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Broadly neutralizing antibodies from human survivors target a conserved site in the Ebola virus glycoprotein HR2–MPER region

Flyak, Andrew I. and Kuzmina, Natalia and Murin, Charles D. and Bryan, Christopher and Davidson, Edgar and Gilchuk, Pavlo and Gulka, Christopher P. and Ilinykh, Philipp A. and Shen, Xiaoli and Huang, Kai and Ramanathan, Palaniappan and Turner, Hannah and Fusco, Marnie L. and Lampley, Rebecca and Kose, Nurgun and King, Hannah and Sapparapu, Gopal and Doranz, Benjamin J. and Ksiazek, Thomas G. and Wright, David W. and Saphire, Erica Ollmann and Ward, Andrew B. and Bukreyev, Alexander and Crowe, James E., Jr. (2018) Broadly neutralizing antibodies from human survivors target a conserved site in the Ebola virus glycoprotein HR2–MPER region. Nature Microbiology, 3 (6). pp. 670-677. ISSN 2058-5276. https://resolver.caltech.edu/CaltechAUTHORS:20180514-102908465

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Abstract

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 infection and has been used under compassionate-treatment protocols in humans. ZMapp is a mixture of three chimerized murine monoclonal antibodies (mAbs) that target EBOV-specific epitopes on the surface glycoprotein. 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.


Item Type:Article
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https://doi.org/10.1038/s41564-018-0157-zDOIArticle
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ORCID:
AuthorORCID
Flyak, Andrew I.0000-0002-8722-479X
Saphire, Erica Ollmann0000-0002-1206-7451
Bukreyev, Alexander0000-0002-0342-4824
Crowe, James E., Jr.0000-0002-0049-1079
Additional Information:© 2018 Macmillan Publishers Limited, part of Springer Nature. Received: 11 May 2017; Accepted: 06 April 2018; Published: 07 May 2018. Data availability: The data that support the findings of this study are available from the corresponding authors upon request. 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 Contributions: 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.
Funders:
Funding AgencyGrant Number
Defense Threat Reduction AgencyHDTRA1-13-1-0034
NIHU19 AI109711
NIHU19 AI109762
NIHHHSN272201400058C
NIHR01 AI067927
Burroughs Wellcome FundUNSPECIFIED
NIHUL1 RR024975-01
NIH2 UL1 TR000445-06
NSF Graduate Research FellowshipUNSPECIFIED
Subject Keywords:Antibodies; Viral host response; Viral infection; Virology
Issue or Number:6
Record Number:CaltechAUTHORS:20180514-102908465
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20180514-102908465
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:86390
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:16 May 2018 14:20
Last Modified:09 Mar 2020 13:19

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