Deaths due to Hepatitis C now outnumber those caused by HIV in developed countries and urgent action is required to reduce the prevalence and incidence of HCV globally. Direct acting antivirals will be an essential part of a global eradication program but will require a coordinated effort to identify those infected, a reduction in price so that those most affected in developing countries can access treatment and careful monitoring of treatment programs to ensure drug resistance does not emerge. An essential adjunct to a global eradication program for HCV is a prophylactic vaccine with the ability to prevent infection by all 7 genotypes of HCV. Modelling suggests that vaccinating 90/1000 people who inject drugs in a setting with 50% chronic prevalence would reduce HCV prevalence by 50% in 15 years. All current vaccines rely on the generation of neutralizing antibody responses (NAbs) targeted to major surface proteins that prevent infection. In the case of HCV, NAbs have been shown to be highly effective at preventing infection and clearance of established infection in animal models of HCV and will be an essential component of a vaccine. The NAb response to HCV is directed towards the two surface glycoproteins E1 and E2. The majority of NAb epitopes map to E2 and overlap with contact residues for the major cellular receptor CD81. Confounding vaccine design is the large amount of antibody generated to the N-terminal hypervariable region 1 that results in immune escape and further diversification of the viral quasispecies. In addition, we have found that HVR2 and the intergenotypic variable region (VR3) are under immune selection pressure and appear to modulate the exposure of neutralizing and non neutralizing antibody epitopes. To overcome this, we have designed a new form of E2 that lacks all three variable regions. The immune response to this modified E2 antigen is profoundly different resulting in high titre broadly neutralizing antibodies effective against all 7 genotypes. This antigen provides a pathway to the development of a prophylactic vaccine for HCV and could be combined with new T cell immunogens to provide both cellular and humoral immunity.