Pan-ebolavirus and pan-filovirus mouse monoclonal antibodies: Protection against Ebola and Sudan viruses

Frederick W. Holtsberg, Sergey Shulenin, Hong Vu, Katie A. Howell, Sonal J. Patel, Bronwyn Gunn, Marcus Karim, Jonathan R. Lai, Julia C. Frei, Elisabeth K. Nyakatura, Larry Zeitlin, Robin Douglas, Marnie L. Fusco, Jeffrey W. Froude, Erica Ollmann Saphire, Andrew S. Herbert, Ariel S. Wirchnianski, Calli M. Lear-Rooney, Galit Alter, John M. DyePamela J. Glass, Kelly L. Warfield, M. Javad Aman

Research output: Contribution to journalArticle

59 Scopus citations

Abstract

The unprecedented 2014-2015 Ebola virus disease (EVD) outbreak in West Africa has highlighted the need for effective therapeutics against filoviruses. Monoclonal antibody (MAb) cocktails have shown great potential as EVD therapeutics; however, the existing protective MAbs are virus species specific. Here we report the development of pan-ebolavirus and pan-filovirus antibodies generated by repeated immunization of mice with filovirus glycoproteins engineered to drive the B cell responses toward conserved epitopes. Multiple pan-ebolavirus antibodies were identified that react to the Ebola, Sudan, Bundibugyo, and Reston viruses. A pan-filovirus antibody that was reactive to the receptor binding regions of all filovirus glycoproteins was also identified. Significant postexposure efficacy of several MAbs, including a novel antibody cocktail, was demonstrated. For the first time, we report cross-neutralization and in vivo protection against two highly divergent filovirus species, i.e., Ebola virus and Sudan virus, with a single antibody. Competition studies indicate that this antibody targets a previously unrecognized conserved neutralizing epitope that involves the glycan cap. Mechanistic studies indicated that, besides neutralization, innate immune cell effector functions may play a role in the antiviral activity of the antibodies. Our findings further suggest critical novel epitopes that can be utilized to design effective cocktails for broad protection against multiple filovirus species.

Original languageEnglish (US)
Pages (from-to)266-278
Number of pages13
JournalJournal of Virology
Volume90
Issue number1
DOIs
StatePublished - 2016

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ASJC Scopus subject areas

  • Immunology
  • Virology

Cite this

Holtsberg, F. W., Shulenin, S., Vu, H., Howell, K. A., Patel, S. J., Gunn, B., Karim, M., Lai, J. R., Frei, J. C., Nyakatura, E. K., Zeitlin, L., Douglas, R., Fusco, M. L., Froude, J. W., Saphire, E. O., Herbert, A. S., Wirchnianski, A. S., Lear-Rooney, C. M., Alter, G., ... Aman, M. J. (2016). Pan-ebolavirus and pan-filovirus mouse monoclonal antibodies: Protection against Ebola and Sudan viruses. Journal of Virology, 90(1), 266-278. https://doi.org/10.1128/JVI.02171-15