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

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

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.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae / genetics
  • Adenoviridae / immunology*
  • Animals
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / virology
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / virology
  • Cell Proliferation
  • Cells, Cultured
  • England
  • Enzyme-Linked Immunospot Assay
  • Healthy Volunteers
  • Hepacivirus / genetics
  • Hepacivirus / immunology*
  • Hepacivirus / pathogenicity
  • Hepatitis C / diagnosis
  • Hepatitis C / immunology
  • Hepatitis C / prevention & control*
  • Hepatitis C / virology
  • Hepatitis C Antibodies / blood
  • Histocompatibility Antigens Class I / immunology
  • Humans
  • Immunologic Memory*
  • Interferon-gamma Release Tests
  • Lymphocyte Activation
  • Pan troglodytes
  • Time Factors
  • Treatment Outcome
  • Vaccination / methods*
  • Viral Hepatitis Vaccines / administration & dosage*
  • Viral Hepatitis Vaccines / genetics
  • Viral Hepatitis Vaccines / immunology
  • Viral Vaccines / administration & dosage*
  • Viral Vaccines / genetics
  • Viral Vaccines / immunology

Substances

  • Hepatitis C Antibodies
  • Histocompatibility Antigens Class I
  • MVA vaccine
  • Viral Hepatitis Vaccines
  • Viral Vaccines

Associated data

  • ClinicalTrials.gov/NCT01296451