Antibodies from a Human Survivor Define Sites of Vulnerability for Broad Protection against Ebolaviruses

Anna Z. Wec, Andrew S. Herbert, Charles D. Murin, Elisabeth K. Nyakatura, Dafna M. Abelson, J. Maximilian Fels, Shihua He, Rebekah M. James, Marc Antoine de La Vega, Wenjun Zhu, Russell R. Bakken, Eileen Goodwin, Hannah L. Turner, Rohit K. Jangra, Larry Zeitlin, Xiangguo Qiu, Jonathan R. Lai, Laura M. Walker, Andrew B. Ward, John M. DyeKartik Chandran, Zachary A. Bornholdt

Research output: Contribution to journalArticle

62 Scopus citations

Abstract

Experimental monoclonal antibody (mAb) therapies have shown promise for treatment of lethal Ebola virus (EBOV) infections, but their species-specific recognition of the viral glycoprotein (GP) has limited their use against other divergent ebolaviruses associated with human disease. Here, we mined the human immune response to natural EBOV infection and identified mAbs with exceptionally potent pan-ebolavirus neutralizing activity and protective efficacy against three virulent ebolaviruses. These mAbs recognize an inter-protomer epitope in the GP fusion loop, a critical and conserved element of the viral membrane fusion machinery, and neutralize viral entry by targeting a proteolytically primed, fusion-competent GP intermediate (GPCL) generated in host cell endosomes. Only a few somatic hypermutations are required for broad antiviral activity, and germline-approximating variants display enhanced GPCL recognition, suggesting that such antibodies could be elicited more efficiently with suitably optimized GP immunogens. Our findings inform the development of both broadly effective immunotherapeutics and vaccines against filoviruses.

Original languageEnglish (US)
Pages (from-to)878-890.e15
JournalCell
Volume169
Issue number5
DOIs
StatePublished - May 18 2017

Keywords

  • 15878
  • EBOV
  • Ebola virus
  • ebolavirus
  • ferret
  • human broadly neutralizing antibodies
  • infection
  • mouse
  • neutralization
  • protection

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Wec, A. Z., Herbert, A. S., Murin, C. D., Nyakatura, E. K., Abelson, D. M., Fels, J. M., He, S., James, R. M., de La Vega, M. A., Zhu, W., Bakken, R. R., Goodwin, E., Turner, H. L., Jangra, R. K., Zeitlin, L., Qiu, X., Lai, J. R., Walker, L. M., Ward, A. B., ... Bornholdt, Z. A. (2017). Antibodies from a Human Survivor Define Sites of Vulnerability for Broad Protection against Ebolaviruses. Cell, 169(5), 878-890.e15. https://doi.org/10.1016/j.cell.2017.04.037