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Adenoviral vectors encoding hepatitis C virus (HCV) non-structural proteins induce multi-specific, high-magnitude, durable CD4+ and CD8+ T-cell responses in healthy volunteers. We now assess 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 non-structural proteins in a dose-escalation, prime-boost regimen, with and without concomitant pegylated interferon-α/ribavirin therapy. Analysis of immune responses ex vivo used human leukocyte antigen class-I pentamers, intracellular cytokine staining and fine mapping in interferon-γ ELISpot 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 recognise 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. This article is protected by copyright. All rights reserved.
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