A Novel Approach to Polyvalent Vaccine Design for Hyper-Variable Viruses

Background and Aims: 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 HCV 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, we evaluate a novel approach to vaccine design based on the hypothesis that polyvalent vaccination with antigenically variable immunogens will bias the immune response to recognize physicochemically conserved residues. Methods: We designed a bivalent HVR1-peptide vaccine by transforming sequence alignments into numerical values describing average non-bonded free energy. Peptides representing the sequence set with the highest physicochemical divergence were synthesized and used to immunize mice. Sera was assessed for neutralization against of a panel of HCV pseudo virus (HCVpp) representing genotypes 1-6. Results: We show that the bivalent vaccine candidate elicited pangenotypic neutralizing antibodies against HCV variants spanning the global sequence space and differing from the immunogen sequences by more than 70% at the amino acid level. Conclusions: These findings suggest that it is possible to elicit humoral immunity to highly variable pathogens by generating AB targeting physicochemically conserved signatures within hypervariable epitopes, which represents a new path in universal vaccine design against highly variable human pathogens for which conserved epitope targeting approaches have faltered, such as HCV, HIV, and malaria.