Abstract
We investigated antibody responses to hepatitis C virus (HCV) antigens E1 and E2 and the relevance of animal models for vaccine development. We compared antibody responses to vaccination with recombinant E1E2 complex in healthy volunteers, non-human primates (NHPs), and mice. We analyzed 519 serum samples from participants in a phase 1 vaccine trial(ClinicalTrials.gov identifier NCT00500747) and compared them with serum or plasma samples from C57BL/6J mice (n= 28) and rhesus macaques (n= 4) immunized with the same HCV E1E2 antigen. Blood samples were collected at different time points and analyzed for antibody binding, neutralizing activity, and epitope specificity. Monoclonal antibodies from the immunized NHPs were isolated from single plasmablasts and memory B cells, and their immunogenetic properties were characterized. Antibody responses of the volunteers, NHPs, and mice to the non-neutralizing epitopes on the E1 N-terminus and E2 hypervariable region 1 did not differ significantly. Antibodies from volunteers and NHPs that neutralized heterologous strains of HCV primarily interacted with epitopes in the antigen region 3. However, the neutralizing antibodies were not produced in sufficient levels for broad neutralization of diverse HCV isolates. Broadly neutralizing antibodies similar to the human VH1-69 class antibody specific for antigen region 3 were produced in the immunized NHPs. In an analysis of vaccinated volunteers, NHPs, and mice, we found that recombinant E1E2 vaccine antigen induces high-antibody titers that are insufficient to neutralize diverse HCV isolates. Antibodies from volunteers and NHPs bind to the same neutralizing epitopes for virus neutralization. NHPs can therefore be used as a preclinical model to develop HCV vaccines. These findings also provide useful baseline values for development of vaccines designed to induce production of neutralizing antibodies.
Highlights
Background & AimsWe investigated antibody responses to hepatitis C virus (HCV) antigens E1 and E2 and the relevance of animal models for vaccine development
In an analysis of vaccinated volunteers, non-human primates (NHPs), and mice, we found that recombinant E1E2 vaccine antigen induces high-antibody titers that are insufficient to neutralize diverse HCV isolates
Antibodies from volunteers and NHPs bind to the same neutralizing epitopes for virus neutralization
Summary
We analyzed 519 serum samples from participants in a phase 1 vaccine trial (NCT00500747) and compared them with serum or plasma samples from C57BL/6J mice (n=28) and rhesus macaques (n=4) immunized with the same HCV E1E2 antigen. Monoclonal antibodies from the immunized NHPs were isolated from single plasmablasts and memory B cells, and their immunogenetic properties were characterized. A total of 519 human serum samples were obtained from a completed phase I, placebocontrolled, dose-escalation clinical trial (DMID 01-002; ClinicalTrials.gov identifier NCT00500747), in which a candidate HCV vaccine constituting a recombinant E1E2 immunogen derived from a genotype 1a isolate (HCV-1) formulated with the MF59 adjuvant (Novartis Vaccines and Diagnostics) was tested for safety and immunogenicity in healthy human volunteers.[16] All samples were heat-inactivated at 56 °C for 30 min prior to all assays to inactivate complement.
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