Characterization of Antigenic MHC-Class-I-Restricted T Cell Epitopes in the Glycoprotein of Ebolavirus

Jonathan Powlson, Daniel Wright, Antra Zeltina, Mark Giza, Morten Nielsen, Tommy Rampling, Navin Venkatrakaman, Thomas A. Bowden, Adrian V.S. Hill, Katie J. Ewer*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)

Abstract

Ebolavirus causes highly lethal hemorrhagic fever in humans. The envelope-displayed viral glycoprotein (GP) is the primary target of humoral immunity induced by natural exposure and vaccination. No T cell epitopes in the GP have been characterized in humans. A phase I clinical trial of a heterologous prime-boost vaccination regime with viral vectors encoding filovirus antigens elicits humoral and T cell responses in vaccinees. The most frequently recognized peptide pools are deconvoluted to identify the minimal epitopes recognized by antigen-specific T cells. We characterize nine immunogenic epitopes on the Ebolavirus GP. Histocompatibility leukocyte antigen (HLA) typing with in silico epitope analysis determines the likely MHC class I restriction elements. Thirteen HLA-A and -B alleles are predicted to present the identified CD8+ T cell epitopes, suggesting promiscuous recognition and a broad immune response. Delivery of the Ebolavirus GP antigen by using a heterologous prime-boost approach is immunogenic in genetically diverse human populations, with responses against multiple epitopes.

Original languageEnglish
Pages (from-to)2537-2545.e3
JournalCell Reports
Volume29
Issue number9
DOIs
Publication statusPublished - 26 Nov 2019
Externally publishedYes

Bibliographical note

Funding Information:
The ChAd3 vaccine was provided by the Vaccine Research Center of the National Institute of Allergy and Infectious Diseases (NIAID) and GlaxoSmithKline. MVA-BN Filo was produced under a contract (FBS-004-009) between the NIAID and Fisher BioServices and a contract (HHSN272200800044C) between the National Institutes of Health and Fisher Bioservices. The original clinical trial was supported by the Welcome Trust ( 106325/Z/14/Z ) and additional support was provided by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC). The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health. We are grateful to all of the clinicians, nurses, scientists, project managers, and investigators who were involved in the clinical trial that generated the samples used in this study. HLA-typing was performed by the Transplant Immunology & Immunogenetics laboratory of the Oxford University Hospitals NHS Trust. T.A.B. is supported by the MRC ( MR/S007555/1 and MR/L009528/1 ) and the Wellcome Centre for Human Genetics is supported by grant 203141/Z/16/Z . We thank Professor Miles Carroll, Dr. Yper Hall, and Dr. Tom Tipton of Public Health England and Dr. Alexander Mentzer of the Wellcome Centre for Human Genetics for helpful discussions and Dr. Sarah Sebastian of the Jenner Institute for reviewing the manuscript.

Funding Information:
The study was reviewed and approved by the United Kingdom National Research Ethics Service, the Committee South Central–Oxford A, the Medicines and Healthcare Products Regulatory Agency, and the Oxford University Clinical Trials and Research Governance team, who monitored compliance with Good Clinical Practice guidelines. An independent data and safety monitoring board provided safety oversight. Written informed consent was obtained from all participants and all participants were adults. The study was conducted in compliance with the clinical trial protocol, International Conference on Harmonisation Good Clinical Practice Guideline E6 (R1) (ICH-GCP) and the applicable regulatory requirements.

Funding Information:
Healthy adult volunteers (n = 60) were vaccinated with ChAd3-ZEBOV (1-5x10 10 viral particles) as part of a recent clinical trial ( ClinicalTrials.gov number, NCT02240875; Ewer et al., 2016 ). Of these, 30 subjects received vaccination with MVA-BN filo (1.5-3x10 8 plaque-forming units) as a heterologous boost 1-10 weeks after the priming vaccination. The original clinical trial from which these samples were obtained was supported by the Welcome Trust, the United Kingdom Medical Research Council, the United Kingdom Department for International Development, and the United Kingdom National Institute for Health Research Oxford Biomedical Research Centre (106325/Z/14/A). The clinical trial protocol was published with the original clinical study ( Ewer et al., 2016 ) and a CONSORT diagram and checklist are provided in the online Supplementary Appendix of Ewer et al. (2016a) . The age and sex information for the participants can be found in Table 1 in the preliminary version of this article that can be downloaded here: https://www.nejm.org/doi/full/10.1056/NEJMoa1411627 . Briefly, 60 participants were enrolled and 28 (47%) were female. The mean age was 32.2 years with a range from 18 to 49 years.

Funding Information:
The ChAd3 vaccine was provided by the Vaccine Research Center of the National Institute of Allergy and Infectious Diseases (NIAID) and GlaxoSmithKline. MVA-BN Filo was produced under a contract (FBS-004-009) between the NIAID and Fisher BioServices and a contract (HHSN272200800044C) between the National Institutes of Health and Fisher Bioservices. The original clinical trial was supported by the Welcome Trust (106325/Z/14/Z) and additional support was provided by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC). The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health. We are grateful to all of the clinicians, nurses, scientists, project managers, and investigators who were involved in the clinical trial that generated the samples used in this study. HLA-typing was performed by the Transplant Immunology & Immunogenetics laboratory of the Oxford University Hospitals NHS Trust. T.A.B. is supported by the MRC (MR/S007555/1 and MR/L009528/1) and the Wellcome Centre for Human Genetics is supported by grant 203141/Z/16/Z. We thank Professor Miles Carroll, Dr. Yper Hall, and Dr. Tom Tipton of Public Health England and Dr. Alexander Mentzer of the Wellcome Centre for Human Genetics for helpful discussions and Dr. Sarah Sebastian of the Jenner Institute for reviewing the manuscript. Conceptualization, K.J.E.; Methodology, K.J.E. M.N. A.Z. and T.A.B.; Investigation, J.P. D.W. and M.G.; Formal Analysis, J.P. D.W. M.G. A.Z. M.N. and K.J.E.; Resources, M.N. T.R. N.V. and T.A.B.; Writing ? Original Draft, J.P. and K.J.E.; Writing ? Review and Editing, all authors; Visualization, J.P. D.W. A.Z. and K.J.E.; Supervision, K.J.E. and A.V.S.H.; Funding Acquisition, T.R. and A.V.S.H. T.A.B. and A.Z. are listed as inventors on the International Patent Application No. PCT/GB2016/050321 ?Filovirus therapy.? K.J.E. and A.V.S.H. are named inventors on patents relating to viral vector vaccines for malaria and other diseases. The other authors declare no competing interests.

Publisher Copyright:
© 2019 The Author(s)

Keywords

  • CD8 T cells
  • Ebola
  • epitope-mapping
  • HLA-restriction
  • humans
  • vaccine

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