The development of a pan-genotypic T cell vaccine against hepatitis C virus using heterologous prime-boost strategies

Rebecca Strain; Matthew Edmans; Gerardo Montalvo Zurbia-Flores; Nicole Frumento; Anthony Brown; Claire Hutchings; Callum Board; Chanice Knight; Andrew I Flyak; Justin Bailey; Georg Lauer; Andrea Cox; Paul Klenerman; Eleanor Barnes

doi:10.1097/HEP.0000000000001599

The development of a pan-genotypic T cell vaccine against hepatitis C virus using heterologous prime-boost strategies

Hepatology. 2025 Nov 14. doi: 10.1097/HEP.0000000000001599. Online ahead of print.

Authors

Rebecca Strain¹, Matthew Edmans¹, Gerardo Montalvo Zurbia-Flores¹, Nicole Frumento¹, Anthony Brown¹, Claire Hutchings¹, Callum Board¹, Chanice Knight¹, Andrew I Flyak², Justin Bailey^{3

4}, Georg Lauer^{5

6}, Andrea Cox^{3

4}, Paul Klenerman^{1

7

8}, Eleanor Barnes^{1

7

8}

Affiliations

¹ Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
² Department of Microbiology and Immunology, Cornell University, Ithaca, New York, USA.
³ Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
⁴ Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, USA.
⁵ Liver Center, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
⁶ Broad Institute, Cambridge, Massachusetts, USA.
⁷ Nuffield Department of Medicine, University of Oxford, Oxford, UK.
⁸ Oxford NIHR Biomedical Research Centre, Oxford, UK.

PMID: 41236497
DOI: 10.1097/HEP.0000000000001599

Abstract

Background and aims: An effective vaccine against hepatitis C virus (HCV) infection is required to achieve viral eradication. A previous viral vectored vaccine encoding a genotype-1b T cell antigen suppressed peak viral RNA but failed to prevent chronic infection. Previous studies showed dominant vaccine-induced T cell responses were not cross-reactive with common HCV strains, possibly contributing to vaccine failure. To address this, we evaluated 2 novel HCV vaccine strategies designed to elicit T cells targeting multiple HCV genotypes.

Approach and results: HCV genetic segments highly conserved between genotypes 1-6 were encoded in chimpanzee adenoviral (ChAd-Gt1-6) and Modified Vaccinia virus Ankara (MVA-Gt1-6) vectors and tested in prime-boost regimens. This was compared with vaccinating with an ancestral genotype-1a non-structural antigen encoded in ChAd (ChAd-Bole1a-NS) boosted with a genotype-3a non-structural antigen encoded in MVA (MVA-Gt3a-NS). Immunogenicity was evaluated in C57BL/6 and transgenic HLA-A*02:01 mice. Splenocytes were stimulated with genotype-1a, genotype-1b, or genotype-3a peptide pools in ex vivo IFNγ ELISpot and intracellular cytokine assays. Priming with ChAd-Gt1-6 elicited broad T cell responses toward all genotypes, whereas ChAd-Bole1a-NS generated a focused response to genotype-1a. Boosting ChAd-Bole1a-NS with MVA-Gt3a-NS generated cross-reactive T cells targeting multiple genotypes, though some responses were genotype-specific. In contrast, ChAd-Gt1-6 and MVA-Gt1-6 prime-boost generated high-magnitude responses that were all cross-reactive between genotypes.

Conclusions: Vaccinating with conserved regions of genotypes 1-6 or sequentially vaccinating with genotype-1a and genotype-3a immunogens are 2 novel approaches to generate cross-reactive T cells. The proportion of intergenotypic cross-reactive T cells generated was higher using the conserved region antigen.

Keywords: ChAd; HCV; MVA; cross-reactive; genotype.