Ebola virus (EBOV) in humans causes a severe illness with high mortality rates. Several strategies have been developed in the past to treat EBOV infection, including the antibody cocktail ZMapp, which has been shown to be effective in nonhuman primate models of infection1 and has been used under compassionate-treatment protocols in humans2. ZMapp is a mixture of three chimerized murine monoclonal antibodies (mAbs)3,4,5,6 that target EBOV-specific epitopes on the surface glycoprotein7,8. However, ZMapp mAbs do not neutralize other species from the genus Ebolavirus, such as Bundibugyo virus (BDBV), Reston virus (RESTV) or Sudan virus (SUDV). Here, we describe three naturally occurring human cross-neutralizing mAbs, from BDBV survivors, that target an antigenic site in the canonical heptad repeat 2 (HR2) region near the membrane-proximal external region (MPER) of the glycoprotein. The identification of a conserved neutralizing antigenic site in the glycoprotein suggests that these mAbs could be used to design universal antibody therapeutics against diverse ebolavirus species. Furthermore, we found that immunization with a peptide comprising the HR2–MPER antigenic site elicits neutralizing antibodies in rabbits. Structural features determined by conserved residues in the antigenic site described here could inform an epitope-based vaccine design against infection caused by diverse ebolavirus species.

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This project received support from the Defense Threat Reduction Agency (grant HDTRA1-13-1-0034 to J.E.C. and A.B.), US NIH grants U19 AI109711 (to J.E.C. and A.B.), U19 AI109762 (to E.O.S. and A.B.W.), NIH contract HHSN272201400058C (to B.J.D.) and R01 AI067927 (to E.O.S.). E.O.S. is an investigator in the Pathogenesis of Infectious Disease of the Burroughs Wellcome Fund. The project was supported by NCRR grant UL1 RR024975-01 and is now at the National Center for Advancing Translational Sciences, grant 2 UL1 TR000445-06. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. We thank S. Graham and L. Loerinc at Vanderbilt University for help with the expression of recombinant antibodies. We thank P. Younan at UTMB for assisting with statistical calculations. We also thank A. McNeal, S. Reddy and R. Fong for technical help with shotgun mutagenesis epitope mapping. C.D.M. is supported by a National Science Foundation Graduate Research Fellowship.

Author information

Author notes

    • Andrew I. Flyak

    Present address: Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA


  1. Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, TN, USA

    • Andrew I. Flyak
    •  & James E. Crowe Jr
  2. Department of Pathology, University of Texas Medical Branch, Galveston, TX, USA

    • Natalia Kuzmina
    • , Philipp A. Ilinykh
    • , Xiaoli Shen
    • , Kai Huang
    • , Palaniappan Ramanathan
    • , Thomas G. Ksiazek
    •  & Alexander Bukreyev
  3. Galveston National Laboratory, Galveston, TX, USA

    • Natalia Kuzmina
    • , Philipp A. Ilinykh
    • , Xiaoli Shen
    • , Kai Huang
    • , Palaniappan Ramanathan
    • , Thomas G. Ksiazek
    •  & Alexander Bukreyev
  4. Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA, USA

    • Charles D. Murin
    • , Hannah Turner
    •  & Andrew B. Ward
  5. Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA, USA

    • Charles D. Murin
    • , Marnie L. Fusco
    •  & Erica Ollmann Saphire
  6. Integral Molecular, Inc., Philadelphia, PA, USA

    • Christopher Bryan
    • , Edgar Davidson
    •  & Benjamin J. Doranz
  7. Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN, USA

    • Pavlo Gilchuk
    • , Rebecca Lampley
    • , Nurgun Kose
    • , Hannah King
    • , Gopal Sapparapu
    •  & James E. Crowe Jr
  8. Department of Chemistry, Vanderbilt University Medical Center, Nashville, TN, USA

    • Christopher P. Gulka
    •  & David W. Wright
  9. The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA, USA

    • Erica Ollmann Saphire
  10. Department of Microbiology & Immunology, University of Texas Medical Branch, Galveston, TX, USA

    • Alexander Bukreyev
  11. Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA

    • James E. Crowe Jr


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A.I.F., A.B. and J.E.C. conceived the study. A.I.F., N.Kuzmina., C.D.M., C.B., E.D., P.G., P.A.I., X.S., K.H., P.R., H.T., R.L., N.Kose., H.K. and G.S. conducted the experiments. C.P.G., M.L.F., D.W.W. and E.O.S. provided reagents. A.I.F., N.Kuzmina., C.D.M., E.D., P.G., P.A.I., X.S., P.R., B.J.D., T.G.K., A.B.W., A.B. and J.E.C. analysed the data. A.I.F. and J.E.C. wrote the paper. All authors reviewed, edited and approved the paper.

Competing interests

C.B., E.D. and B.J.D. are employees of Integral Molecular. B.J.D. is a shareholder of Integral Molecular. J.E.C. is a consultant for Sanofi, and is on the Scientific Advisory Boards of PaxVax, CompuVax, GigaGen and Meissa Vaccines, is a recipient of previous unrelated research grants from Moderna and Sanofi and is founder of IDBiologics. A.I.F., P.A.I., A.B. and J.E.C. are co-inventors on a patent applied for that includes the BDBV223, BDBV317 and BDBV340 antibodies.

Corresponding authors

Correspondence to Alexander Bukreyev or James E. Crowe Jr.

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