Format

Send to

Choose Destination
Hepatology. 2016 May;63(5):1455-70. doi: 10.1002/hep.28294. Epub 2016 Jan 22.

Chronic hepatitis C viral infection subverts vaccine-induced T-cell immunity in humans.

Author information

1
Nuffield Department of Medicine, University of Oxford, Oxford, UK.
2
Oxford NIHR BRC and Translational Gastroenterology Unit, Oxford, UK.
3
ReiThera Srl (formerly Okairos Srl), Viale Città d'Europa, Rome, Italy.
4
Department of Hepatology, Queen Elizabeth Hospital, Birmingham, UK.
5
The Jenner Institute, University of Oxford, Oxford, UK.
6
CEINGE, Naples, Italy.
7
Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy.
8
Keires AG, Basel, Switzerland.

Abstract

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-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 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.

PMID:
26474390
PMCID:
PMC4842008
DOI:
10.1002/hep.28294
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Wiley Icon for PubMed Central
Loading ...
Support Center