1. Potently neutralizing and protective human antibodies against SARS-CoV-2.
- Author
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Zost SJ, Gilchuk P, Case JB, Binshtein E, Chen RE, Nkolola JP, Schäfer A, Reidy JX, Trivette A, Nargi RS, Sutton RE, Suryadevara N, Martinez DR, Williamson LE, Chen EC, Jones T, Day S, Myers L, Hassan AO, Kafai NM, Winkler ES, Fox JM, Shrihari S, Mueller BK, Meiler J, Chandrashekar A, Mercado NB, Steinhardt JJ, Ren K, Loo YM, Kallewaard NL, McCune BT, Keeler SP, Holtzman MJ, Barouch DH, Gralinski LE, Baric RS, Thackray LB, Diamond MS, Carnahan RH, and Crowe JE Jr
- Subjects
- Angiotensin-Converting Enzyme 2, Animals, Antibodies, Monoclonal immunology, Betacoronavirus chemistry, Binding, Competitive, COVID-19, Cell Line, Cross Reactions, Disease Models, Animal, Epitopes, B-Lymphocyte chemistry, Epitopes, B-Lymphocyte immunology, Female, Humans, Macaca mulatta, Male, Mice, Middle Aged, Neutralization Tests, Peptidyl-Dipeptidase A genetics, Peptidyl-Dipeptidase A metabolism, Pre-Exposure Prophylaxis, Severe acute respiratory syndrome-related coronavirus chemistry, Severe acute respiratory syndrome-related coronavirus immunology, SARS-CoV-2, Severe Acute Respiratory Syndrome immunology, Spike Glycoprotein, Coronavirus chemistry, Spike Glycoprotein, Coronavirus immunology, Spike Glycoprotein, Coronavirus metabolism, Antibodies, Neutralizing immunology, Antibodies, Viral immunology, Betacoronavirus immunology, Coronavirus Infections immunology, Coronavirus Infections prevention & control, Pandemics prevention & control, Pneumonia, Viral immunology, Pneumonia, Viral prevention & control
- 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 health
1 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.- Published
- 2020
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