Potently neutralizing and protective human antibodies against SARS-CoV-2
- 14 July 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature
- Vol. 584 (7821), 443-+
- https://doi.org/10.1038/s41586-020-2548-6
Abstract
An analysis identifies human monoclonal antibodies that potently neutralize wild-type SARS-CoV-2 and protect animals from disease, including two that synergize in a cocktail, suggesting that these could be candidates for use as therapeutic agents for the treatment of COVID-19 in humans. The ongoing pandemic of coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a major threat to global health(1)and the medical countermeasures available so far are limited(2,3). Moreover, we currently lack a thorough understanding of the mechanisms of humoral immunity to SARS-CoV-2(4). Here we analyse a large panel of human monoclonal antibodies that target the spike (S) glycoprotein(5), and identify several that exhibit potent neutralizing activity and fully block the receptor-binding domain of the S protein (S-RBD) from interacting with human angiotensin-converting enzyme 2 (ACE2). Using competition-binding, structural and functional studies, we show that the monoclonal antibodies can be clustered into classes that recognize distinct epitopes on the S-RBD, as well as distinct conformational states of the S trimer. Two potently neutralizing monoclonal antibodies, COV2-2196 and COV2-2130, which recognize non-overlapping sites, bound simultaneously to the S protein and neutralized wild-type SARS-CoV-2 virus in a synergistic manner. In two mouse models of SARS-CoV-2 infection, passive transfer of COV2-2196, COV2-2130 or a combination of both of these antibodies protected mice from weight loss and reduced the viral burden and levels of inflammation in the lungs. In addition, passive transfer of either of two of the most potent ACE2-blocking monoclonal antibodies (COV2-2196 or COV2-2381) as monotherapy protected rhesus macaques from SARS-CoV-2 infection. These results identify protective epitopes on the S(RBD)and provide a structure-based framework for rational vaccine design and the selection of robust immunotherapeutic agents.This publication has 59 references indexed in Scilit:
- Potent Neutralization of MERS-CoV by Human Neutralizing Monoclonal Antibodies to the Viral Spike GlycoproteinScience Translational Medicine, 2014
- Structural Basis for Potent Cross-Neutralizing Human Monoclonal Antibody Protection against Lethal Human and Zoonotic Severe Acute Respiratory Syndrome Coronavirus ChallengeJournal of Virology, 2008
- Potent cross-reactive neutralization of SARS coronavirus isolates by human monoclonal antibodiesProceedings of the National Academy of Sciences of the United States of America, 2007
- Human Monoclonal Antibody Combination against SARS Coronavirus: Synergy and Coverage of Escape MutantsPLoS Medicine, 2006
- Automated electron microscope tomography using robust prediction of specimen movementsJournal of Structural Biology, 2005
- UCSF Chimera?A visualization system for exploratory research and analysisJournal of Computational Chemistry, 2004
- Human monoclonal antibody as prophylaxis for SARS coronavirus infection in ferretsThe Lancet, 2004
- Potent neutralization of severe acute respiratory syndrome (SARS) coronavirus by a human mAb to S1 protein that blocks receptor associationProceedings of the National Academy of Sciences of the United States of America, 2004
- Negative staining and image classification — powerful tools in modern electron microscopyBiological Procedures Online, 2004
- Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirusNature, 2003