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Sci Transl Med. 2014 Nov 5;6(261):261ra153. doi: 10.1126/scitranslmed.3009185.

A human vaccine strategy based on chimpanzee adenoviral and MVA vectors that primes, boosts, and sustains functional HCV-specific T cell memory.

Author information

1
Nuffield Department of Medicine, University of Oxford, Oxford OX1 3SY, UK.
2
ReiThera Srl (ex Okairos), Viale Città d'Europa 679, 00144 Rome, Italy.
3
Nuffield Department of Medicine, University of Oxford, Oxford OX1 3SY, UK. The Jenner Institute, University of Oxford, Oxford OX3 7DQ, UK.
4
Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305, USA. Singapore Immunology Network, Singapore 138648, Singapore.
5
Nuffield Department of Medicine, University of Oxford, Oxford OX1 3SY, UK. National Institute for Health Research Oxford Biomedical Research Centre, and Translational Gastroenterology Unit, Oxford OX3 7LE, UK.
6
Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305, USA.
7
ReiThera Srl (ex Okairos), Viale Città d'Europa 679, 00144 Rome, Italy. CEINGE, via Gaetano Salvatore 486, 80145 Naples, Italy. Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Via S. Pansini 5, 80131 Naples, Italy.
8
Okairos AG, 4051 Basel, Switzerland.
9
Nuffield Department of Medicine, University of Oxford, Oxford OX1 3SY, UK. The Jenner Institute, University of Oxford, Oxford OX3 7DQ, UK. National Institute for Health Research Oxford Biomedical Research Centre, and Translational Gastroenterology Unit, Oxford OX3 7LE, UK. ellie.barnes@ndm.ox.ac.uk.

Abstract

A protective vaccine against hepatitis C virus (HCV) remains an unmet clinical need. HCV infects millions of people worldwide and is a leading cause of liver cirrhosis and hepatocellular cancer. Animal challenge experiments, immunogenetics studies, and assessment of host immunity during acute infection highlight the critical role that effective T cell immunity plays in viral control. In this first-in-man study, we have induced antiviral immunity with functional characteristics analogous to those associated with viral control in natural infection, and improved upon a vaccine based on adenoviral vectors alone. We assessed a heterologous prime-boost vaccination strategy based on a replicative defective simian adenoviral vector (ChAd3) and modified vaccinia Ankara (MVA) vector encoding the NS3, NS4, NS5A, and NS5B proteins of HCV genotype 1b. Analysis used single-cell mass cytometry and human leukocyte antigen class I peptide tetramer technology in healthy human volunteers. We show that HCV-specific T cells induced by ChAd3 are optimally boosted with MVA, and generate very high levels of both CD8(+) and CD4(+) HCV-specific T cells targeting multiple HCV antigens. Sustained memory and effector T cell populations are generated, and T cell memory evolved over time with improvement of quality (proliferation and polyfunctionality) after heterologous MVA boost. We have developed an HCV vaccine strategy, with durable, broad, sustained, and balanced T cell responses, characteristic of those associated with viral control, paving the way for the first efficacy studies of a prophylactic HCV vaccine.

TRIAL REGISTRATION:

ClinicalTrials.gov NCT01296451.

PMID:
25378645
PMCID:
PMC4669853
DOI:
10.1126/scitranslmed.3009185
[Indexed for MEDLINE]
Free PMC Article

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