Structures of protective antibodies reveal sites of vulnerability on Ebola virus
- 17 November 2014
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 111 (48), 17182-17187
- https://doi.org/10.1073/pnas.1414164111
Abstract
Ebola virus (EBOV) and related filoviruses cause severe hemorrhagic fever, with up to 90% lethality, and no treatments are approved for human use. Multiple recent outbreaks of EBOV and the likelihood of future human exposure highlight the need for pre- and postexposure treatments. Monoclonal antibody (mAb) cocktails are particularly attractive candidates due to their proven postexposure efficacy in nonhuman primate models of EBOV infection. Two candidate cocktails, MB-003 and ZMAb, have been extensively evaluated in both in vitro and in vivo studies. Recently, these two therapeutics have been combined into a new cocktail named ZMapp, which showed increased efficacy and has been given compassionately to some human patients. Epitope information and mechanism of action are currently unknown for most of the component mAbs. Here we provide single-particle EM reconstructions of every mAb in the ZMapp cocktail, as well as additional antibodies from MB-003 and ZMAb. Our results illuminate key and recurring sites of vulnerability on the EBOV glycoprotein and provide a structural rationale for the efficacy of ZMapp. Interestingly, two of its components recognize overlapping epitopes and compete with each other for binding. Going forward, this work now provides a basis for strategic selection of next-generation antibody cocktails against Ebola and related viruses and a model for predicting the impact of ZMapp on potential escape mutations in ongoing or future Ebola outbreaks.Keywords
Funding Information
- HHS | National Institutes of Health (NIH) (R01AI067927)
- HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID) (U19AI109762)
This publication has 66 references indexed in Scilit:
- Enhanced potency of a fucose-free monoclonal antibody being developed as an Ebola virus immunoprotectantProceedings of the National Academy of Sciences of the United States of America, 2011
- A shared structural solution for neutralizing ebolavirusesNature Structural & Molecular Biology, 2011
- Small molecule inhibitors reveal Niemann–Pick C1 is essential for Ebola virus infectionNature, 2011
- Prospects for immunisation against Marburg and Ebola virusesReviews in Medical Virology, 2010
- Structure of the Ebola virus glycoprotein bound to an antibody from a human survivorNature, 2008
- Complex of a Protective Antibody with Its Ebola Virus GP Peptide Epitope: Unusual Features of a Vλx Light ChainJournal of Molecular Biology, 2008
- Rapid high-yield expression of full-size IgG antibodies in plants coinfected with noncompeting viral vectorsProceedings of the National Academy of Sciences of the United States of America, 2006
- EMAN2: An extensible image processing suite for electron microscopyJournal of Structural Biology, 2006
- UCSF Chimera?A visualization system for exploratory research and analysisJournal of Computational Chemistry, 2004
- A New Generation of the IMAGIC Image Processing SystemJournal of Structural Biology, 1996