Molec Approach To Vaccine Development For Hepatitis C

Diabetes, Digestive, Kidney Diseases

Investigators

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Abstract

Hepatitis C virus (HCV) is a leading cause of chronic hepatitis and hepatocellular carcinoma worldwide and infects more than 1% of the world population. Successful vaccine development is pivotal in controlling this global health problem. A system for efficient assembly of HCV structural proteins into HCV-like particles (HCV-LPs) in insect cells has been developed in our laboratory. These noninfectious HCV-like particles have similar morphologic, serologic and biophysical properties as the putative virions isolated from HCV infected humans. In contrast to recombinant subunit vaccines, the viral proteins of HCV-like particles may be presented in a native, virion-like conformation and may therefore be superior in eliciting a protective humoral and cellular immune response. The humoral and cellular immunogenicity of the HCV-LP had been studied in BALB/c or AAD (C57BL/6 transgenic for HLA-A2.1) mice. Immunized mice developed high titers of anti-E2 antibodies and virus-specific cellular immune responses including cytotoxic T lymphocytes and T helper responses with gamma interferon production. To evaluate the potential of HCV-LP as a protective immunogen in a surrogate model, we challenged HCV-LP-immunized mice with a recombinant vaccinia virus expressing core, E1 and E2 (vvHCV-ST). Mice immunized with HCV-LP were protected from challenge with the recombinant vvHCV.S but not the control virus (vvlacZ). In comparison, DNA immunization with a construct expressing the HCV structural genes resulted in much less protection from HCV-vaccinia challenge. We also evaluated the effects of adjuvant AS01B (monophosphoryl lipid A and QS21) and CpG oligodeoxynucleotides (ODN) 10105 on the immunogenicity of HCV-LPs in mice, and showed that the adjuvants, especially the combination of both, enhanced the immune response with a more TH1 bias. We tested the HCV-LP and the adjuvants in a nonhuman primate model (baboon) and demonstrated induction of robust and broad humoral and cellular immune responses that were marginally enhanced by the AS01 adjuvants. The overall HCV-specific immune responses were robust and long-lasting (>8 months). We have begun the immunization and challenge experiment in chimpanzees. Two groups of chimpanzees (two each) were immunized with HCV-LP or HCV-LP + adjuvant ASO1B. After four immunizations over an 8-month period, all animals developed strong HCV-specific cellular immune response including IFN-gamma+CD4+ and IFN-gamma+CD8+ T-cell and proliferative lymphocyte responses against core, E1 and E2. The immunogenicity of HCV-LP was not enhanced by the adjuvant. The chimpanzees in both groups were challenged with100 CID50 of HCV CG1b inoculum. Upon challenge with HCV, one chimpanzee developed transient viremia with low HCV RNA titers (~10E4 copies/ml) in the third and fourth weeks post-challenge. The three other chimpanzees became infected with higher levels of viremia (up to 10E5 copies/ml) but their viral levels became nonquantifiable (<1000 copies/ml) on the fourteenth week post-challenge. Previously, three other naive chimpanzees have been challenged with the same HCV inoculum at lower CID50 (<10), and two developed persistent infection with viremia in the range of 10E5-6 copies/ml. Our results suggest that HCV-LP immunization induces strong HCV-specific cellular immune responses and confers partial protection against HCV challenge in chimpanzee.