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Human antibody repertoire after VSV-Ebola vaccination identifies novel targets and virus-neutralizing IgM antibodies

Nature Medicine volume 22, pages 1439–1447 (2016)Cite this article

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A Corrigendum to this article was published on 07 February 2017

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Abstract

Development of an effective vaccine against Ebola virus is of high priority. However, knowledge about potential correlates of protection and the durability of immune response after vaccination is limited. Here, we elucidate the human antibody repertoire after administration of vesicular stomatitis virus (VSV)-Ebola vaccine at 3 million, 20 million and 100 million plaque-forming units (PFU) and homologous VSV-Ebola vaccine boost in healthy adult volunteers. Whole genome-fragment phage display libraries, expressing linear and conformational epitopes of Ebola glycoprotein (GP), showed higher diversity of antibody epitopes in individuals vaccinated with 20 million PFU than in those vaccinated with 3 million or 100 million PFU. Surface plasmon resonance kinetics showed higher levels of GP-binding antibodies after a single vaccination with 20 million or 100 million PFU than with 3 million PFU, and these correlated strongly with neutralization titers. A second vaccination did not boost antibody or virus neutralization titers, which declined rapidly, and induced only minimal antibody affinity maturation. Isotype analysis revealed a predominant IgM response even after the second vaccination, which contributed substantially to virus neutralization in vitro. These findings may help identify new vaccine targets and aid development and evaluation of effective countermeasures against Ebola.

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Figure 1: Analysis of antibody repertoires elicited in adults after first and second vaccinations with different doses of rVSVΔG-ZEBOV-GP.
Figure 2: Elucidation of antibody epitope profile against Ebola GP after rVSVΔG-ZEBOV-GP vaccination in humans.
Figure 3: Structural representation of antigenic sites in EBOV GP identified with GFPDL.
Figure 4: SPR-based analysis of sera from rVSVΔG-ZEBOV-GP-vaccinated individuals with EBOV GP purified protein.
Figure 5: Antibody isotypes in human serum binding to EBOV GP after vaccination and the role of IgM antibodies in virus neutralization.

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  • 15 November 2016

    In the version of this article initially published online, the authors omitted acknowledging a funding agency and researchers for providing the pseudovirion neutralization assay data. The acknowledgments section has been revised to state, “We thank the US Army Medical Research Institute of Infectious Diseases team, including S. Kwilas, M. Wisniewski and J. Hooper, for providing the pseudovirion neutralization assay data used in this study. The pseudovirion work was funded by the US Department of Defense (DoD) Medical Countermeasures Systems' Joint Vaccine Acquisition Program at Fort Detrick, Maryland. The opinions, interpretations, conclusions and recommendations contained herein are those of the authors and are not necessarily endorsed by the US DoD.” The error has been corrected for all versions of this article.

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Acknowledgements

We thank S. Rubin and H. Golding for reviewing the manuscript and J. Voell, P. Munoz, R. McConnell, H. Baus, C. Rehm and J. Metcalf for help with clinical studies. We thank J. Crowe (Vanderbilt University) for the gift of MAb 289 and MAb 324. The clinical trial from which the test sera were derived was funded partly by the US National Institute of Allergy and Infectious Diseases. The antibody characterization work described in this manuscript was supported by FDA-MCMi-Ebola funds to S.K. The latter funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. This project was funded in whole or in part with federal funds from the US National Cancer Institute under contract HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the US Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US government. We thank the US Army Medical Research Institute of Infectious Diseases team, including S. Kwilas, M. Wisniewski and J. Hooper, for providing the pseudovirion neutralization assay data used in this study. The pseudovirion work was funded by the US Department of Defense (DoD) Medical Countermeasures Systems' Joint Vaccine Acquisition Program at Fort Detrick, Maryland. The opinions, interpretations, conclusions and recommendations contained herein are those of the authors and are not necessarily endorsed by the US DoD.

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Authors and Affiliations

  1. Division of Viral Products, Center for Biologics Evaluation and Research (CBER), US Food and Drug Administration, Silver Spring, Maryland, USA

    Surender Khurana, Sandra Fuentes, Elizabeth M Coyle & Supriya Ravichandran

  2. National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA

    Richard T Davey Jr

  3. Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA

    John H Beigel

Authors
  1. Surender Khurana
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  2. Sandra Fuentes
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Contributions

S.K. designed research; S.F., S.R., E.M.C. and S.K. performed research; J.H.B. and R.T.D. conducted phase 1 study and contributed clinical samples; S.K., J.H.B. and R.T.D. contributed to writing the manuscript.

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Correspondence to Surender Khurana.

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Khurana, S., Fuentes, S., Coyle, E. et al. Human antibody repertoire after VSV-Ebola vaccination identifies novel targets and virus-neutralizing IgM antibodies. Nat Med 22, 1439–1447 (2016). https://doi.org/10.1038/nm.4201

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