Systematic Analysis of Monoclonal Antibodies against Ebola Virus GP Defines Features that Contribute to Protection

Erica Ollmann Saphire; Sharon L Schendel; Marnie L Fusco; Karthik Gangavarapu; Bronwyn M Gunn; Anna Z Wec; Peter J Halfmann; Jennifer M Brannan; Andrew S Herbert; Xiangguo Qiu; Kshitij Wagh; Shihua He; Elena E Giorgi; James Theiler; Kathleen B J Pommert; Tyler B Krause; Hannah L Turner; Charles D Murin; Jesper Pallesen; Edgar Davidson; Rafi Ahmed; M Javad Aman; Alexander Bukreyev; Dennis R Burton; James E Crowe Jr; Carl W Davis; George Georgiou; Florian Krammer; Christos A Kyratsous; Jonathan R Lai; Cory Nykiforuk; Michael H Pauly; Pramila Rijal; Ayato Takada; Alain R Townsend; Viktor Volchkov; Laura M Walker; Cheng-I Wang; Larry Zeitlin; Benjamin J Doranz; Andrew B Ward; Bette Korber; Gary P Kobinger; Kristian G Andersen; Yoshihiro Kawaoka; Galit Alter; Kartik Chandran; John M Dye; Viral Hemorrhagic Fever Immunotherapeutic Consortium

doi:10.1016/j.cell.2018.07.033

Systematic Analysis of Monoclonal Antibodies against Ebola Virus GP Defines Features that Contribute to Protection

Cell. 2018 Aug 9;174(4):938-952.e13. doi: 10.1016/j.cell.2018.07.033.

Authors

Erica Ollmann Saphire¹, Sharon L Schendel², Marnie L Fusco², Karthik Gangavarapu², Bronwyn M Gunn³, Anna Z Wec⁴, Peter J Halfmann⁵, Jennifer M Brannan⁶, Andrew S Herbert⁶, Xiangguo Qiu⁷, Kshitij Wagh⁸, Shihua He⁷, Elena E Giorgi⁸, James Theiler⁸, Kathleen B J Pommert², Tyler B Krause⁴, Hannah L Turner⁹, Charles D Murin⁹, Jesper Pallesen⁹, Edgar Davidson¹⁰, Rafi Ahmed¹¹, M Javad Aman¹², Alexander Bukreyev¹³, Dennis R Burton², James E Crowe Jr¹⁴, Carl W Davis¹¹, George Georgiou¹⁵, Florian Krammer¹⁶, Christos A Kyratsous¹⁷, Jonathan R Lai¹⁸, Cory Nykiforuk¹⁹, Michael H Pauly²⁰, Pramila Rijal²¹, Ayato Takada²², Alain R Townsend²¹, Viktor Volchkov²³, Laura M Walker²⁴, Cheng-I Wang²⁵, Larry Zeitlin²⁰, Benjamin J Doranz¹⁰, Andrew B Ward⁹, Bette Korber⁸, Gary P Kobinger²⁶, Kristian G Andersen²⁷, Yoshihiro Kawaoka²⁸, Galit Alter²⁹, Kartik Chandran³⁰, John M Dye³¹; Viral Hemorrhagic Fever Immunotherapeutic Consortium

Affiliations

¹ Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA. Electronic address: erica@scripps.edu.
² Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA.
³ Ragon Institute, Cambridge, MA 02139, USA.
⁴ Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
⁵ Division of Pathobiological Sciences, University of Wisconsin, Madison, WI 53706, USA.
⁶ Division of Virology, United States Army Research Institute for Infectious Diseases, Ft. Detrick, MD 21702, USA.
⁷ National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg R3E 3R2, Canada.
⁸ Los Alamos National Laboratory, Los Alamos, NM 87545, USA.
⁹ Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
¹⁰ Integral Molecular, Philadelphia, PA 19104, USA.
¹¹ Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322, USA.
¹² Integrated BioTherapeutics, Rockville, MD 20850, USA.
¹³ Galveston National Laboratory, University of Texas Medical Branch, Galveston, TX 77555, USA.
¹⁴ Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
¹⁵ Department of Chemical Engineering, University of Texas at Austin, Austin, TX 78712, USA.
¹⁶ Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
¹⁷ Regeneron Pharmaceuticals, Inc., Tarrytown, NY 10591, USA.
¹⁸ Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
¹⁹ Emergent BioSolutions, Winnipeg, Manitoba, R3T 5Y3, Canada.
²⁰ Mapp Biopharmaceutical, San Diego, CA 92121, USA.
²¹ Human Immunology Unit, University of Oxford, Oxford OX3 9DS, UK.
²² Research Center for Zoonosis Control, Hokkaido University, Sapporo 001-0020, Japan.
²³ INSERM CNRS, Université Lyon, Lyon, France.
²⁴ Adimab, LLC. Lebanon, NH 03766, USA.
²⁵ Singapore Immunology Network, Agency for Science, Technology and Research (A(∗)STAR), Biopolis 138648, Singapore.
²⁶ Département de Microbiologie-Infectiologie et d'Immunologie, Médecine, Université Laval Quebec, G1V 046 Canada. Electronic address: gary.kobinger@crchudequebec.ulaval.ca.
²⁷ Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA. Electronic address: andersen@scripps.edu.
²⁸ Division of Pathobiological Sciences, University of Wisconsin, Madison, WI 53706, USA. Electronic address: kawaokay@svm.vetmed.wisc.edu.
²⁹ Ragon Institute, Cambridge, MA 02139, USA. Electronic address: galter@mgh.harvard.edu.
³⁰ Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA. Electronic address: kartik.chandran@einstein.yu.edu.
³¹ Division of Virology, United States Army Research Institute for Infectious Diseases, Ft. Detrick, MD 21702, USA. Electronic address: john.m.dye1.civ@mail.mil.

Abstract

Antibodies are promising post-exposure therapies against emerging viruses, but which antibody features and in vitro assays best forecast protection are unclear. Our international consortium systematically evaluated antibodies against Ebola virus (EBOV) using multidisciplinary assays. For each antibody, we evaluated epitopes recognized on the viral surface glycoprotein (GP) and secreted glycoprotein (sGP), readouts of multiple neutralization assays, fraction of virions left un-neutralized, glycan structures, phagocytic and natural killer cell functions elicited, and in vivo protection in a mouse challenge model. Neutralization and induction of multiple immune effector functions (IEFs) correlated most strongly with protection. Neutralization predominantly occurred via epitopes maintained on endosomally cleaved GP, whereas maximal IEF mapped to epitopes farthest from the viral membrane. Unexpectedly, sGP cross-reactivity did not significantly influence in vivo protection. This comprehensive dataset provides a rubric to evaluate novel antibodies and vaccine responses and a roadmap for therapeutic development for EBOV and related viruses.

Keywords: antibody; consortium; ebola virus; epitope; glycoprotein; neutralization; protection.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Antibodies, Monoclonal / administration & dosage
Antibodies, Monoclonal / immunology*
Antibodies, Monoclonal / isolation & purification*
Ebolavirus / immunology*
Epitopes / immunology*
Female
Hemorrhagic Fever, Ebola / immunology
Hemorrhagic Fever, Ebola / prevention & control*
Hemorrhagic Fever, Ebola / virology
Immunization
Membrane Glycoproteins / immunology*
Mice
Mice, Inbred BALB C
Treatment Outcome

Substances

Antibodies, Monoclonal
Epitopes
Membrane Glycoproteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding