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 - Funding Information:
Competing interests R.S.B. has served as a consultant for Takeda and Sanofi Pasteur on issues related to vaccines. M.S.D. is a consultant for Inbios, Vir Biotechnology, NGM Biopharmaceuticals and Eli Lilly; is on the Scientific Advisory Board of Moderna; is a past recipient of an unrelated research grant from Moderna; and is a current recipient of an unrelated research grant from Emergent BioSolutions. J.E.C. has served as a consultant for Sanofi; is on the Scientific Advisory Boards of CompuVax and Meissa Vaccines; is a recipient of previous unrelated research grants from Moderna and Sanofi; and is a founder of IDBiologics. Vanderbilt University has applied for patents concerning SARS-CoV-2 antibodies that are related to this work. AstraZeneca has filed patents for materials and findings that are related to this work. J.J.S., K.R., Y.-M.L. and N.L.K. are employees of AstraZeneca and currently hold AstraZeneca stock or stock options. M.J.H. is a member of a data safety monitoring board for AstraZeneca and a founder of NuPeak Therapeutics. All other authors declare no competing interests.
Funding Information:
Acknowledgements We thank A. Jones and the staff of the Vanderbilt Technologies for Advanced Genomics (VANTAGE) core laboratory for expedited sequencing; R. Trosseth for assistance with data management and analysis; R. Bombardi and C. Soto of VUMC for technical consultation on genomics approaches; A. Kim, A. Bailey, L. VanBlargan and J. Earnest of WUSTL for experimental assistance and key reagents; K. M. Tuffy, S. Diallo, P. M. McTamney and L. Clarke of AstraZeneca for the generation of protein and pseudovirus reagents and related data; and H. Andersen, M. G. Lewis, R. Nityanandam, M. Kirilova and K. Verrington for research assistance with the NHP studies. This study was supported by Defense Advanced Research Projects Agency (DARPA) grants HR0011-18-2-0001 and HR00 11-18-3-0001; NIH contracts 75N93019C00074 and 75N93019C00062; NIH grants U01 AI150739, R01 AI130591 and R35 HL145242; the Dolly Parton COVID-19 Research Fund at Vanderbilt; and NIH grant S10 RR028106 for the Next Generation Nucleic Acid Sequencer, housed in VANTAGE and the Vanderbilt Institute for Clinical and Translational Research with grant support from UL1TR002243 from NCATS/NIH. S.J.Z. was supported by NIH T32 AI095202; J.B.C. was supported by a Helen Hay Whitney Foundation postdoctoral fellowship; B.T.M. was supported by NIH F32 AI138392; D.R.M. was supported by NIH T32 AI007151 and a Burroughs Wellcome Fund Postdoctoral Enrichment Program Award; L.E.W. was supported by NIH F31 AI145189; E.C.C. was supported by NIH T32 AI138932; and J.E.C. is the recipient of the 2019 Future Insight Prize from Merck KGaA, which supported this research with a research grant. The content is solely the responsibility of the authors and does not necessarily represent the official views of the US government or the other sponsors.
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 -