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

the Viral Hemorrhagic Fever Immunotherapeutic Consortium

    Research output: Contribution to journalArticle

    27 Citations (Scopus)

    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.

    Original languageEnglish (US)
    Pages (from-to)938-952.e13
    JournalCell
    Volume174
    Issue number4
    DOIs
    StatePublished - Aug 9 2018

    Fingerprint

    Ebolavirus
    Viruses
    Glycoproteins
    Monoclonal Antibodies
    Antibodies
    Epitopes
    Assays
    Implosive Therapy
    Antibody Binding Sites
    Membrane Glycoproteins
    Virus Diseases
    Natural Killer Cells
    Virion
    Antibody Formation
    Polysaccharides
    Vaccines
    Membranes

    Keywords

    • antibody
    • consortium
    • ebola virus
    • epitope
    • glycoprotein
    • neutralization
    • protection

    ASJC Scopus subject areas

    • Biochemistry, Genetics and Molecular Biology(all)

    Cite this

    Systematic Analysis of Monoclonal Antibodies against Ebola Virus GP Defines Features that Contribute to Protection. / the Viral Hemorrhagic Fever Immunotherapeutic Consortium.

    In: Cell, Vol. 174, No. 4, 09.08.2018, p. 938-952.e13.

    Research output: Contribution to journalArticle

    the Viral Hemorrhagic Fever Immunotherapeutic Consortium. / Systematic Analysis of Monoclonal Antibodies against Ebola Virus GP Defines Features that Contribute to Protection. In: Cell. 2018 ; Vol. 174, No. 4. pp. 938-952.e13.
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    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.",
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