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Cell. 2017 May 18;169(5):891-904.e15. doi: 10.1016/j.cell.2017.04.038.

Immunization-Elicited Broadly Protective Antibody Reveals Ebolavirus Fusion Loop as a Site of Vulnerability.

Author information

1
Institute for Bioscience and Biotechnology Research, University of Maryland, Rockville, MD 20878, USA.
2
Integrated BioTherapeutics, Rockville, MD 20850, USA.
3
Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, MB R3E 3R2, Canada; Deparment of Medical Microbiology, University of Manitoba, MB R3E 0J9, Canada.
4
US Army Medical Research Institute of Infectious Diseases, Frederick, MD 21701, USA.
5
Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
6
Integral Molecular, Philadelphia, PA 19104, USA.
7
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
8
Immunology Division, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia.
9
Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA.
10
Institute for Bioscience and Biotechnology Research, University of Maryland, Rockville, MD 20878, USA; Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USA. Electronic address: liy@ibbr.umd.edu.
11
Integrated BioTherapeutics, Rockville, MD 20850, USA. Electronic address: javad@integratedbiotherapeutics.com.

Abstract

While neutralizing antibodies are highly effective against ebolavirus infections, current experimental ebolavirus vaccines primarily elicit species-specific antibody responses. Here, we describe an immunization-elicited macaque antibody (CA45) that clamps the internal fusion loop with the N terminus of the ebolavirus glycoproteins (GPs) and potently neutralizes Ebola, Sudan, Bundibugyo, and Reston viruses. CA45, alone or in combination with an antibody that blocks receptor binding, provided full protection against all pathogenic ebolaviruses in mice, guinea pigs, and ferrets. Analysis of memory B cells from the immunized macaque suggests that elicitation of broadly neutralizing antibodies (bNAbs) for ebolaviruses is possible but difficult, potentially due to the rarity of bNAb clones and their precursors. Unexpectedly, germline-reverted CA45, while exhibiting negligible binding to full-length GP, bound a proteolytically remodeled GP with picomolar affinity, suggesting that engineered ebolavirus vaccines could trigger rare bNAb precursors more robustly. These findings have important implications for developing pan-ebolavirus vaccine and immunotherapeutic cocktails.

PMID:
28525756
PMCID:
PMC5803079
DOI:
10.1016/j.cell.2017.04.038
[Indexed for MEDLINE]
Free PMC Article

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