+ T-cell response in acute hepatitis C. Gastroenterology 117:933–941 [CrossRef]
    [Google Scholar]
  15. Goh P.-Y., Tan Y.-J., Lim S. P., Lim S. G., Tan Y. H., Hong W. J. 2001; The hepatitis C virus core protein interacts with NS5A and activates its caspase-mediated proteolytic cleavage. Virology 290:224–236 [CrossRef]
    [Google Scholar]
  16. Grakoui A., Shoukry N. H., Woollard D. J., Han J.-H., Hanson H. L., Ghrayeb J., Murthy K. K., Rice C. M., Walker C. M. 2003; HCV persistence and immune evasion in the absence of memory T cell help. Science 302:659–662 [CrossRef]
    [Google Scholar]
  17. Heineman T. C., Clements-Mann M. L., Poland G. A., Jacobson R. M., Izu A. E., Sakamoto D., Eiden J., van Nest G. A., Hsu H. H. 1999; A randomized, controlled study in adults of the immunogenicity of a novel hepatitis B vaccine containing MF59 adjuvant. Vaccine 17:2769–2778 [CrossRef]
    [Google Scholar]
  18. Hemmi H., Takeuchi O., Kawai T. & 9 other authors 2000; A toll-like receptor recognizes bacterial DNA. Nature 408:740–745 [CrossRef]
    [Google Scholar]
  19. Higgins D. A., Carlson J. R., Van Nest G. 1996; MF59 adjuvant enhances the immunogenicity of influenza vaccine in both young and old mice. Vaccine 14:478–484 [CrossRef]
    [Google Scholar]
  20. Kanke M., Sniecinski I., DeLuca P. P. 1983; Interaction of microspheres with blood constituents: I. Uptake of polystyrene spheres by monocytes and granulocytes and effect on immune responsiveness of lymphocytes. J Parenter Sci Technol 37:210–217
    [Google Scholar]
  21. Kazzaz J., Neidleman J., Singh M., Ott G., O'Hagan D. T. 2000; Novel anionic microparticles are a potent adjuvant for the induction of cytotoxic T lymphocytes against recombinant p55 gag from HIV-1. J Control Release 67:347–356 [CrossRef]
    [Google Scholar]
  22. Klinman D. M., Currie D., Gursel I., Verthelyi D. 2004; Use of CpG oligodeoxynucleotides as immune adjuvants. Immunol Rev 199:201–216 [CrossRef]
    [Google Scholar]
  23. Krieg A. M., Yi A.-K., Matson S., Waldschmidt T. J., Bishop G. A., Teasdale R., Koretzky G. A., Klinman D. M. 1995; CpG motifs in bacterial DNA trigger direct B-cell activation. Nature 374:546–549 [CrossRef]
    [Google Scholar]
  24. Lechner F., Wong D. K. H., Dunbar P. R. & 7 other authors 2000; Analysis of successful immune responses in persons infected with hepatitis C virus. J Exp Med 191:1499–1512 [CrossRef]
    [Google Scholar]
  25. Lin S., Arcangel P., Medina-Selby A. & 9 other authors 2005; Design of novel conformational and genotype-specific antigens for improving sensitivity of immunoassays for hepatitis C virus-specific antibodies. J Clin Microbiol 43:3917–3924 [CrossRef]
    [Google Scholar]
  26. Lindblad E. B. 2004; Aluminium compounds for use in vaccines. Immunol Cell Biol 82:497–505 [CrossRef]
    [Google Scholar]
  27. Liu Z.-X., Nishida H., He J.-W., Lai M. M. C., Feng N., Dennert G. 2002; Hepatitis C virus genotype 1b core protein does not exert immunomodulatory effects on virus-induced cellular immunity. J Virol 76:990–997 [CrossRef]
    [Google Scholar]
  28. Major M. E., Mihalik K., Puig M., Rehermann B., Nascimbeni M., Rice C. M., Feinstone S. M. 2002; Previously infected and recovered chimpanzees exhibit rapid responses that control hepatitis C virus replication upon rechallenge. J Virol 76:6586–6595 [CrossRef]
    [Google Scholar]
  29. McHutchison J. G., Gordon S. C., Schiff E. R. & 7 other authors 1998; Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. Hepatitis Interventional Therapy Group. N Engl J Med 339:1485–1492 [CrossRef]
    [Google Scholar]
  30. Missale G., Bertoni R., Lamonaca V. & 7 other authors 1996; Different clinical behaviors of acute hepatitis C virus infection are associated with different vigor of the anti-viral cell-mediated immune response. J Clin Invest 98:706–714 [CrossRef]
    [Google Scholar]
  31. Murphy J. E., Uno T., Hamer J. D., Cohen F. E., Dwarki V., Zuckermann R. N. 1998; A combinatorial approach to the discovery of efficient cationic peptoid reagents for gene delivery. Proc Natl Acad Sci U S A 95:1517–1522 [CrossRef]
    [Google Scholar]
  32. Nelson D. R., Marousis C. G., Davis G. L., Rice C. M., Wong J., Houghton M., Lau J. Y. 1997; The role of hepatitis C virus-specific cytotoxic T lymphocytes in chronic hepatitis C. J Immunol 158:1473–1481
    [Google Scholar]
  33. O'Hagan D. T., Singh M. 2003; Microparticles as vaccine adjuvants and delivery systems. Expert Rev Vaccines 2:269–283 [CrossRef]
    [Google Scholar]
  34. O'Hagan D. T., Ott G. S., van Nest G. 1997; Recent advances in vaccine adjuvants: the development of MF59 emulsion and polymeric microparticles. Mol Med Today 3:69–75 [CrossRef]
    [Google Scholar]
  35. O'Hagan D. T., Singh M., Kazzaz J., Ugozzoli M., Briones M., Donnelly J., Ott G. 2002; Synergistic adjuvant activity of immunostimulatory DNA and oil/water emulsions for immunization with HIV p55 gag antigen. Vaccine 20:3389–3398 [CrossRef]
    [Google Scholar]
  36. O'Hagan D. T., Singh M., Dong C. & 10 other authors 2004; Cationic microparticles are a potent delivery system for a HCV DNA vaccine. Vaccine 23:672–680 [CrossRef]
    [Google Scholar]
  37. Ott G., Barchfeld G. L., Chernoff D., Radhakrishnan R., van Hoogevest P., van Nest G. 1995; MF59: design and evaluation of a safe and potent adjuvant for human vaccines. In Vaccine Design: the Subunit and Adjuvant Approach pp  277–296 Edited by Powell M. F., Newman M. J. New York: Plenum;
    [Google Scholar]
  38. Otten G. R., Schaefer M., Greer C. & 12 other authors 2003; Induction of broad and potent anti-HIV immune responses in rhesus macaques by priming with a DNA vaccine and boosting with protein-adsorbed polylactide coglycolide microparticles. J Virol 77:6087–6092 [CrossRef]
    [Google Scholar]
  39. Podda A., Del Giudice G. 2003; MF59-adjuvanted vaccines: increased immunogenicity with an optimal safety profile. Expert Rev Vaccines 2:197–203 [CrossRef]
    [Google Scholar]
  40. Poynard T., Marcellin P., Lee S. S. & 8 other authors 1998; Randomised trial of interferon α 2b plus ribavirin for 48 weeks or for 24 weeks versus interferon α 2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. International Hepatitis Interventional Therapy Group (IHIT). Lancet 352:1426–1432 [CrossRef]
    [Google Scholar]
  41. Pulendran B. 2004; Modulating vaccine responses with dendritic cells and Toll-like receptors. Immunol Rev 199:227–250 [CrossRef]
    [Google Scholar]
  42. Ray R. B., Meyer K., Steele R., Shrivastava A., Aggarwal B. B., Ray R. 1998; Inhibition of tumor necrosis factor (TNF- α )-mediated apoptosis by hepatitis C virus core protein. J Biol Chem 273:2256–2259 [CrossRef]
    [Google Scholar]
  43. Raz E., Spiegelberg H. L. 1999; Deviation of the allergic IgE to an IgG response by gene immunotherapy. Int Rev Immunol 18:271–289 [CrossRef]
    [Google Scholar]
  44. Schetter C., Vollmer J. 2004; Toll-like receptors involved in the response to microbial pathogens: development of agonists for toll-like receptor 9. Curr Opin Drug Discov Devel 7:204–210
    [Google Scholar]
  45. Selby M. J., Choo Q. L., Berger K. & 7 other authors 1993; Expression, identification and subcellular localization of the proteins encoded by the hepatitis C viral genome. J Gen Virol 74:1103–1113 [CrossRef]
    [Google Scholar]
  46. Singh M., Ott G., Kazzaz J., Ugozzoli M., Briones M., Donnelly J., O'Hagan D. T. 2001; Cationic microparticles are an effective delivery system for immune stimulatory CpG DNA. Pharm Res 18:1476–1479 [CrossRef]
    [Google Scholar]
  47. Singh M., Kazzaz J., Chesko J., Soenawan E., Ugozzoli M., Giuliani M., Pizza M., Rappuoli R., O'Hagan D. T. 2004a; Anionic microparticles are a potent delivery system for recombinant antigens from Neisseria meningitidis serotype B. J Pharm Sci 93:273–282 [CrossRef]
    [Google Scholar]
  48. Singh M., Kazzaz J., Ugozzoli M., Chesko J., O'Hagan D. T. 2004b; Charged polylactide co-glycolide microparticles as antigen delivery systems. Expert Opin Biol Ther 4:483–491 [CrossRef]
    [Google Scholar]
  49. Sparwasser T., Koch E.-S., Vabulas R. M., Heeg K., Lipford G. B., Ellwart J. W., Wagner H. 1998; Bacterial DNA and immunostimulatory CpG oligonucleotides trigger maturation and activation of murine dendritic cells. Eur J Immunol 28:2045–2054 [CrossRef]
    [Google Scholar]
  50. Tabata Y., Ikada Y. 1988; Macrophage phagocytosis of biodegradable microspheres composed of l-lactic acid/glycolic acid homo- and copolymers. J Biomed Mater Res 22:837–858 [CrossRef]
    [Google Scholar]
  51. Tabata Y., Ikada Y. 1990; Phagocytosis of polymer microspheres by macrophages. Adv Polym Sci 94:107–141
    [Google Scholar]
  52. Traquina P., Morandi M., Contorni M., van Nest G. 1996; MF59 adjuvant enhances the antibody response to recombinant hepatitis B surface antigen vaccine in primates. J Infect Dis 174:1168–1175 [CrossRef]
    [Google Scholar]
  53. Tsai S.-L., Liaw Y.-F., Chen M.-H., Huang C.-Y., Kuo G. C. 1997; Detection of type 2-like T-helper cells in hepatitis C virus infection: implications for hepatitis C virus chronicity. Hepatology 25:449–458 [CrossRef]
    [Google Scholar]
  54. Valensi J. P., Carlson J. R., van Nest G. A. 1994; Systemic cytokine profiles in BALB/c mice immunized with trivalent influenza vaccine containing MF59 oil emulsion and other advanced adjuvants. J Immunol 153:4029–4039
    [Google Scholar]
  55. Xavier R. M., Nakamura M., Tsunematsu T. 1994; Isolation and characterization of a human nonspecific suppressor factor from ascitic fluid of systemic lupus erythematosus. Evidence for a human counterpart of the monoclonal nonspecific suppressor factor and relationship to the T cell receptor alpha-chain. J Immunol 152:2624–2632
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/vir.0.81849-0
Loading
/content/journal/jgv/10.1099/vir.0.81849-0
Loading

Data & Media loading...

Most cited this month Most Cited RSS feed

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