title: Chronic hepatitis C viral infection subverts vaccine-induced T-cell immunity in humans.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Nuffield Department of Medicine, University of Oxford, Oxford, UK.|Oxford NIHR BRC and Translational Gastroenterology Unit, Oxford, UK.
authors.forename: Christabel
authors.initials: C
authors.lastname: Kelly
authors.affiliation: Nuffield Department of Medicine, University of Oxford, Oxford, UK.
authors.forename: Leo
authors.initials: L
authors.lastname: Swadling
authors.affiliation: ReiThera Srl (formerly Okairos Srl), Viale Città d'Europa, Rome, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Capone
authors.affiliation: Nuffield Department of Medicine, University of Oxford, Oxford, UK.
authors.forename: Anthony
authors.initials: A
authors.lastname: Brown
authors.affiliation: Nuffield Department of Medicine, University of Oxford, Oxford, UK.
authors.forename: Rachel
authors.initials: R
authors.lastname: Richardson
authors.affiliation: Nuffield Department of Medicine, University of Oxford, Oxford, UK.|Oxford NIHR BRC and Translational Gastroenterology Unit, Oxford, UK.
authors.forename: John
authors.initials: J
authors.lastname: Halliday
authors.affiliation: Nuffield Department of Medicine, University of Oxford, Oxford, UK.
authors.forename: Annette
authors.initials: A
authors.lastname: von Delft
authors.affiliation: Department of Hepatology, Queen Elizabeth Hospital, Birmingham, UK.
authors.forename: Ye
authors.initials: Y
authors.lastname: Oo
authors.affiliation: Department of Hepatology, Queen Elizabeth Hospital, Birmingham, UK.
authors.forename: David
authors.initials: D
authors.lastname: Mutimer
authors.affiliation: Nuffield Department of Medicine, University of Oxford, Oxford, UK.
authors.forename: Ayako
authors.initials: A
authors.lastname: Kurioka
authors.affiliation: Nuffield Department of Medicine, University of Oxford, Oxford, UK.
authors.forename: Felicity
authors.initials: F
authors.lastname: Hartnell
authors.affiliation: Oxford NIHR BRC and Translational Gastroenterology Unit, Oxford, UK.
authors.forename: Jane
authors.initials: J
authors.lastname: Collier
authors.affiliation: ReiThera Srl (formerly Okairos Srl), Viale Città d'Europa, Rome, Italy.
authors.forename: Virginia
authors.initials: V
authors.lastname: Ammendola
authors.affiliation: ReiThera Srl (formerly Okairos Srl), Viale Città d'Europa, Rome, Italy.
authors.forename: Mariarosaria
authors.initials: M
authors.lastname: Del Sorbo
authors.affiliation: ReiThera Srl (formerly Okairos Srl), Viale Città d'Europa, Rome, Italy.
authors.forename: Fabiana
authors.initials: F
authors.lastname: Grazioli
authors.affiliation: ReiThera Srl (formerly Okairos Srl), Viale Città d'Europa, Rome, Italy.
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Esposito
authors.affiliation: ReiThera Srl (formerly Okairos Srl), Viale Città d'Europa, Rome, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Di Marco
authors.affiliation: ReiThera Srl (formerly Okairos Srl), Viale Città d'Europa, Rome, Italy.
authors.forename: Loredana
authors.initials: L
authors.lastname: Siani
authors.affiliation: ReiThera Srl (formerly Okairos Srl), Viale Città d'Europa, Rome, Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Traboni
authors.affiliation: Nuffield Department of Medicine, University of Oxford, Oxford, UK.|The Jenner Institute, University of Oxford, Oxford, UK.
authors.forename: Adrian V S
authors.initials: AV
authors.lastname: Hill
authors.affiliation: ReiThera Srl (formerly Okairos Srl), Viale Città d'Europa, Rome, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Colloca
authors.affiliation: Oxford NIHR BRC and Translational Gastroenterology Unit, Oxford, UK.|ReiThera Srl (formerly Okairos Srl), Viale Città d'Europa, Rome, Italy.|CEINGE, Naples, Italy.|Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Nicosia
authors.affiliation: Keires AG, Basel, Switzerland.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Cortese
authors.affiliation: ReiThera Srl (formerly Okairos Srl), Viale Città d'Europa, Rome, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Folgori
authors.affiliation: Nuffield Department of Medicine, University of Oxford, Oxford, UK.|Oxford NIHR BRC and Translational Gastroenterology Unit, Oxford, UK.|The Jenner Institute, University of Oxford, Oxford, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Klenerman
authors.affiliation: Nuffield Department of Medicine, University of Oxford, Oxford, UK.|Oxford NIHR BRC and Translational Gastroenterology Unit, Oxford, UK.|The Jenner Institute, University of Oxford, Oxford, UK.
authors.forename: Eleanor
authors.initials: E
authors.lastname: Barnes
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D018984:Epitopes, T-Lymphocyte; D016174:Hepacivirus / Q000276:immunology*; D019698:Hepatitis C, Chronic / Q000188:drug therapy / Q000276:immunology* / Q000821:virology; D006801:Humans; D016898:Interferon-alpha / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D011092:Polyethylene Glycols / Q000008:administration & dosage; D011994:Recombinant Proteins / Q000008:administration & dosage; D012256:Riboflavin / Q000008:administration & dosage; D013601:T-Lymphocytes / Q000276:immunology*; D014611:Vaccination; D014761:Viral Hepatitis Vaccines / Q000276:immunology*
chemical_list: D018984:Epitopes, T-Lymphocyte; D016898:Interferon-alpha; D011994:Recombinant Proteins; D014761:Viral Hepatitis Vaccines; D011092:Polyethylene Glycols; C100416:peginterferon alfa-2a; D012256:Riboflavin