Introduction: Around 25% of hepatitis C virus (HCV) infected subjects spontaneously clear the virus while 75% develop chronic infection. Despite the availability of effective DAAs, the development of a protective vaccine remains a priority. All successful vaccines to-date are based on the induction of neutralising antibodies (nAbs). Recently, the development of early nAbs have been implicated in natural clearance of HCV. Although broad nAbs do eventually develop in chronic infection and can neutralize many HCV variants in vitro, they fail to facilitate clearance of ongoing infection. In this study the breadth and specificity of nAbs developed in subjects that naturally cleared multiple HCV infections (‘superclearers’) were compared to nAbs developed in chronic infection.
Methods: Subjects for this study were obtained from the HITS-p cohort (n=590) and were divided into four groups based on their infection history: 1) 'super-clearers’ (n=8), 2) clearer-chronic’ (n=6), 3) ‘potentially protected’ (n=6) and 4) ‘chronic’ (n=10). The breadth of nAb responses was analysed using a library of heterologous HCV psuedoparticles (HCVpps) (n=11) representing all six genotypes (G1-6). Measurement of antibody titre and target epitopes was done using a competition ELISA that employed several well characterized monoclonal Abs.
Results & discussion: Our results indicate that an early broad nAb response upon exposure to the virus may enable subjects to clear subsequent secondary infections as compared to an early genotype-specific nAb response. While genotype-specific nAb responses appear to be associated with clearance of the infecting genotype, these responses fail to protect from a re-challenge with a different genotype. Additionally, high-risk behavior appears to be associated with maintenance of nAb responses, and the lack of detectable viremia in these subjects suggests that these nAbs are protective from HCV infection. Characterisation of broad nAb responses has shown that antigenic region 3/domain B are the most immunodominant epitopes in all cases.