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Cell. 2017 May 18;169(5):878-890.e15. doi: 10.1016/j.cell.2017.04.037.

Antibodies from a Human Survivor Define Sites of Vulnerability for Broad Protection against Ebolaviruses.

Author information

1
Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
2
U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, MD 21702, USA.
3
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA; Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA.
4
Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
5
Mapp Biopharmaceutical, San Diego, CA 92121, USA.
6
Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, MB R3E 3R2, Canada; Department of Medical Microbiology, University of Manitoba, Winnipeg, MB R3E 0J9, Canada.
7
Adimab, LLC, Lebanon, NH 03766, USA.
8
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
9
U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, MD 21702, USA. Electronic address: john.m.dye1.civ@mail.mil.
10
Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA. Electronic address: kartik.chandran@einstein.yu.edu.
11
Mapp Biopharmaceutical, San Diego, CA 92121, USA. Electronic address: zachary.bornholdt@mappbio.com.

Abstract

Experimental monoclonal antibody (mAb) therapies have shown promise for treatment of lethal Ebola virus (EBOV) infections, but their species-specific recognition of the viral glycoprotein (GP) has limited their use against other divergent ebolaviruses associated with human disease. Here, we mined the human immune response to natural EBOV infection and identified mAbs with exceptionally potent pan-ebolavirus neutralizing activity and protective efficacy against three virulent ebolaviruses. These mAbs recognize an inter-protomer epitope in the GP fusion loop, a critical and conserved element of the viral membrane fusion machinery, and neutralize viral entry by targeting a proteolytically primed, fusion-competent GP intermediate (GPCL) generated in host cell endosomes. Only a few somatic hypermutations are required for broad antiviral activity, and germline-approximating variants display enhanced GPCL recognition, suggesting that such antibodies could be elicited more efficiently with suitably optimized GP immunogens. Our findings inform the development of both broadly effective immunotherapeutics and vaccines against filoviruses.

KEYWORDS:

15878; EBOV; Ebola virus; ebolavirus; ferret; human broadly neutralizing antibodies; infection; mouse; neutralization; protection

PMID:
28525755
PMCID:
PMC5808922
DOI:
10.1016/j.cell.2017.04.037
[Indexed for MEDLINE]
Free PMC Article

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