Chronic Hepatitis C Viral Infection Subverts Vaccine-Induced T-cell Immunity in Humans

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae / genetics
  • Adult
  • Aged
  • Amino Acid Sequence
  • Epitopes, T-Lymphocyte
  • Hepacivirus / immunology*
  • Hepatitis C, Chronic / drug therapy
  • Hepatitis C, Chronic / immunology*
  • Hepatitis C, Chronic / virology
  • Humans
  • Interferon-alpha / administration & dosage
  • Male
  • Middle Aged
  • Molecular Sequence Data
  • Polyethylene Glycols / administration & dosage
  • Recombinant Proteins / administration & dosage
  • Riboflavin / administration & dosage
  • T-Lymphocytes / immunology*
  • Vaccination
  • Viral Hepatitis Vaccines / immunology*

Substances

  • Epitopes, T-Lymphocyte
  • Interferon-alpha
  • Recombinant Proteins
  • Viral Hepatitis Vaccines
  • Polyethylene Glycols
  • peginterferon alfa-2a
  • Riboflavin