@article{4c157c196fa34e2a9ab4ab61a8f4f52b,
title = "Multifunctional Pan-ebolavirus Antibody Recognizes a Site of Broad Vulnerability on the Ebolavirus Glycoprotein",
abstract = "Ebolaviruses cause severe disease in humans, and identification of monoclonal antibodies (mAbs) that are effective against multiple ebolaviruses are important for therapeutics development. Here we describe a distinct class of broadly neutralizing human mAbs with protective capacity against three ebolaviruses infectious for humans: Ebola (EBOV), Sudan (SUDV), and Bundibugyo (BDBV) viruses. We isolated mAbs from human survivors of ebolavirus disease and identified a potent mAb, EBOV-520, which bound to an epitope in the glycoprotein (GP) base region. EBOV-520 efficiently neutralized EBOV, BDBV, and SUDV and also showed protective capacity in relevant animal models of these infections. EBOV-520 mediated protection principally by direct virus neutralization and exhibited multifunctional properties. This study identified a potent naturally occurring mAb and defined key features of the human antibody response that may contribute to broad protection. This multifunctional mAb and related clones are promising candidates for development as broadly protective pan-ebolavirus therapeutic molecules. Ebola virus, a member of the Filoviridae family, causes severe disease in humans. Gilchuk et al. isolated and characterized broadly neutralizing human monoclonal antibodies active against all three clinically relevant ebolavirus species. Potent monoclonal antibody EBOV-520 binds to the glycoprotein base region, acts principally by direct virus neutralization, and exploits several mechanisms for contributing to pan-ebolavirus protective immunity.",
keywords = "Ebola hemorrhagic fever, cross protection, ebolavirus, epitope mapping, epitopes, glycoproteins, heterologous immunity, monoclonal antibodies, neutralizing antibodies, viral antibodies",
author = "Pavlo Gilchuk and Natalia Kuzmina and Ilinykh, {Philipp A.} and Kai Huang and Gunn, {Bronwyn M.} and Aubrey Bryan and Edgar Davidson and Doranz, {Benjamin J.} and Turner, {Hannah L.} and Fusco, {Marnie L.} and Bramble, {Matthew S.} and Hoff, {Nicole A.} and Elad Binshtein and Nurgun Kose and Flyak, {Andrew I.} and Robin Flinko and Chiara Orlandi and Robert Carnahan and Parrish, {Erica H.} and Sevy, {Alexander M.} and Bombardi, {Robin G.} and Singh, {Prashant K.} and Patrick Mukadi and Muyembe-Tamfum, {Jean Jacques} and Ohi, {Melanie D.} and Saphire, {Erica Ollmann} and Lewis, {George K.} and Galit Alter and Ward, {Andrew B.} and Rimoin, {Anne W.} and Alexander Bukreyev and Crowe, {James E.}",
note = "Funding Information: We thank Emile Okitolonda Wemakoy and Benoit Kebela Illunga who oversaw sample collection in DRC. We thank Drs. Morris Ibeawuchi, Ada Igonoh, and Benjamin Ohiaeri for advice and assistance with human subject matters related to the Nigerian outbreak. We thank Cinque Soto and Andre Branchizio for assistance with data visualization. The Jurkat-EBOV GP cell line and the protocol for cell surface GP cleavage were a kind gift from Carl Davis and Rafi Ahmed. This work was supported by U.S. NIH grants U19 AI109711 (to J.E.C. and A. Bukreyev), R01 AI067927 (to E.O.S.), and U19 AI109762 (to E.O.S. and A.B.W.), Defense Threat Reduction Agency grant HDTRA1-13-1-0034 (to J.E.C. and A. Bukreyev), HHS contract HHSN272201400058C (to J.E.C. and B.J.D.), Defense Advanced Research Project Agency grant W31P4Q-14-1-0010 (to J.E.C.), Fogarty International Center of the National Institutes of Health (NIH) under award number D43TW009343 and the University of California Global Health Institute (UCGHI) (to M.S.B.), and funding from the Bill and Melinda Gates Foundation (to J.E.C. and A.W.R. by subcontract from Atreca, Inc.). E.O.S. is an Investigator in the Pathogenesis of Infectious Disease of the Burroughs Welcome Fund . The project was supported by NCRR grant UL1 RR024975-01 , which 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. Flow cytometry experiments were performed in the VUMC Flow Cytometry Shared Resource, supported by NIH grants P30 CA68485 and DK058404 . The Intellicyt iQue is managed within the Vanderbilt Antibody and Protein Resource and was funded by NIH Shared Instrumentation Grant 1S10OD021737 . The EM work was conducted at The Scripps Research Institute electron microscopy facility. Work in BSL-4/ABSL-4 containment of the Galveston National Laboratory was supported by NIH grant 5UC7AI094660-07 . Animal studies were supported by the Animal Resource Center of the Galveston National Laboratory. Funding Information: We thank Emile Okitolonda Wemakoy and Benoit Kebela Illunga who oversaw sample collection in DRC. We thank Drs. Morris Ibeawuchi, Ada Igonoh, and Benjamin Ohiaeri for advice and assistance with human subject matters related to the Nigerian outbreak. We thank Cinque Soto and Andre Branchizio for assistance with data visualization. The Jurkat-EBOV GP cell line and the protocol for cell surface GP cleavage were a kind gift from Carl Davis and Rafi Ahmed. This work was supported by U.S. NIH grants U19 AI109711 (to J.E.C. and A. Bukreyev), R01 AI067927 (to E.O.S.), and U19 AI109762 (to E.O.S. and A.B.W.), Defense Threat Reduction Agency grant HDTRA1-13-1-0034 (to J.E.C. and A. Bukreyev), HHS contract HHSN272201400058C (to J.E.C. and B.J.D.), Defense Advanced Research Project Agency grant W31P4Q-14-1-0010 (to J.E.C.), Fogarty International Center of the National Institutes of Health (NIH) under award number D43TW009343 and the University of California Global Health Institute (UCGHI) (to M.S.B.), and funding from the Bill and Melinda Gates Foundation (to J.E.C. and A.W.R. by subcontract from Atreca, Inc.). E.O.S. is an Investigator in the Pathogenesis of Infectious Disease of the Burroughs Welcome Fund. The project was supported by NCRR grant UL1 RR024975-01, which 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. Flow cytometry experiments were performed in the VUMC Flow Cytometry Shared Resource, supported by NIH grants P30 CA68485 and DK058404. The Intellicyt iQue is managed within the Vanderbilt Antibody and Protein Resource and was funded by NIH Shared Instrumentation Grant 1S10OD021737. The EM work was conducted at The Scripps Research Institute electron microscopy facility. Work in BSL-4/ABSL-4 containment of the Galveston National Laboratory was supported by NIH grant 5UC7AI094660-07. Animal studies were supported by the Animal Resource Center of the Galveston National Laboratory. Publisher Copyright: {\textcopyright} 2018 The Author(s)",
year = "2018",
month = aug,
day = "21",
doi = "10.1016/j.immuni.2018.06.018",
language = "English (US)",
volume = "49",
pages = "363--374.e10",
journal = "Immunity",
issn = "1074-7613",
publisher = "Cell Press",
number = "2",
}