A human vaccine strategy based on chimpanzee adenoviral and MVA vectors that primes, boosts, and sustains functional HCV-specific T cell memory.
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.
Nuffield Department of Medicine, University of Oxford, Oxford OX1 3SY, UK.
Leo
L
Swadling
ReiThera Srl (ex Okairos), Viale Città d'Europa 679, 00144 Rome, Italy.
Stefania
S
Capone
Nuffield Department of Medicine, University of Oxford, Oxford OX1 3SY, UK. The Jenner Institute, University of Oxford, Oxford OX3 7DQ, UK.
Richard D
RD
Antrobus
Nuffield Department of Medicine, University of Oxford, Oxford OX1 3SY, UK.
Anthony
A
Brown
Nuffield Department of Medicine, University of Oxford, Oxford OX1 3SY, UK.
Rachel
R
Richardson
Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305, USA. Singapore Immunology Network, Singapore 138648, Singapore.
Evan W
EW
Newell
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.
John
J
Halliday
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.
Christabel
C
Kelly
Nuffield Department of Medicine, University of Oxford, Oxford OX1 3SY, UK.
Dan
D
Bowen
Nuffield Department of Medicine, University of Oxford, Oxford OX1 3SY, UK.
Joannah
J
Fergusson
Nuffield Department of Medicine, University of Oxford, Oxford OX1 3SY, UK.
Ayako
A
Kurioka
ReiThera Srl (ex Okairos), Viale Città d'Europa 679, 00144 Rome, Italy.
Virginia
V
Ammendola
ReiThera Srl (ex Okairos), Viale Città d'Europa 679, 00144 Rome, Italy.
Mariarosaria
M
Del Sorbo
ReiThera Srl (ex Okairos), Viale Città d'Europa 679, 00144 Rome, Italy.
Fabiana
F
Grazioli
ReiThera Srl (ex Okairos), Viale Città d'Europa 679, 00144 Rome, Italy.
Maria Luisa
ML
Esposito
ReiThera Srl (ex Okairos), Viale Città d'Europa 679, 00144 Rome, Italy.
Loredana
L
Siani
ReiThera Srl (ex Okairos), Viale Città d'Europa 679, 00144 Rome, Italy.
Cinzia
C
Traboni
Nuffield Department of Medicine, University of Oxford, Oxford OX1 3SY, UK. The Jenner Institute, University of Oxford, Oxford OX3 7DQ, UK.
Adrian
A
Hill
ReiThera Srl (ex Okairos), Viale Città d'Europa 679, 00144 Rome, Italy.
Stefano
S
Colloca
Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305, USA.
Mark
M
Davis
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.
Alfredo
A
Nicosia
Okairos AG, 4051 Basel, Switzerland.
Riccardo
R
Cortese
ReiThera Srl (ex Okairos), Viale Città d'Europa 679, 00144 Rome, Italy.
Antonella
A
Folgori
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.
Paul
P
Klenerman
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.
Eleanor
E
Barnes
D000256:Adenoviridae / Q000235:genetics / Q000276:immunology*; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology; D049109:Cell Proliferation; D002478:Cells, Cultured; D004739:England; D058501:Enzyme-Linked Immunospot Assay; D064368:Healthy Volunteers; D016174:Hepacivirus / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity; D006526:Hepatitis C / Q000175:diagnosis / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D018937:Hepatitis C Antibodies / Q000097:blood; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D006801:Humans; D007156:Immunologic Memory; D059425:Interferon-gamma Release Tests; D008213:Lymphocyte Activation; D002679:Pan troglodytes; D013997:Time Factors; D016896:Treatment Outcome; D014611:Vaccination / Q000379:methods*; D019444:Vaccines, DNA; D014761:Viral Hepatitis Vaccines / Q000008:administration & dosage* / Q000235:genetics / Q000276:immunology; D014765:Viral Vaccines / Q000008:administration & dosage* / Q000235:genetics / Q000276:immunology
D018937:Hepatitis C Antibodies; D015395:Histocompatibility Antigens Class I; C560489:MVA vaccine; D019444:Vaccines, DNA; D014761:Viral Hepatitis Vaccines; D014765:Viral Vaccines