The availability of highly effective non-toxic direct acting antivirals (DAAs) that cure HCV infection in >95% of chronically infected people will make an enormous impact on treating those currently infected with HCV. However, their high cost to health payers, restricted availability, approximately 50 million people with undiagnosed HCV, the potential risk of drug resistance due to improper use and the ability to be reinfected after clearing HCV means that there remains an urgent need to develop a prophylactic vaccine that can be used in combination with DAAs to achieve HCV elimination. HCV is an antigenically diverse pathogen classified into 7 genotypes and possesses immune evasion mechanisms to restrict the generation of broadly neutralizing antibody responses (bNAbs) and their effectiveness that has confounded vaccine design. Neutralizing antibodies are key components of all currently licensed vaccines and bNAbs have been shown to prevent and cure HCV in experimental animal models. HCV contains two viral glycoproteins E1 and E2 that attach virions to liver cells and mediate viral fusion. Glycoprotein E2 is a major target for the bNAb response and the majority of bNAbs also block the ability of E2 to bind the cell surface receptor CD81. Within E2 are three variable regions that alternate with conserved regions containing amino acid residues that form the CD81 binding site. The immunodominant hypervariable region 1 (HVR1) is located at the N-terminus of E2 and elicits type-specific NAbs that drive immune escape. Hypervariable region 2 (HVR2) and the intergenotypic variable region (igVR) are located internally, flanked by conserved cysteine motifs and form surface exposed loops on the non-neutralizing face of E2 and are not targets of the antibody response. Resolution of a three dimensional structure of an E2 core domain revealed that the CD81 binding sequences are located on the neutralizing face of E2 in close proximity to HVR1 and surrounded by a glycan shield. Our studies show that the three variable regions function to modulate the antigenicity and immunogenicity of E2 and reveal why HVR2 and the igVR are under considerable pressure to evolve in natural infection. In addition, we have shown that occlusion of the non-neutralizing face of E2 significantly alters the breadth and specificity of the antibody response and we have identified a lead candidate vaccine antigen that elicits bNAbs effective against all 7 genotypes of HCV.