1887

Abstract

Immunological control of hepatitis C virus (HCV) is possible and is probably mediated by host T-cell responses, but the genetic diversity of the virus poses a major challenge to vaccine development. We considered monovalent and polyvalent candidates for an HCV vaccine, including natural, consensus and synthetic ‘mosaic’ sequence cocktails. Mosaic vaccine reagents were designed using a computational approach first applied to and demonstrated experimentally for human immunodeficiency virus type 1 (HIV-Δ). Mosaic proteins resemble natural proteins, but are assembled from fragments of natural sequences via a genetic algorithm and optimized to maximize the coverage of potential T-cell epitopes (all 9-mers) found in natural sequences and to minimize the inclusion of rare 9-mers to avoid vaccine-specific responses. Genotype 1-specific and global vaccine cocktails were evaluated. Among vaccine candidates considered, polyvalent mosaic sequences provided the best coverage of both known and potential epitopes and had the fewest rare epitopes. A global vaccine based on conserved proteins across genotypes may be feasible, as a five-antigen mosaic cocktail provided 90, 77 and 70 % coverage of the Core, NS3 and NS4 proteins, respectively; protein coverage diminished with increased protein variability, dropping to 38 % for NS2. For the genotype 1-specific vaccine, the H77 prototype vaccine sequence matched only 50 % of the potential epitopes in the population, whilst a polyprotein three-antigen mosaic cocktail increased potential epitope coverage to 83 %. More than 75 % coverage of all HCV proteins was achieved with a three-antigen mosaic cocktail, suggesting that genotype-specific vaccines could also include the more variable proteins.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.017491-0
2010-05-01
2019-11-21
Loading full text...

Full text loading...

/deliver/fulltext/jgv/91/5/1194.html?itemId=/content/journal/jgv/10.1099/vir.0.017491-0&mimeType=html&fmt=ahah

References

  1. Alter, M. J., Kruszon-Moran, D., Nainan, O. V., McQuillan, G. M., Gao, F., Moyer, L. A., Kaslow, R. A. & Margolis, H. S. ( 1999; ). The prevalence of hepatitis C virus infection in the United States, 1988 through 1994. N Engl J Med 341, 556–562.[CrossRef]
    [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. Barouch, D., O'Brien, K., Simmons, N., King, S., Abbink, P., Maxfield, L., Sun, Y. H., La Porte, A., Riggs, A. & other authors ( 2010; ). Mosaic HIV-1 antigens expand the breadth and depth of cellular immune responses in rhesus monkeys. Nat Med 16, 319–323.[CrossRef]
    [Google Scholar]
  4. Catanzaro, A. T., Koup, R. A., Roederer, M., Bailer, R. T., Enama, M. E., Moodie, Z., Gu, L., Martin, J. E., Novik, L. & other authors ( 2006; ). Phase 1 safety and immunogenicity evaluation of a multiclade HIV-1 candidate vaccine delivered by a replication-defective recombinant adenovirus vector. J Infect Dis 194, 1638–1649.[CrossRef]
    [Google Scholar]
  5. Cerny, A. & Chisari, F. V. ( 1999; ). Pathogenesis of chronic hepatitis C: immunological features of hepatic injury and viral persistence. Hepatology 30, 595–601.[CrossRef]
    [Google Scholar]
  6. Conry-Cantilena, C., VanRaden, M., Gibble, J., Melpolder, J., Shakil, A. O., Viladomiu, L., Cheung, L., DiBisceglie, A., Hoofnagle, J. & other authors ( 1996; ). Routes of infection, viremia, and liver disease in blood donors found to have hepatitis C virus infection. N Engl J Med 334, 1691–1696.[CrossRef]
    [Google Scholar]
  7. 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]
  8. Cucchiarini, M., Kammer, A. R., Grabscheid, B., Diepolder, H. M., Gerlach, T. J., Gruner, N., Santantonio, T., Reichen, J., Pape, G. R. & Cerny, A. ( 2000; ). Vigorous peripheral blood cytotoxic T cell response during the acute phase of hepatitis C virus infection. Cell Immunol 203, 111–123.[CrossRef]
    [Google Scholar]
  9. Darling, J. M. & Wright, T. L. ( 2004; ). Immune responses in hepatitis C: is virus or host the problem? Curr Opin Infect Dis 17, 193–198.[CrossRef]
    [Google Scholar]
  10. Davis, G. L., Esteban-Mur, R., Rustgi, V., Hoefs, J., Gordon, S. C., Trepo, C., Shiffman, M. L., Zeuzem, S., Craxi, A. & other authors ( 1998; ). Interferon alfa-2b alone or in combination with ribavirin for the treatment of relapse of chronic hepatitis C. International Hepatitis Interventional Therapy Group. N Engl J Med 339, 1493–1499.[CrossRef]
    [Google Scholar]
  11. Doria-Rose, N. A., Learn, G. H., Rodrigo, A. G., Nickle, D. C., Li, F., Mahalanabis, M., Hensel, M. T., McLaughlin, S., Edmonson, P. F. & other authors ( 2005; ). Human immunodeficiency virus type 1 subtype B ancestral envelope protein is functional and elicits neutralizing antibodies in rabbits similar to those elicited by a circulating subtype B envelope. J Virol 79, 11214–11224.[CrossRef]
    [Google Scholar]
  12. Erickson, A. L., Kimura, Y., Igarashi, S., Eichelberger, J., Houghton, M., Sidney, J., McKinney, D., Sette, A., Hughes, A. L. & Walker, C. M. ( 2001; ). The outcome of hepatitis C virus infection is predicted by escape mutations in epitopes targeted by cytotoxic T lymphocytes. Immunity 15, 883–895.[CrossRef]
    [Google Scholar]
  13. Farci, P. & Purcell, R. H. ( 2000; ). Clinical significance of hepatitis C virus genotypes and quasispecies. Semin Liver Dis 20, 103–126.
    [Google Scholar]
  14. Farci, P., Alter, H. J., Govindarajan, S., Wong, D. C., Engle, R., Lesniewski, R. R., Mushahwar, I. K., Desai, S. M., Miller, R. H. & other authors ( 1992; ). Lack of protective immunity against reinfection with hepatitis C virus. Science 258, 135–140.[CrossRef]
    [Google Scholar]
  15. Fischer, W., Perkins, S., Theiler, J., Bhattacharya, T., Yusim, K., Funkhouser, R., Kuiken, C., Haynes, B., Letvin, N. L. & other authors ( 2007; ). Polyvalent vaccines for optimal coverage of potential T-cell epitopes in global HIV-1 variants. Nat Med 13, 100–106.[CrossRef]
    [Google Scholar]
  16. Fischer, W., Liao, H. X., Haynes, B. F., Letvin, N. L. & Korber, B. ( 2008; ). Coping with viral diversity in HIV vaccine design: a response to Nickle et al. PLOS Comput Biol 4, e15 [CrossRef]
    [Google Scholar]
  17. Fried, M. W., Shiffman, M. L., Reddy, K. R., Smith, C., Marinos, G., Goncales, F. L., Jr, Haussinger, D., Diago, M., Carosi, G. & other authors ( 2002; ). Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 347, 975–982.[CrossRef]
    [Google Scholar]
  18. Gao, F., Weaver, E. A., Lu, Z., Li, Y., Liao, H. X., Ma, B., Alam, S. M., Scearce, R. M., Sutherland, L. L. & other authors ( 2005; ). Antigenicity and immunogenicity of a synthetic human immunodeficiency virus type 1 group m consensus envelope glycoprotein. J Virol 79, 1154–1163.[CrossRef]
    [Google Scholar]
  19. Gaschen, B., Taylor, J., Yusim, K., Foley, B., Gao, F., Lang, D., Novitsky, V., Haynes, B., Hahn, B. H. & other authors ( 2002; ). Diversity considerations in HIV-1 vaccine selection. Science 296, 2354–2360.[CrossRef]
    [Google Scholar]
  20. Gerlach, J. T., Diepolder, H. M., Jung, M. C., Gruener, N. H., Schraut, W. W., Zachoval, R., Hoffmann, R., Schirren, C. A., Santantonio, T. & Pape, G. R. ( 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]
  21. Gerlach, J. T., Diepolder, H. M., Zachoval, R., Gruener, N. H., Jung, M. C., Ulsenheimer, A., Schraut, W. W., Schirren, C. A., Waechtler, M. & other authors ( 2003; ). Acute hepatitis C: high rate of both spontaneous and treatment-induced viral clearance. Gastroenterology 125, 80–88.[CrossRef]
    [Google Scholar]
  22. Gruner, N. H., Gerlach, T. J., Jung, M. C., Diepolder, H. M., Schirren, C. A., Schraut, W. W., Hoffmann, R., Zachoval, R., Santantonio, T. & other authors ( 2000; ). Association of hepatitis C virus-specific CD8+ T cells with viral clearance in acute hepatitis C. J Infect Dis 181, 1528–1536.[CrossRef]
    [Google Scholar]
  23. Harcourt, G. C., Lucas, M., Godkin, A. J., Kantzanou, M., Phillips, R. E. & Klenerman, P. ( 2003; ). Evidence for lack of cross-genotype protection of CD4+ T cell responses during chronic hepatitis C virus infection. Clin Exp Immunol 131, 122–129.[CrossRef]
    [Google Scholar]
  24. Houghton, M. & Abrignani, S. ( 2005; ). Prospects for a vaccine against the hepatitis C virus. Nature 436, 961–966.[CrossRef]
    [Google Scholar]
  25. Inchauspe, G. & Michel, M. L. ( 2007; ). Vaccines and immunotherapies against hepatitis B and hepatitis C viruses. J Viral Hepat 14 (Suppl. 1), 97–103.[CrossRef]
    [Google Scholar]
  26. Inchauspe, G., Bach, G., Martin, P. & Bonnefoy, J. Y. ( 2009; ). Vaccination against hepatitis B and C: towards therapeutic application. Int Rev Immunol 28, 7–19.[CrossRef]
    [Google Scholar]
  27. Jutavijittum, P., Jiviriyawat, Y., Yousukh, A., Pantip, C., Maneekarn, N. & Toriyama, K. ( 2009; ). Genotypic distribution of hepatitis C virus in voluntary blood donors of northern Thailand. Southeast Asian J Trop Med Public Health 40, 471–479.
    [Google Scholar]
  28. Kong, W. P., Wu, L., Wallstrom, T. C., Fischer, W., Yang, Z. Y., Ko, S. Y., Letvin, N. L., Haynes, B. F., Hahn, B. H. & other authors ( 2009; ). Expanded breadth of the T-cell response to mosaic human immunodeficiency virus type 1 envelope DNA vaccination. J Virol 83, 2201–2215.[CrossRef]
    [Google Scholar]
  29. Korber, B. T., MacInnes, K., Smith, R. F. & Myers, G. ( 1994; ). Mutational trends in V3 loop protein sequences observed in different genetic lineages of human immunodeficiency virus type 1. J Virol 68, 6730–6744.
    [Google Scholar]
  30. Korber, B. T., Letvin, N. L. & Haynes, B. F. ( 2009; ). T cell vaccine strategies for human immunodeficiency virus, the virus with a thousand faces. J Virol 83, 8300–8314.[CrossRef]
    [Google Scholar]
  31. Lauer, G. M. & Walker, B. D. ( 2001; ). Hepatitis C virus infection. N Engl J Med 345, 41–52.[CrossRef]
    [Google Scholar]
  32. Lauer, G. M., Barnes, E., Lucas, M., Timm, J., Ouchi, K., Kim, A. Y., Day, C. L., Robbins, G. K., Casson, D. R. & other authors ( 2004; ). High resolution analysis of cellular immune responses in resolved and persistent hepatitis C virus infection. Gastroenterology 127, 924–936.[CrossRef]
    [Google Scholar]
  33. Lechner, F., Wong, D. K., Dunbar, P. R., Chapman, R., Chung, R. T., Dohrenwend, P., Robbins, G., Phillips, R., Klenerman, P. & Walker, B. D. ( 2000; ). Analysis of successful immune responses in persons infected with hepatitis C virus. J Exp Med 191, 1499–1512.[CrossRef]
    [Google Scholar]
  34. Letourneau, S., Im, E. J., Mashishi, T., Brereton, C., Bridgeman, A., Yang, H., Dorrell, L., Dong, T., Korber, B. & other authors ( 2007; ). Design and pre-clinical evaluation of a universal HIV-1 vaccine. PLoS One 2, e984 [CrossRef]
    [Google Scholar]
  35. Li, F., Malhotra, U., Gilbert, P. B., Hawkins, N. R., Duerr, A. C., McElrath, J. M., Corey, L. & Self, S. G. ( 2006; ). Peptide selection for human immunodeficiency virus type 1 CTL-based vaccine evaluation. Vaccine 24, 6893–6904.[CrossRef]
    [Google Scholar]
  36. Manns, M. P., McHutchison, J. G., Gordon, S. C., Rustgi, V. K., Shiffman, M., Reindollar, R., Goodman, Z. D., Koury, K., Ling, M. & Albrecht, J. K. ( 2001; ). Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 358, 958–965.[CrossRef]
    [Google Scholar]
  37. Mehta, S. H., Cox, A., Hoover, D. R., Wang, X. H., Mao, Q., Ray, S., Strathdee, S. A., Vlahov, D. & Thomas, D. L. ( 2002; ). Protection against persistence of hepatitis C. Lancet 359, 1478–1483.[CrossRef]
    [Google Scholar]
  38. Pawlotsky, J. M. ( 2003; ). The nature of interferon-alpha resistance in hepatitis C virus infection. Curr Opin Infect Dis 16, 587–592.[CrossRef]
    [Google Scholar]
  39. Prince, A. M., Brotman, B., Lee, D. H., Pfahler, W., Tricoche, N., Andrus, L. & Shata, M. T. ( 2005; ). Protection against chronic hepatitis C virus infection after rechallenge with homologous, but not heterologous, genotypes in a chimpanzee model. J Infect Dis 192, 1701–1709.[CrossRef]
    [Google Scholar]
  40. Rappuoli, R. ( 2001; ). Reverse vaccinology, a genome-based approach to vaccine development. Vaccine 19, 2688–2691.[CrossRef]
    [Google Scholar]
  41. Santra, S., Korber, B. T., Muldoon, M., Barouch, D. H., Nabel, G. J., Gao, F., Hahn, B. H., Haynes, B. F. & Letvin, N. L. ( 2008; ). A centralized gene-based HIV-1 vaccine elicits broad cross-clade cellular immune responses in rhesus monkeys. Proc Natl Acad Sci U S A 105, 10489–10494.[CrossRef]
    [Google Scholar]
  42. Santra, S., Hua-Xin, L., Zhang, R., Muldoon, M., Watson, S., Fischer, W., Theiler, J., Balachandran, H., Busby, A. & other authors ( 2010; ). Mosaic vaccines elicit CD8+ T cell responses in monkeys that confer immune coverage of diverse HIV strains. Nat Med (in press).
    [Google Scholar]
  43. Serruto, D., Serino, L., Masignani, V. & Pizza, M. ( 2009; ). Genome-based approaches to develop vaccines against bacterial pathogens. Vaccine 27, 3245–3250.[CrossRef]
    [Google Scholar]
  44. Shoukry, N. H., Grakoui, A., Houghton, M., Chien, D. Y., Ghrayeb, J., Reimann, K. A. & Walker, C. M. ( 2003; ). Memory CD8+ T cells are required for protection from persistent hepatitis C virus infection. J Exp Med 197, 1645–1655.[CrossRef]
    [Google Scholar]
  45. Stoll-Keller, F., Barth, H., Fafi-Kremer, S., Zeisel, M. B. & Baumert, T. F. ( 2009; ). Development of hepatitis C virus vaccines: challenges and progress. Expert Rev Vaccines 8, 333–345.[CrossRef]
    [Google Scholar]
  46. Swofford, D. L. ( 2003; ). paup*: phylogenetic analysis using parsimony (*and other methods), version 4. Sunderland, MA: Sinauer Associates.
  47. Thimme, R., Oldach, D., Chang, K. M., Steiger, C., Ray, S. C. & Chisari, F. V. ( 2001; ). Determinants of viral clearance and persistence during acute hepatitis C virus infection. J Exp Med 194, 1395–1406.[CrossRef]
    [Google Scholar]
  48. Thurmond, J., Yoon, H., Kuiken, C., Yusim, K., Perkins, S., Theiler, J., Bhattacharya, T., Korber, B. & Fischer, W. ( 2008; ). Web-based design and evaluation of T-cell vaccine candidates. Bioinformatics 24, 1639–1640.[CrossRef]
    [Google Scholar]
  49. Verma, V., Chakravarti, A. & Kar, P. ( 2008; ). Genotypic characterization of hepatitis C virus and its significance in patients with chronic liver disease from Northern India. Diagn Microbiol Infect Dis 61, 408–414.[CrossRef]
    [Google Scholar]
  50. Ward, S., Lauer, G., Isba, R., Walker, B. & Klenerman, P. ( 2002; ). Cellular immune responses against hepatitis C virus: the evidence base 2002. Clin Exp Immunol 128, 195–203.[CrossRef]
    [Google Scholar]
  51. Yusim, K., Kesmir, C., Gaschen, B., Addo, M. M., Altfeld, M., Brunak, S., Chigaev, A., Detours, V. & Korber, B. T. ( 2002; ). Clustering patterns of cytotoxic T-lymphocyte epitopes in human immunodeficiency virus type 1 (HIV-1) proteins reveal imprints of immune evasion on HIV-1 global variation. J Virol 76, 8757–8768.[CrossRef]
    [Google Scholar]
  52. Yusim, K., Richardson, R., Tao, N., Dalwani, A., Agrawal, A., Szinger, J., Funkhouser, R., Korber, B. & Kuiken, C. ( 2005; ). Los Alamos hepatitis C immunology database. Appl Bioinformatics 4, 217–225.[CrossRef]
    [Google Scholar]
  53. Zeuzem, S. ( 2004; ). Heterogeneous virologic response rates to interferon-based therapy in patients with chronic hepatitis C: who responds less well? Ann Intern Med 140, 370–381.
    [Google Scholar]
  54. Zeuzem, S., Feinman, S. V., Rasenack, J., Heathcote, E. J., Lai, M. Y., Gane, E., O'Grady, J., Reichen, J., Diago, M. & other authors ( 2000; ). Peginterferon alfa-2a in patients with chronic hepatitis C. N Engl J Med 343, 1666–1672.[CrossRef]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/vir.0.017491-0
Loading
/content/journal/jgv/10.1099/vir.0.017491-0
Loading

Data & Media loading...

Supplements

Vaccine designs corresponding to Table 1 [ .txt file] (265 KB)

TEXT

Coverage of published epitopes and their variants by H77 and three-mosaic cocktail optimized for genotype 1 sequences [ PDF] (309 KB)

PDF

Schematic representation of mosaic algorithm [ PDF] (165 KB)

PDF

Most Cited This Month

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