Journal
HEPATOLOGY
Volume 63, Issue 5, Pages 1455-1470Publisher
WILEY-BLACKWELL
DOI: 10.1002/hep.28294
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Funding
- Medical Research Council (MRC) UK Development Clinical Scheme award [G0701694]
- Wellcome Trust
- Oxford NHIR BRC
- MRC CASE studentship
- MRC
- Oxford Martin School
- Jenner Institute
- [2U19AI082630-06]
- MRC [G1002552, MR/K010239/1, G0701694] Funding Source: UKRI
- Medical Research Council [G1002552, MR/K010239/1, G0701694, 1890672] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0515-10005, NF-SI-0510-10204] Funding Source: researchfish
- Wellcome Trust [109965/Z/15/Z] Funding Source: researchfish
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Adenoviral vectors encoding hepatitis C virus (HCV) nonstructural (NS) proteins induce multispecific, high-magnitude, durable CD4(+) and CD8(+) T-cell responses in healthy volunteers. We assessed the capacity of these vaccines to induce functional HCV-specific immune responses and determine T-cell cross-reactivity to endogenous virus in patients with chronic HCV infection. HCV genotype 1-infected patients were vaccinated using heterologous adenoviral vectors (ChAd3-NSmut and Ad6-NSmut) encoding HCV NS proteins in a dose escalation, prime-boost regimen, with and without concomitant pegylated interferon-/ribavirin therapy. Analysis of immune responses ex vivo used human leukocyte antigen class I pentamers, intracellular cytokine staining, and fine mapping in interferon- enzyme-linked immunospot assays. Cross-reactivity of T cells with population and endogenous viral variants was determined following viral sequence analysis. Compared to healthy volunteers, the magnitude of HCV-specific T-cell responses following vaccination was markedly reduced. CD8(+) HCV-specific T-cell responses were detected in 15/24 patients at the highest dose, whereas CD4(+) T-cell responses were rarely detectable. Analysis of the host circulating viral sequence showed that T-cell responses were rarely elicited when there was sequence homology between vaccine immunogen and endogenous virus. In contrast, T cells were induced in the context of genetic mismatch between vaccine immunogen and endogenous virus; however, these commonly failed to recognize circulating epitope variants and had a distinct partially functional phenotype. Vaccination was well tolerated but had no significant effect on HCV viral load. Conclusion: Vaccination with potent HCV adenoviral vectored vaccines fails to restore T-cell immunity except where there is genetic mismatch between vaccine immunogen and endogenous virus; this highlights the major challenge of overcoming T-cell exhaustion in the context of persistent antigen exposure with implications for cancer and other persistent infections. (Hepatology 2016;63:1455-1470)
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