Grant: Project Grant

Hepatitis C virus (HCV) causes chronic liver infection with life-threatening complications. Effective antivirals have recently become available but their use is limited because of high costs and cured patients can still be reinfected. Therefore, a prophylactic vaccine is urgently needed to prevent the estimated two million new infections world-wide. Current evidence points to a protective role for virus neutralizing antibodies and virus-specific cellular immune responses. Accordingly, we are designing a vaccine formulation capable of eliciting such broad immune responses. One of the obstacles for HCV vaccine development is the genetic diversity of the virus. Previously we showed that a recombinant envelope glycoprotein vaccine containing the gpE1/gpE2 heterodimer is protective in the chimpanzee challenge model. Vaccination of human volunteers in a phase 1 clinical trial elicited strong T helper cell responses and antibodies that prevent infection in tissue culture cells by all major HCV genotypes observed around the world. While very encouraging, cross-neutralization appeared to favor certain genotypes. In order to enhance a broadly protective vaccine, we are investigating the mechanism behind this genotype bias and also how HCV evades antibody control. Our proposed studies aim to improve the immunogenicity of the HCV vaccine by enhancing cross-protective neutralizing antibodies which are one component of an effective global HCV vaccine.