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Antibody Responses to Immunization With HCV Envelope Glycoproteins as a Baseline for B cell-Based Vaccine Development

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  1. Development of a downstream process for the production of an inactivated whole hepatitis C virus vaccine

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  3. An alternate conformation of HCV E2 neutralizing face as an additional vaccine target

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  • Fang Chen
  • Kenna Nagy
  • Deborah Chavez
  • Shelby Willis
  • Ryan McBride
  • Erick Giang
  • Andrew Honda
  • Jens Bukh
  • Phillip Ordoukhanian
  • Jiang Zhu
  • Sharon Frey
  • Robert Lanford
  • Mansun Law
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BACKGROUND & AIMS: 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 heathy volunteers, non-human primates (NHPs), and mice METHODS: 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. Blood samples were collected at different timepoints 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.

RESULTS: 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.

CONCLUSIONS: 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.

Original languageEnglish
JournalGastroenterology
Volume158
Issue number4
Pages (from-to)1058-1071
Number of pages14
ISSN0016-5085
DOIs
Publication statusPublished - Mar 2020

ID: 58540664