Up to 170 million people worldwide are chronically infected with HCV, with many at significant risk for cirrhosis, liver failure and hepatocellular carcinoma. The World Health Organization estimates an annual increase in the global burden by 2 million new infections (Shepard et al. (2005) Lancet Infect Dis 5:558-567). Efforts at vaccine development have yet to succeed despite two decades of work. A key step towards reaching this goal is to identify and exploit relevant mechanisms of immune protection. Although there are no clearly established in vitro correlates of protective immunity, multiple lines of evidence suggest that CD4+ and CD8+ T cell responses, while critical for controlling acute HCV infection, are inadequate for prevention of long-term persistence in most infected individuals (Bowen et al. (2005) Nature 436:946-952). Emerging evidence supports the importance of virus-neutralizing (Vn) antibodies, and the ability of B cell responses to modify the course of infection.
The development of in vitro cell culture models, based on HCV retroviral pseudotype particles expressing E1E2 (HCVpp) and infectious cell culture-derived HCV virions (HCVcc), has facilitated the measurement of antibody-mediated virus neutralization, and thus to evaluate the impact of antibody in the control of infection (Bartosch et al. (2003) J Exp Med 197:633-642, Cai et al. (2005) J Virol 79:13963-13973, Hsu et al. (2003) Proc Natl Acad Sci USA 100:7271-7276, Lindenbach et al. (2005) Science 309:623-626, Wakita et al. (2005) Nat Med 11:791-796, Zhong et al. (2005) Proc Natl Acad Sci USA 102:9294-9299). Chimpanzee studies have shown that protection from an infectious HCV inoculum with HCV-specific IgG is correlated with antibody titers blocking infection of target cells with HCVpp (Bartosch et al. (2003) Proc Natl Acad Sci USA 100:14199-14204). Control of virus infection and the Vn antibody response measured via HCVpp have been associated in single source outbreaks of acute HCV infection (Lavillette et al. (2005) J Virol 79:6023-6034, Pestka et al. (2007) C. Proc Natl Acad Sci USA 104:6025-6030), and confirmed in a study of active injection drug users (Osburn et al. (2010) Gastroenterology 138:315-324). While only 25% of subjects in this study cleared primary HCV infection, 83% cleared re-infection, and clearance in some subjects was associated with cross-reactive Vn antibodies.
In addition, antibodies to HCV E2 prevent infection in a human liver-mouse chimeric model (Law et al. (2008) Nature Medicine 14:25-27, Meuleman et al. (2008) Hepatology 48:1761-1768). Finally, an immunocompetent humanized mouse model for HCV exhibited a robust antibody response to a recombinant vaccinia virus expressing HCV proteins that protected against a heterologous infectious HCV challenge in some of the animals, which was correlated with the serum level of antibodies to E2 (Dorner et al. (2011) Nature 474:208-211).
A significant challenge for vaccine development is defining conserved epitopes that i) are capable of eliciting protective antibodies in this highly diverse virus, and ii) are resistant to development of escape mutants. Treatment of HCV and the development of vaccines that broadly protect against highly diverse HCV genotypes and subtypes are of interest in the field. The present invention addresses this issue.