Unravelling signatures of anti-Hepatitis C virus immune response associated with infection outcome for rational vaccine design

Hepatitis C virus (HCV) is a major public health concern, with over 70 million people infected worldwide, who are at risk for developing life-threatening liver disease. No vaccine is available, and immunity against the virus is not well understood. Following the acute stage, HCV usually causes chronic infections. However, approximately 30% of infected individuals spontaneously clear the virus. Therefore, using HCV as a model for comparing immune responses between spontaneous clearer (SC) and chronically infected (CI) individuals may empower the identification of mechanisms governing viral infection outcomes and lead to designing effective vaccines. We demonstrate that SC individuals, in contrast to CI patients, develop a cluster of antibodies with distinct properties, that can accurately predict infection outcome. We generated antibodies that are associated with viral clearance and showed that they have unique properties of high neutralization breadth. In addition, we revealed distinct epitopes that are associated with infection outcome. We designed a peptide vaccine that is based on the epitopes that are associated with viral clearance, and showed its efficacy in eliciting anti-HCV neutralizing antibodies with high neutralization breath. We also developed HCV attenuated viruses generated by designing synonymous mutations affecting viral mRNA folding to reduce viral fitness, as a potential rationally designed live attenuated HCV-vaccine. This study provides insight into the nature of effective immune response against HCV. It may have clinical implications for prognosis of the future status of infection, and the design of effective immunotherapies and a vaccine for HCV.