Multifunctional Pan-ebolavirus Antibody Recognizes a Site of Broad Vulnerability on the Ebolavirus Glycoprotein

Pavlo Gilchuk; Natalia Kuzmina; Philipp A Ilinykh; Kai Huang; Bronwyn M Gunn; Aubrey Bryan; Edgar Davidson; Benjamin J Doranz; Hannah L Turner; Marnie L Fusco; Matthew S Bramble; Nicole A Hoff; Elad Binshtein; Nurgun Kose; Andrew I Flyak; Robin Flinko; Chiara Orlandi; Robert Carnahan; Erica H Parrish; Alexander M Sevy; Robin G Bombardi; Prashant K Singh; Patrick Mukadi; Jean Jacques Muyembe-Tamfum; Melanie D Ohi; Erica Ollmann Saphire; George K Lewis; Galit Alter; Andrew B Ward; Anne W Rimoin; Alexander Bukreyev; James E Crowe Jr

doi:10.1016/j.immuni.2018.06.018

Multifunctional Pan-ebolavirus Antibody Recognizes a Site of Broad Vulnerability on the Ebolavirus Glycoprotein

Immunity. 2018 Aug 21;49(2):363-374.e10. doi: 10.1016/j.immuni.2018.06.018. Epub 2018 Jul 17.

Authors

Pavlo Gilchuk¹, Natalia Kuzmina², Philipp A Ilinykh², Kai Huang², Bronwyn M Gunn³, Aubrey Bryan⁴, Edgar Davidson⁴, Benjamin J Doranz⁴, Hannah L Turner⁵, Marnie L Fusco⁶, Matthew S Bramble⁷, Nicole A Hoff⁸, Elad Binshtein⁹, Nurgun Kose¹, Andrew I Flyak¹⁰, Robin Flinko¹¹, Chiara Orlandi¹¹, Robert Carnahan¹, Erica H Parrish¹, Alexander M Sevy¹², Robin G Bombardi¹, Prashant K Singh⁹, Patrick Mukadi¹³, Jean Jacques Muyembe-Tamfum¹³, Melanie D Ohi⁹, Erica Ollmann Saphire¹⁴, George K Lewis¹¹, Galit Alter³, Andrew B Ward⁵, Anne W Rimoin⁸, Alexander Bukreyev¹⁵, James E Crowe Jr¹⁶

Affiliations

¹ Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
² Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA; Galveston National Laboratory, Galveston, TX 77550, USA.
³ Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA.
⁴ Integral Molecular, Inc., Philadelphia, PA 19104, USA.
⁵ Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
⁶ The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
⁷ Department of Epidemiology, Jonathan and Karin Fielding School of Public Health, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Genetic Medicine Research, Children's Research Institute, Children's National Medical Center, Washington, DC 20010, USA.
⁸ Department of Epidemiology, Jonathan and Karin Fielding School of Public Health, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁹ Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN 37232, USA.
¹⁰ Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
¹¹ Division of Vaccine Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
¹² Chemical and Physical Biology Program, Vanderbilt University, Nashville, TN 37232, USA.
¹³ Institut Nationale de Recherche Biomédicale, Kinshasa, Democratic Republic of the Congo.
¹⁴ Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA; Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA; The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
¹⁵ Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA; Galveston National Laboratory, Galveston, TX 77550, USA; Department of Microbiology & Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA. Electronic address: alexander.bukreyev@utmb.edu.
¹⁶ Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Chemical and Physical Biology Program, Vanderbilt University, Nashville, TN 37232, USA; Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232, USA. Electronic address: james.crowe@vanderbilt.edu.

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.

Keywords: Ebola hemorrhagic fever; cross protection; ebolavirus; epitope mapping; epitopes; glycoproteins; heterologous immunity; monoclonal antibodies; neutralizing antibodies; viral antibodies.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

3T3 Cells
Adult
Animals
Antibodies, Monoclonal / immunology*
Antibodies, Monoclonal / pharmacology*
Antibodies, Neutralizing / immunology*
Antibodies, Neutralizing / pharmacology*
Antibodies, Viral / immunology*
Antibodies, Viral / pharmacology*
CHO Cells
Cell Line
Chlorocebus aethiops
Cricetulus
Disease Models, Animal
Drosophila
Ebolavirus / immunology*
Female
Ferrets
Glycoproteins / immunology*
Guinea Pigs
Hemorrhagic Fever, Ebola / immunology*
Hemorrhagic Fever, Ebola / prevention & control
Hemorrhagic Fever, Ebola / virology
Humans
Immunoglobulin G / immunology
Jurkat Cells
Male
Mice
Mice, Inbred BALB C
Mice, Knockout
THP-1 Cells
Vero Cells

Substances

Antibodies, Monoclonal
Antibodies, Neutralizing
Antibodies, Viral
Glycoproteins
Immunoglobulin G

Abstract

Publication types

MeSH terms

Substances

Grants and funding