Synthetic antigens representing the antigenic variation of human hepatitis C virus

Hepatitis C virus (HCV) vaccine development could require simultaneous induction of humoral and cellular immune responses. This response should include broadly reactive antibodies given that divergent strains of HCV circulate throughout the human population and that individuals are often infected with a swarm of HCV variants. In addition, it should also induce both helper and cytotoxic cellular responses strong enough to eliminate the viral isolates. A major problem in the design of an effective vaccine against HCV is that the viral epitope variability enables virus to escape immune response generated to eliminate the infection. Some of HCV patients develop self-resolution of virus. However, 80% of patients infected with HCV develop chronic infection and a portion of them develops eventually cirrhosis and hepatocellular carcinoma. We have previously prepared synthetic immunogens that represent the variation within major hypervariable neutralization epitopes of the envelope glycoproteins of human immunodeficiency viruses (HIV), simian immunodeficiency viruses (SIV), and human papilloma virus (HPV). These immunogens are comprised of customized peptide mixtures that represent the cumulative permutations of amino acid substitutions found within each viral epitope and named as Hypervariable Epitope Constructs (HEC).; Immunization of rodents and primates with these immunogens elicits both antigen-specific humoral and cellular responses with enhanced and broad reactivity to divergent viral sequences. We similarly synthesized constructs representing the HCV hypervariable epitopes HVR1 and HVR2 found in the envelope protein (E2), another variable epitope, called here as HVR3, also found in the E2 protein as well as variable epitopes present in the non-structural core proteins (NS3 and NS4). We also prepared four different formulations of these seven HCV HEC and studied the immune responses elicited by these formulations in mice to compare their immunogenicity. This approach could represent a new strategy for the design of vaccines against antigenically variable pathogens that cause chronic infections such as HCV.