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Author Notes:

Correspondence: erica@scripps.edu (EOS); Gary.Kobinger@crchudequebec.ulaval.ca (GPK); andersen@scripps.edu (KGA); kawaokay@svm.vetmed.wisc.edu (YK); galter@mgh.harvard.edu (GA); kchandra@aecom.yu.edu (KC); john.m.dye1.civ@mail.mil (JMD)

Conceptualization, EOS, GPK, YK, KC, JMD; Validation, EOS, SLS, KG, YK, KC, JMD, XQ, GPK, KW, BK; Formal Analysis, EOS, MLF, KG, SLS, JMB, ASH, PJH, AZW, BMG, XQ, CDM, KW, EEG, JT, ABW, KGA, GA; Investigation, MLF, JMB, ASH, KW, PJH, AZW, BMG, SH, XQ, KBJP, HLT, CDM, JP, ED; TBK; Resources, EOS, XQ, RA, MJA, AB, DRB, JEC, CWD, GG, FK, CAK, JRL, CN, MHP, PR, AT, ART, VV, LMW, CIW, LZ, BJD, ABW, BK, GPK, YK, GA, KC, JMD; Data Curation, MLF, SLS; Writing-Original Draft, EOS, Review & Editing, EOS, SLS; Visualization, SLS, KG, JMB, AZW, BMG, CDM, KW, EOS; Funding Acquisition, EOS, GPK, YK, KC, JMD.

CN, MJA, ED, MHP and CAK are employees of Emergent BioSolutions, Integrated BioTherapeutics, Integral Molecular and Mapp Biopharmaceutical, respectively.

LMW and BJD are employees and shareholders of Adimab and Integral Molecular, respectively.

LZ is a shareholder and owner of Mapp Biopharmaceutical.

We thank the over 200 individuals who contributed their time, reagents and expertise. We also thank Julius Lutwama (UVRI), Leslie Lobel (Ben Gurion), Robert Garry and James Robinson (Tulane), Frederick Holtsberg (IBT), Luis Branco (Zalgen), Armand Sprecher (MSF), Lisa Hensley (NIAID IRF), and Heinz Feldmann (NIAID RML) for valuable discussions.

Subjects:

Research Funding:

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:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Biochemistry & Molecular Biology
  • Cell Biology
  • NATURAL-KILLER-CELLS
  • NONNEUTRALIZING ANTIBODIES
  • MEDIATED NEUTRALIZATION
  • IMMUNOGLOBULIN GENES
  • VIRION GLYCOPROTEINS
  • HEMORRHAGIC-FEVER
  • MARBURG VIRUS
  • IN-VIVO
  • INFECTION
  • EPITOPES

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

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Journal Title:

Analytical Cellular Pathology / Cellular Oncology

Volume:

Volume 174, Number 4

Publisher:

, Pages 938-+

Type of Work:

Article | Post-print: After Peer Review

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.

Copyright information:

© 2018 Elsevier Inc.

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