Candidate Bivalent HCV Vaccine: A Novel Approach To Vaccine Design for Hyper-variable Viruses

One percent of the world’s population is chronically infected with the hepatitis C Virus (HCV), and it estimated nearly 500,000 HCV related deaths will occur in 2020. Despite remarkable progress in treatment, the high number of occult infections, risk of reinfection following treatment, and the nearly 2 million new cases annually underscores the urgent need for a prophylactic vaccine. Vaccine development has faltered because the extreme genetic diversity of the virus has precluded the induction of broadly protective antibodies (AB) with classical vaccines. Here, I describe a novel approach to vaccine design for antigenically variable pathogens based on transformation of genetic diversity into physicochemical variability, using HCV as a prototypical variable pathogen. Based on the hypothesis that polyvalent vaccination with antigenically variable immunogens will bias the immune response to recognize physicochemically conserved residues, our approach selects for multivalent constituents relationally defined by their physicochemical divergence. Though it has been proposed that highly variable, immunodominant epitopes should be amputated from HCV vaccine antigens to avoid induction of strain-specific antibodies, as a proof-of-concept our approach was used to develop a bivalent HCV vaccine explicitly designed to elicit AB to HVR1 (hypervariable region 1), the most variable epitope of any known human pathogen. Remarkably, the polyclonal response induced by vaccination was pan-genotypically neutralizing. These results support our hypothesis that physiochemically constrained signatures within hypervariable epitopes can be effectively targeted by vaccines designed using our novel approach.Ph.D