HEPATITIS C VIRUS

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

1. Leo Swadling1,*, 
2. Stefania Capone2,*, 
3. Richard D. Antrobus1,3,*, 
4. Anthony Brown1, 
5. Rachel Richardson1,
6. Evan W. Newell4,5, 
7. John Halliday1,6, 
8. Christabel Kelly1,6, 
9. Dan Bowen1, 
10. Joannah Fergusson1,
11. Ayako Kurioka1, 
12. Virginia Ammendola2, 
13. Mariarosaria Del Sorbo2, 
14. Fabiana Grazioli2,
15. Maria Luisa Esposito2, 
16. Loredana Siani2, 
17. Cinzia Traboni2, 
18. Adrian Hill1,3, 
19. Stefano Colloca2, 
20. Mark Davis4,
21. Alfredo Nicosia2,7,8, 
22. Riccardo Cortese9,†, 
23. Antonella Folgori2, 
24. Paul Klenerman1,6 and
25. Eleanor Barnes1,3,6,‡

+Author Affiliations

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

+Author Notes

• ↵* These authors contributed equally to this work.
• ↵† Present address: Keires AG, Elisabethenstrasse 15, 4051 Basel, Switzerland.

1. ↵‡Corresponding author. E-mail: 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.