Toward HCV vaccine – Structural studies of HCV E2 envelop glycoprotein that facilitates rational design of HCV vaccine

A cross-genotype effective vaccine is obligated to achieve global elimination of hepatitis C virus (HCV). Recent studies underscore the importance of broadly neutralizing antibodies (bnAbs) in HCV clearance and protection. Structural and functional studies of bnAbs in complexes with their antigen can provide critical information to guide prophylactic vaccine design. For this purpose, we determined the crystal structures of HCV E2 envelope glycoprotein in complex with a large panel of bnAbs. Structural analysis indicated that cross-neutralization of HCV by this group of bnAbs is mediated by their binding to highly conserved hydrophobic surface that overlaps with the CD81 receptor binding site. Structural based design of the E2 core fragment (E2c) resulted in improved antigens that demonstrate greater antigenicity and thermostability. Crystal structures of the optimized E2c revealed how our designs stabilize E2 without altering key neutralizing epitopes. Displaying of the optimized E2c on self-assembling nanoparticles resulted in enhanced antigenicity and more effective elicitation of nAbs response in mice immunization experiments, assessing their potential as HCV vaccine candidates for eliciting a broadly neutralizing B-cell response.