Structural and biochemical studies of the hepatitis C virus envelope proteins to promote germline-targeting vaccine design

Hepatitis is a serious liver disease also caused by the Hepatitis C virus (HCV). It is a growing health concern, despite improvements in antiviral medication. An effective prophylactic vaccine is crucial to eliminating global HCV. Thus far, vaccination trials have failed to elicit an effective broadly neutralizing immune response due to inefficient vaccine antigens. HCV E2 envelope (Env) glycoprotein is the main target for neutralizing antibodies (nAbs) and thus the primary candidate for B-cells based vaccine design. A mlecular-level understanding of HCV neutralization by broadly nAbs (bnAbs) is imperative for the design of cross-reactive vaccine antigens to elicit high levels of bnAbs.

Previous studies indicated that the broad neutralization response against HCV is biased towards VH1-69-encoded bnAbs that target the E2 main neutralization epitope. These results suggest the potential for vaccine strategies that aim to amplify VH1-69-encoded antibody responses by targeting the corresponding antibody germline precursors to elicit a potent, broadly neutralizing response. Therefore, a better understanding of the recognition of HCV E2 by VH1-69-encoded germline B-cells can facilitate designing a more effective vaccine. To this aim, we express the germline reverted Abs of well-characterized VH1-69-encoded bnAbs. Utilizing biochemical and functional studies, we characterize the cross-binding and neutralization potency of the reverted Abs. The E2-reverted Abs interactions were further analysed by the crystal structures of two E2-reverted Abs complexes. These results will be used to design and improve antigens and develop a more effective vaccine against HCV.