Publications & Reports

A pan-genotype hepatitis C virus viral vector vaccine generates T-cells and neutralizing antibodies in mice.

Donnison T, McGregor J, Chinnakannan S, Hutchings C, Center RJ, Poumbourios P, Klenerman P, Drummer HE, Barnes E
Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, OX1 3SY.

Abstract

BACKGROUND & AIMS: A prophylactic vaccine targeting multiple HCV genotypes (gt) is urgently required to meet World Health Organization (WHO) elimination targets. Neutralizing antibodies (nAb), CD4(+) and CD8(+) T-cells are associated with spontaneous clearance of HCV, and each may contribute to protective immunity. However, current vaccine candidates generate either nAbs or T-cells targeting genetically variable epitopes and have failed to show efficacy in human trials. We have previously shown that a simian adenovirus vector (ChAdOx1) encoding conserved sequences across gt1-6 (ChAd-Gt1-6), and separately gt-1a E2 protein with variable regions deleted (E2Delta123HMW ), generates pan-genotypic T-cells and nAbs respectively. We now aim to develop a vaccine to generate both viral-specific B and T-cell responses concurrently. APPROACH & RESULTS: We show that vaccinating with ChAd-Gt1-6 and E2Delta123HMW sequentially in mice generates T-cell and antibody (Ab) responses comparable to either vaccine given alone. We encoded E2Delta123 in ChAdOx1 (ChAd-E2Delta123) and show that this given with E2Delta123HMW protein boost induces greater CD81-E2 inhibitory and HCV-pseudoparticle nAb titers compared to E2Delta123HMW prime-boost. We developed ‘bivalent’ viral vector vaccines (ChAdOx1 and modified vaccinia Ankara (MVA)) encoding both Gt1-6 and E2Delta123 immunogens (‘Gt1-6-E2Delta123’) generating polyfunctional CD4(+) and CD8(+) T-cells and nAb titers in prime/boost strategies. This approach generated nAb responses comparable to monovalent E2Delta123 ChAd/MVA vaccines and superior to three doses of recombinant E2Delta123HMW protein, whilst also generating high magnitude T-cell responses. CONCLUSION: These data are an important step forward for the development of a pan-genotype HCV vaccine to elicit T-cells and nAbs for future assessment in humans.

Link to publisher’s web site

Publication

  • Journal: Hepatology
  • Published: 21/03/2022
  • Volume: Epub ahead of print

Authors