From Structural Studies to HCV Vaccine Design

Abstract

Hepatitis C virus (HCV) is a serious and growing public health problem despite recent developments of antiviral therapeutics. To achieve global elimination of HCV, an effective cross-genotype vaccine is needed. The failure of previous vaccination trials to elicit an effective cross-reactive immune response demands better vaccine antigens to induce a potent cross-neutralizing response to improve vaccine efficacy. HCV E1 and E2 envelope (Env) glycoproteins are the main targets for neutralizing antibodies (nAbs), which aid in HCV clearance and protection. Therefore, a molecular-level understanding of the nAb responses against HCV is imperative for the rational design of cross-genotype vaccine antigens. Here we summarize the recent advances in structural studies of HCV Env and Env-nAb complexes and how they improve our understanding of immune recognition of HCV. We review the structural data defining HCV neutralization epitopes and conformational plasticity of the Env proteins, and the knowledge applicable to rational vaccine design.

Vaccination induces broadly neutralizing antibody precursors to HIV gp41

“…Broad vaccine protection against highly antigenically diverse viruses, such as human immunodeficiency virus (HIV), hepatitis C virus, influenza or the family of betacoronaviruses, has not been achieved in humans but will likely require induction of broadly neutralizing antibodies (bnAbs) that bind to conserved epitopes on otherwise variable membrane glycoproteins. Monoclonal bnAbs for each of the above pathogens have been discovered, and specific genetic and structural features of each bnAb allow binding to its cognate epitope [1][2][3][4] . To use known bnAbs as guides for the design of vaccines that elicit similar responses, strategies to induce bnAbs with predefined genetic properties and binding specificities are needed [5][6][7] .…”

Where to Next? Research Directions after the First Hepatitis C Vaccine Efficacy Trial

“…Together, studies of the recombinant HCV-1 E1E2 vaccines provide a solid basis for the pursuit of an antibody vaccine, while highlighting the need for optimization to better elicit robust neutralizing responses against conserved regions of the envelope glycoprotein. As such, significant effort has been made to engineer a rational antibody vaccine for HCV, as recently reviewed in detail by several groups [ 93 , 94 , 95 ]. These efforts follow insights gained from crystal structures of antibody-bound constructs of truncated E2, improved modeling of the E1E2 heterodimer, and expanded mapping of neutralizing and non-neutralizing antibody binding sites on E1E2.…”

Hepatitis C Virus E1E2 Structure, Diversity, and Implications for Vaccine Development

“…Structural characterization of the E2 glycoprotein has provided substantial information on the major antigenic sites that are the targets of bnAb-binding, particularly as it pertains to binding to primary CD81 receptor binding domain [14][15][16][17][18][19][20][21][22]. More recently, the cryo-EM structural characterization of the E1E2 heterodimer, either as a membrane-extracted E1E2 heterodimer [23] or as a soluble, secreted E1E2 heterodimer ectodomain [1], was a major advance in the field to more fully understand the structural antigenic features of this complex molecule.…”