We describe a peptide-based strategy for HCV vaccine design that addresses the problem of variability in hypervariable region 1 (HVR1). Peptides representing antibody epitopes of HVR1 from genotype 1a were synthesized and incorporated into multideterminant immunogens that also included lipid moieties and helper T (T(h)) cell epitopes. Mice inoculated with these polyepitopes generated strong antibody responses. Antibody titers were highest in mice inoculated with polyepitope immunogens which contained the lipid moiety dipalmitoyl-S-glyceryl cysteine (Pam2Cys). Antisera were tested for their potential to neutralize HCV by 3 currently available assays. Antibodies elicited in mice by the polyepitope-based vaccine candidates were able to (1) bind to E2 expressed on the surface of E1/E2-transfected human embryonic kidney (HEK) 293T cells, (2) capture HCV of different genotypes (1, 2, and 3) from the serum of chronically infected humans in an immune capture RT-PCR assay and (3) inhibit HCVpp entry into Huh7 cells. Antibody present in the sera of patients chronically infected with HCV genotypes 1, 2, 3, and 4 also bound to the HVR1-based polyepitope.

These results demonstrate the potential of self-adjuvanting epitope-based constructs in the development and delivery of cross-reactive immunogens that incorporate potential neutralizing epitopes present within the viral envelope of HCV.