Hepatitis C virus (HCV) is a major cause of life-threatening liver disease and currently affects 3% of the global human population. Licensed therapies are ineffective and there is no vaccine. The correlates of protective immunity are poorly understood. It has been shown that the antibody response in HCV-positive individuals largely targets envelope glycoprotein E2. This is the receptor-binding subunit of the HCV envelope that mediates antibody-accessible stages of viral entry. We hypothesize that immunizing mice with soluble E2 (sE2)-derived immunogens coupled with strategies that non-specifically boost innate immunity, will focus the humoral response on functional domains of the protein thereby eliciting high titers of broadly-reactive neutralizing antibodies. We are currently optimizing novel derivatives of sE2 and comparing antibody responses elicited by these novel immunogens in combination with different adjuvants. Monoclonal antibodies (MAbs) derived from animals with the highest neutralizing serum titers will be characterized. Finally, we will seek to identify neutralizing sera, MAbs or combinations of MAbs that can attenuate or prevent outgrowth of viral escape variants. Our studies will have broad implications for designing prophylactic and therapeutic approaches that specifically interfere with HCV entry to block infection.

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