CHARACTERIZATION OF THE ROLE OF BROADLY NEUTRALIZING ANTIBODIES IN CLEARANCE OF HUMAN HEPATITIS C VIRUS INFECTION

Hepatitis C virus (HCV) remains a global health epidemic, with approximately 71 million people infected worldwide. While direct acting antivirals are effective at treating HCV infection, infection rates are on the rise. A prophylactic vaccine is critical to efforts to eradicate HCV. Vaccine efforts have been hindered by HCV’s immense genetic diversity and a poor understanding of the characteristics of an effective antibody response to HCV infection. However, approximately 25% of individuals who are infected with HCV spontaneously clear their infections. Importantly, clearance of HCV infection is associated with the development of broadly neutralizing antibodies. A better understanding of the antibody epitopes targeted in clearance of HCV infection would inform vaccine design. Here, we characterize the antibody response in individuals who develop broadly neutralizing antibody responses and clear their HCV infections. We provide strong in vivo evidence that bNAbs directed at the CD81 binding residues of E2 may result in infection clearance through a combination of neutralization and pressure that selects replication-deficient viruses through impaired CD81 binding. This work suggests that an antibody-based vaccine to HCV is possible, and any HCV vaccine antigen selected should elicit antibodies targeting the CD81 epitope. It is likely that antibodies with a combination of specificities will need to be elicited to develop a vaccine to HCV. However, it is unclear which, if any, combinations of antibody specificities are key in driving neutralizing breadth in individuals who clear their HCV infections. To better understand the neutralizing antibody response associated with clearance of HCV infection, we developed an assay to identify the antibody specificities present in polyclonal plasma. This approach determined that we found that presence of a combination of antibodies, including HEPC74, AR3A, AR4A and HEPC98 was associated with clearance. This suggests that a vaccine will need to elicit multiple types of antibody responses. i This research highlights the importance of the neutralizing antibody response in clearance of human HCV infection, and informs HCV vaccine design. Importantly, this work suggests that an HCV vaccine antigen will need to be carefully selected to elicit a protective antibody response