Potently neutralizing and protective human antibodies against SARS-CoV-2

Seth J. Zost, Pavlo Gilchuk, James Brett Case, Elad Binshtein, Rita E. Chen, Joseph P. Nkolola, Alexandra Schäfer, Joseph X. Reidy, Andrew Trivette, Rachel S. Nargi, Rachel E. Sutton, Naveenchandra Suryadevara, David R. Martinez, Lauren E. Williamson, Elaine C. Chen, Taylor Jones, Samuel Day, Luke Myers, Ahmed O. Hassan, Natasha M. Kafai, Emma S. Winkler, Julie M. Fox, Swathi Shrihari, Benjamin K. Mueller, Jens Meiler, Abishek Chandrashekar, Noe B. Mercado, James J. Steinhardt, Kuishu Ren, Yueh-Ming Loo, Nicole L. Kallewaard, Broc T. McCune, Shamus P. Keeler, Michael J. Holtzman, Dan H. Barouch, Lisa E. Gralinski, Ralph S. Baric, Larissa B. Thackray, Michael S. Diamond, Robert H. Carnahan () and James E. Crowe ()
Additional contact information
Seth J. Zost: Vanderbilt University Medical Center
Pavlo Gilchuk: Vanderbilt University Medical Center
James Brett Case: Washington University School of Medicine
Elad Binshtein: Vanderbilt University Medical Center
Rita E. Chen: Washington University School of Medicine
Joseph P. Nkolola: Harvard Medical School
Alexandra Schäfer: University of North Carolina at Chapel Hill
Joseph X. Reidy: Vanderbilt University Medical Center
Andrew Trivette: Vanderbilt University Medical Center
Rachel S. Nargi: Vanderbilt University Medical Center
Rachel E. Sutton: Vanderbilt University Medical Center
Naveenchandra Suryadevara: Vanderbilt University Medical Center
David R. Martinez: University of North Carolina at Chapel Hill
Lauren E. Williamson: Vanderbilt University Medical Center
Elaine C. Chen: Vanderbilt University Medical Center
Taylor Jones: Vanderbilt University Medical Center
Samuel Day: Vanderbilt University Medical Center
Luke Myers: Vanderbilt University Medical Center
Ahmed O. Hassan: Washington University School of Medicine
Natasha M. Kafai: Washington University School of Medicine
Emma S. Winkler: Washington University School of Medicine
Julie M. Fox: Washington University School of Medicine
Swathi Shrihari: Washington University School of Medicine
Benjamin K. Mueller: Vanderbilt University
Jens Meiler: Vanderbilt University
Abishek Chandrashekar: Harvard Medical School
Noe B. Mercado: Harvard Medical School
James J. Steinhardt: Antibody Discovery and Protein Engineering, BioPharmaceuticals R&D, AstraZeneca
Kuishu Ren: Microbial Sciences, BioPharmaceuticals R&D, AstraZeneca
Yueh-Ming Loo: Microbial Sciences, BioPharmaceuticals R&D, AstraZeneca
Nicole L. Kallewaard: Microbial Sciences, BioPharmaceuticals R&D, AstraZeneca
Broc T. McCune: Washington University School of Medicine
Shamus P. Keeler: Washington University School of Medicine
Michael J. Holtzman: Washington University School of Medicine
Dan H. Barouch: Harvard Medical School
Lisa E. Gralinski: University of North Carolina at Chapel Hill
Ralph S. Baric: University of North Carolina at Chapel Hill
Larissa B. Thackray: Washington University School of Medicine
Michael S. Diamond: Washington University School of Medicine
Robert H. Carnahan: Vanderbilt University Medical Center
James E. Crowe: Vanderbilt University Medical Center

Nature, 2020, vol. 584, issue 7821, 443-449

Abstract: Abstract 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 health1 and the medical countermeasures available so far are limited2,3. Moreover, we currently lack a thorough understanding of the mechanisms of humoral immunity to SARS-CoV-24. Here we analyse a large panel of human monoclonal antibodies that target the spike (S) glycoprotein5, and identify several that exhibit potent neutralizing activity and fully block the receptor-binding domain of the S protein (SRBD) 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 SRBD, 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 SRBD and provide a structure-based framework for rational vaccine design and the selection of robust immunotherapeutic agents.

Date: 2020
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DOI: 10.1038/s41586-020-2548-6

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