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Asymmetric and non-stoichiometric glycoprotein recognition by two distinct antibodies results in broad protection against ebolaviruses

  1. Author:
    Milligan, Jacob C
    Davis, Carl W
    Yu, Xiaoying
    Ilinykh, Philipp A
    Huang, Kai
    Halfmann, Peter J
    Cross, Robert W
    Borisevich, Viktoriya
    Agans, Krystle N
    Geisbert, Joan B
    Chennareddy, Chakravarthy
    Goff, Arthur J
    Piper, Ashley E
    Hui, Sean
    Shaffer, Kelly C L
    Buck, Tierra
    Heinrich, Megan L
    Branco, Luis M
    Crozier,Ian
    Holbrook, Michael R
    Kuhn, Jens H
    Kawaoka, Yoshihiro
    Glass, Pamela J
    Bukreyev, Alexander
    Geisbert, Thomas W
    Worwa, Gabriella
    Ahmed, Rafi
    Saphire, Erica Ollmann

  2. Author Address

    Center for Infectious Disease and Vaccine Discovery, La Jolla Institute for Immunology, La Jolla, CA 92037, USA., Emory Vaccine Center and Department of Microbiology and Immunology, Emory University, Atlanta, GA 30322, USA., Center for Infectious Disease and Vaccine Discovery, La Jolla Institute for Immunology, La Jolla, CA 92037, USA; Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA., Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA; Galveston National Laboratory, Galveston, TX, 77550, USA., Division of Pathobiological Sciences, University of Wisconsin, Madison, WI 53706, USA., Galveston National Laboratory, Galveston, TX, 77550, USA; Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA., Virology Division, United States Army Research Institute for Infectious Disease, Fort Detrick, Frederick, MD 21702, USA., Zalgen Labs, Germantown, MD 20876, USA., Clinical Monitoring Research Program Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA., Integrated Research Facility at Fort Detrick, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Fort Detrick, Frederick, MD 21702, USA., Division of Pathobiological Sciences, University of Wisconsin, Madison, WI 53706, USA; Department of Microbiology and Immunology, Division of Virology, Institute of Medical Science, Department of Special Pathogens, International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo, Japan., Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA; Galveston National Laboratory, Galveston, TX, 77550, USA; Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA., Integrated Research Facility at Fort Detrick, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Fort Detrick, Frederick, MD 21702, USA. Electronic address: gabriella.worwa@nih.gov., Emory Vaccine Center and Department of Microbiology and Immunology, Emory University, Atlanta, GA 30322, USA. Electronic address: rahmed@emory.edu., Center for Infectious Disease and Vaccine Discovery, La Jolla Institute for Immunology, La Jolla, CA 92037, USA; Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: erica@lji.org.,
    1. Year: 2022
    2. Date: Mar 17
  2. Journal: Cell
    1. 185
    2. 6
    3. Pages: 995-1007.e18
  4. Type of Article: Article
  1. Abstract:

    Several ebolaviruses cause outbreaks of severe disease. Vaccines and monoclonal antibody cocktails are available to treat Ebola virus (EBOV) infections, but not Sudan virus (SUDV) or other ebolaviruses. Current cocktails contain antibodies that cross-react with the secreted soluble glycoprotein (sGP) that absorbs virus-neutralizing antibodies. By sorting memory B cells from EBOV infection survivors, we isolated two broadly reactive anti-GP monoclonal antibodies, 1C3 and 1C11, that potently neutralize, protect rodents from disease, and lack sGP cross-reactivity. Both antibodies recognize quaternary epitopes in trimeric ebolavirus GP. 1C11 bridges adjacent protomers via the fusion loop. 1C3 has a tripartite epitope in the center of the trimer apex. One 1C3 antigen-binding fragment anchors simultaneously to the three receptor-binding sites in the GP trimer, and separate 1C3 paratope regions interact differently with identical residues on the three protomers. A cocktail of both antibodies completely protected nonhuman primates from EBOV and SUDV infections, indicating their potential clinical value. Copyright © 2022 Elsevier Inc. All rights reserved.

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External Sources

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  2. DOI: 10.1016/j.cell.2022.02.023
  3. PMID: 35303429
  4. PII : S0092-8674(22)00203-3

Library Notes

  1. Fiscal Year: FY2021-2022
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