Chronic Hepatitis C Virus infection subverts vaccine induced T-cell immunity in humans

Christabel Kelly, Leo Swadling, Stefania Capone, Anthony Brown, Rachel Richardson, John Halliday, Annette von Delft, Ye Htun Oo, David Mutimer, Ayako Kurioka, Felicity Hartnell, Jane Collier, Virginia Ammendola, Mariarosaria Del Sorbo, Fabiana Grazioli, Maria Luisa Esposito, Stefania Di Marco, Loredana Siani, Cinzia Traboni, Adrian V S HillStefano Colloca, Alfredo Nicosia, Riccardo Cortese, Antonella Folgori, Paul Klenerman, Eleanor Barnes

Research output: Contribution to journalArticlepeer-review

29 Citations (Scopus)

Abstract

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.

Original languageEnglish
JournalHepatology
Early online date22 Jan 2016
DOIs
Publication statusPublished - May 2016

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