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

34 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.
@article{296223a9b3d749d88b2f1d3abedbf463,
title = "Systematic Analysis of Monoclonal Antibodies against Ebola Virus GP Defines Features that Contribute to Protection",
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.",
keywords = "antibody, consortium, ebola virus, epitope, glycoprotein, neutralization, protection",
author = "{the Viral Hemorrhagic Fever Immunotherapeutic Consortium} and Saphire, {Erica Ollmann} and Schendel, {Sharon L.} and Fusco, {Marnie L.} and Karthik Gangavarapu and Gunn, {Bronwyn M.} and Wec, {Anna Z.} and Halfmann, {Peter J.} and Brannan, {Jennifer M.} and Herbert, {Andrew S.} and Xiangguo Qiu and Kshitij Wagh and Shihua He and Giorgi, {Elena E.} and James Theiler and Pommert, {Kathleen B.J.} and Krause, {Tyler B.} and Turner, {Hannah L.} and Murin, {Charles D.} and Jesper Pallesen and Edgar Davidson and Rafi Ahmed and Aman, {M. Javad} and Alexander Bukreyev and Burton, {Dennis R.} and Crowe, {James E.} and Davis, {Carl W.} and George Georgiou and Florian Krammer and Kyratsous, {Christos A.} and Lai, {Jonathan R.} and Cory Nykiforuk and Pauly, {Michael H.} and Pramila Rijal and Ayato Takada and Townsend, {Alain R.} and Viktor Volchkov and Walker, {Laura M.} and Wang, {Cheng I.} and Larry Zeitlin and Doranz, {Benjamin J.} and Ward, {Andrew B.} and Bette Korber and Kobinger, {Gary P.} and Andersen, {Kristian G.} and Yoshihiro Kawaoka and Galit Alter and Kartik Chandran and Dye, {John M.}",
year = "2018",
month = "8",
day = "9",
doi = "10.1016/j.cell.2018.07.033",
language = "English (US)",
volume = "174",
pages = "938--952.e13",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "4",

}

TY - JOUR

T1 - Systematic Analysis of Monoclonal Antibodies against Ebola Virus GP Defines Features that Contribute to Protection

AU - the Viral Hemorrhagic Fever Immunotherapeutic Consortium

AU - Saphire, Erica Ollmann

AU - Schendel, Sharon L.

AU - Fusco, Marnie L.

AU - Gangavarapu, Karthik

AU - Gunn, Bronwyn M.

AU - Wec, Anna Z.

AU - Halfmann, Peter J.

AU - Brannan, Jennifer M.

AU - Herbert, Andrew S.

AU - Qiu, Xiangguo

AU - Wagh, Kshitij

AU - He, Shihua

AU - Giorgi, Elena E.

AU - Theiler, James

AU - Pommert, Kathleen B.J.

AU - Krause, Tyler B.

AU - Turner, Hannah L.

AU - Murin, Charles D.

AU - Pallesen, Jesper

AU - Davidson, Edgar

AU - Ahmed, Rafi

AU - Aman, M. Javad

AU - Bukreyev, Alexander

AU - Burton, Dennis R.

AU - Crowe, James E.

AU - Davis, Carl W.

AU - Georgiou, George

AU - Krammer, Florian

AU - Kyratsous, Christos A.

AU - Lai, Jonathan R.

AU - Nykiforuk, Cory

AU - Pauly, Michael H.

AU - Rijal, Pramila

AU - Takada, Ayato

AU - Townsend, Alain R.

AU - Volchkov, Viktor

AU - Walker, Laura M.

AU - Wang, Cheng I.

AU - Zeitlin, Larry

AU - Doranz, Benjamin J.

AU - Ward, Andrew B.

AU - Korber, Bette

AU - Kobinger, Gary P.

AU - Andersen, Kristian G.

AU - Kawaoka, Yoshihiro

AU - Alter, Galit

AU - Chandran, Kartik

AU - Dye, John M.

PY - 2018/8/9

Y1 - 2018/8/9

N2 - 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.

AB - 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.

KW - antibody

KW - consortium

KW - ebola virus

KW - epitope

KW - glycoprotein

KW - neutralization

KW - protection

UR - http://www.scopus.com/inward/record.url?scp=85050869127&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85050869127&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2018.07.033

DO - 10.1016/j.cell.2018.07.033

M3 - Article

C2 - 30096313

AN - SCOPUS:85050869127

VL - 174

SP - 938-952.e13

JO - Cell

JF - Cell

SN - 0092-8674

IS - 4

ER -