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

• Type of Material: Article
• Authors: Erica Ollmann Saphire, Scripps Research Institute; Sharon L. Schendel, Scripps Research Institute; Marnie L. Fusco, Scripps Research Institute; Karthik Gangavarapu, Scripps Research Institute; Bronwyn M. Gunn, Ragon Institute; Anna Z. Wec, Albert Einstein College of Medicine; Peter J. Halfmann, University of Wisconsin; Jennifer M. Brannan, United States Army Research Institute for Infectious Diseases; Andrew S. Herbert, United States Army Research Institute for Infectious Diseases; Xiangguo Qiu, Public Health Agency of Canada; Kshitiji Wagh, Los Alamos National Laboratory; Shihua He, Los Alamos National Laboratory; Elena E. Giorgi, Los Alamos National Laboratory; James Theiler, Los Alamos National Laboratory; Kathleen B.J. Pommert, Scripps Research Institute; Tyler B. Krause, Albert Einstein College of Medicine; Hannah L. Turner, Scripps Research Institute; Charles D. Murin, Scripps Research Institute; Jesper Pallesen, Scripps Research Institute; Edgar Davidson, Integral Molecular; Rafi Ahmed, Emory University; M. Javad Aman, Integrated BioTherapeutics; Alexander Bukreyev, University of Texas Medical Branch; Dennis R. Burton, Scripps Research Institute; James E. Crowe, Vanderbilt University; Carl W. Davis, Emory University; George Georgiou, University of Texas Austin; Florian Krammer, Icahn School of Medicine at Mount Sinai; Christos A. Kyratsous, Regeneron Pharmaceut Inc; Jonathan R. Lai, Albert Einstein College of Medicine; Cory Nykiforuk, Emergent BioSolutions; Michael H. Pauly, Mapp Biopharmaceutical; Pramila Rijal, University of Oxford; Ayato Takada, Hokkaido University; Alain R. Townsend, University of Oxford; Viktor Volchkov, Université Lyon; Laura M. Walker, Adimab LLC; Cheng-I Wang, Agency for Science, Technology and Research ASTAR; Larry Zeitlin, Mapp Biopharmaceutical; Benjamin J. Doranz, Integral Molecular; Andrew B. Ward, Scripps Research Institute; Bette Korber, Los Alamos National Laboratory; Gary P. Kobinger, Université Laval Quebec; Kristian G. Andersen, Scripps Research Institute; Yoshihiro Kawaoka, University of Wisconsin; Galit Alter, Ragon Institute; Kartik Chandran, Albert Einstein College of Medicine; John M. Dye, United States Army Research Institute for Infectious Diseases
• Language: English
• Date: 2018-08-09
• Publisher: IOS Press
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2018 Elsevier Inc.
• Final Published Version (URL): http://dx.doi.org/10.1016/j.cell.2018.07.033
• Title of Journal or Parent Work: Analytical Cellular Pathology / Cellular Oncology
• ISSN: 1570-5870
• Volume: 174
• Issue: 4
• Start Page: 938
• End Page: +
• Grant/Funding Information: The major support for this project was U19 AI109762, a Centers of Excellence in Translational Research Award of NIAID.; This is manuscript #29635 of TSRI. Alanine scanning was done under NIAID contract HHSN272201400058C to B. Doranz; C-I Wang was supported by Human Therapeutic Monoclonal Antibodies Platform IAF311007; K. Andersen was also supported by U19AI135995.
• Keywords: NATURAL-KILLER-CELLS; MARBURG VIRUS; EPITOPES; Cell Biology; Biochemistry & Molecular Biology; Life Sciences & Biomedicine; INFECTION; VIRION GLYCOPROTEINS; NONNEUTRALIZING ANTIBODIES; IN-VIVO; HEMORRHAGIC-FEVER; Science & Technology; MEDIATED NEUTRALIZATION; IMMUNOGLOBULIN GENES
• Research Categories: Chemistry, Biochemistry; Biology, Microbiology; Health Sciences, Immunology

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. The systematic assessment of the effector functions and binding sites of antibodies against Ebola virus provides a generalizable framework to evaluate the determinants of antibody-mediated protection in viral disease.