TY - JOUR
T1 - Potently neutralizing and protective human antibodies against SARS-CoV-2
AU - Zost, Seth J.
AU - Gilchuk, Pavlo
AU - Case, James Brett
AU - Binshtein, Elad
AU - Chen, Rita E.
AU - Nkolola, Joseph P.
AU - Schäfer, Alexandra
AU - Reidy, Joseph X.
AU - Trivette, Andrew
AU - Nargi, Rachel S.
AU - Sutton, Rachel E.
AU - Suryadevara, Naveenchandra
AU - Martinez, David R.
AU - Williamson, Lauren E.
AU - Chen, Elaine C.
AU - Jones, Taylor
AU - Day, Samuel
AU - Myers, Luke
AU - Hassan, Ahmed O.
AU - Kafai, Natasha M.
AU - Winkler, Emma S.
AU - Fox, Julie M.
AU - Shrihari, Swathi
AU - Mueller, Benjamin K.
AU - Meiler, Jens
AU - Chandrashekar, Abishek
AU - Mercado, Noe B.
AU - Steinhardt, James J.
AU - Ren, Kuishu
AU - Loo, Yueh Ming
AU - Kallewaard, Nicole L.
AU - McCune, Broc T.
AU - Keeler, Shamus P.
AU - Holtzman, Michael J.
AU - Barouch, Dan H.
AU - Gralinski, Lisa E.
AU - Baric, Ralph S.
AU - Thackray, Larissa B.
AU - Diamond, Michael S.
AU - Carnahan, Robert H.
AU - Crowe, James E.
N1 - Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2020/8/20
Y1 - 2020/8/20
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85087912666&partnerID=8YFLogxK
U2 - 10.1038/s41586-020-2548-6
DO - 10.1038/s41586-020-2548-6
M3 - Article
C2 - 32668443
AN - SCOPUS:85087912666
SN - 0028-0836
VL - 584
SP - 443
EP - 449
JO - Nature
JF - Nature
IS - 7821
ER -