The generation of a simian adenoviral vectored HCV vaccine encoding genetically conserved gene segments to target multiple HCV genotypes

•This study describes HCV prophylactic vaccines designed to target multiple genotypes.•HCV conserved immunogens were encoded within a simian adenoviral vector (ChAdOx1).•Vaccines are highly immunogenic in mice and induce T-cells targeting multiple genotypes.•HCV immunogens contain multiple human T-c...

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Bibliographic Details
Published in:	Vaccine 2018-01, Vol.36 (2), p.313-321
Main Authors:	von Delft, Annette, Donnison, Timothy A., Lourenço, José, Hutchings, Claire, Mullarkey, Caitlin E., Brown, Anthony, Pybus, Oliver G., Klenerman, Paul, Chinnakannan, Senthil, Barnes, Eleanor
Format:	Article
Language:	eng
Subjects:	Adenoviruses, Simian - genetics Animal models Animals CD4 antigen CD8 antigen Conserved segments Conserved Sequence Cross-reactivity Cytokines - analysis Drug Carriers Enzyme-linked immunosorbent assay Enzyme-Linked Immunospot Assay Epitopes Expression vectors Female Genomes Genotype Genotype & phenotype Genotypes HCV vaccine Hepacivirus - classification Hepacivirus - genetics Hepacivirus - immunology Hepatitis Hepatitis C Hepatitis C - prevention & control Hepatology Immunogenicity Infections Leukocytes, Mononuclear - immunology Lymphocytes T Male Mice Mice, Inbred C57BL Mutation Peptides Simian adenovirus T cell Tumor necrosis factor-α Vaccines Vaccines, Synthetic - genetics Vaccines, Synthetic - immunology Viral Vaccines - genetics Viral Vaccines - immunology Viruses
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Summary:	•This study describes HCV prophylactic vaccines designed to target multiple genotypes.•HCV conserved immunogens were encoded within a simian adenoviral vector (ChAdOx1).•Vaccines are highly immunogenic in mice and induce T-cells targeting multiple genotypes.•HCV immunogens contain multiple human T-cell epitopes as defined in natural infection. Hepatitis C virus (HCV) genomic variability is a major challenge to the generation of a prophylactic vaccine. We have previously shown that HCV specific T-cell responses induced by a potent T-cell vaccine encoding a single strain subtype-1b immunogen target epitopes dominant in natural infection. However, corresponding viral regions are highly variable at a population level, with a reduction in T-cell reactivity to these variants. We therefore designed and manufactured second generation simian adenovirus vaccines encoding genomic segments, conserved between viral genotypes and assessed these for immunogenicity. We developed a computer algorithm to identify HCV genomic regions that were conserved between viral subtypes. Conserved segments below a pre-defined diversity threshold spanning the entire HCV genome were combined to create novel immunogens (1000–1500 amino-acids), covering variation in HCV subtypes 1a and 1b, genotypes 1 and 3, and genotypes 1–6 inclusive. Simian adenoviral vaccine vectors (ChAdOx) encoding HCV conserved immunogens were constructed. Immunogenicity was evaluated in C57BL6 mice using panels of genotype-specific peptide pools in ex-vivo IFN-ϒ ELISpot and intracellular cytokine assays. ChAdOx1 conserved segment HCV vaccines primed high-magnitude, broad, cross-reactive T-cell responses; the mean magnitude of total HCV specific T-cell responses was 1174 SFU/106 splenocytes for ChAdOx1-GT1-6 in C57BL6 mice targeting multiple genomic regions, with mean responses of 935, 1474 and 1112 SFU/106 against genotype 1a, 1b and 3a peptide panels, respectively. Functional assays demonstrated IFNg and TNFa production by vaccine-induced CD4 and CD8 T-cells. In silico analysis shows that conserved immunogens contain multiple epitopes, with many described in natural HCV infection, predicting immunogenicity in humans. Simian adenoviral vectored vaccines encoding genetic segments that are conserved between all major HCV genotypes contain multiple T-cell epitopes and are highly immunogenic in pre-clinical models. These studies pave the way for the assessment of multi-genotypic HCV T-cell vaccines in humans.
ISSN:	0264-410X 1873-2518