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Potently neutralizing and protective human antibodies against SARS-CoV-2.
Nature. 2020 08; 584(7821):443-449.Nat

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.

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Authors+Show Affiliations

Zost SJ
Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN, USA.
Gilchuk P
Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN, USA.
Case JB
Department of Medicine, Washington University School of Medicine, St Louis, MO, USA.
Binshtein E
Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN, USA.
Chen RE
Department of Medicine, Washington University School of Medicine, St Louis, MO, USA. Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO, USA.
Nkolola JP
Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
Schäfer A
Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Reidy JX
Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN, USA.
Trivette A
Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN, USA.
Nargi RS
Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN, USA.
Sutton RE
Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN, USA.
Suryadevara N
Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN, USA.
Martinez DR
Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Williamson LE
Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.
Chen EC
Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.
Jones T
Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN, USA.
Day S
Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN, USA.
Myers L
Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN, USA.
Hassan AO
Department of Medicine, Washington University School of Medicine, St Louis, MO, USA.
Kafai NM
Department of Medicine, Washington University School of Medicine, St Louis, MO, USA. Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO, USA.
Winkler ES
Department of Medicine, Washington University School of Medicine, St Louis, MO, USA. Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO, USA.
Fox JM
Department of Medicine, Washington University School of Medicine, St Louis, MO, USA.
Shrihari S
Department of Medicine, Washington University School of Medicine, St Louis, MO, USA.
Mueller BK
Department of Chemistry, Vanderbilt University, Nashville, TN, USA.
Meiler J
Department of Chemistry, Vanderbilt University, Nashville, TN, USA. Leipzig University Medical School, Institute for Drug Discovery, Leipzig, Germany.
Chandrashekar A
Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
Mercado NB
Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
Steinhardt JJ
Antibody Discovery and Protein Engineering, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA.
Ren K
Microbial Sciences, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA.
Loo YM
Microbial Sciences, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA.
Kallewaard NL
Microbial Sciences, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA.
McCune BT
Department of Medicine, Washington University School of Medicine, St Louis, MO, USA.
Keeler SP
Department of Medicine, Washington University School of Medicine, St Louis, MO, USA. Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine, St Louis, MO, USA.
Holtzman MJ
Department of Medicine, Washington University School of Medicine, St Louis, MO, USA. Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine, St Louis, MO, USA.
Barouch DH
Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
Gralinski LE
Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Baric RS
Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Thackray LB
Department of Medicine, Washington University School of Medicine, St Louis, MO, USA.
Diamond MS
Department of Medicine, Washington University School of Medicine, St Louis, MO, USA. Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO, USA. Department of Molecular Microbiology, Washington University School of Medicine, St Louis, MO, USA. Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St Louis, MO, USA.
Carnahan RH
Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN, USA. Robert.carnahan@vumc.org. Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA. Robert.carnahan@vumc.org.
Crowe JE
Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN, USA. james.crowe@vumc.org. Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA. james.crowe@vumc.org. Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA. james.crowe@vumc.org.

MeSH

Angiotensin-Converting Enzyme 2AnimalsAntibodies, MonoclonalAntibodies, NeutralizingAntibodies, ViralBetacoronavirusBinding, CompetitiveCOVID-19Cell LineCoronavirus InfectionsCross ReactionsDisease Models, AnimalEpitopes, B-LymphocyteFemaleHumansMacaca mulattaMaleMiceMiddle AgedNeutralization TestsPandemicsPeptidyl-Dipeptidase APneumonia, ViralPre-Exposure ProphylaxisSARS VirusSARS-CoV-2Severe Acute Respiratory SyndromeSpike Glycoprotein, Coronavirus

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

32668443

Citation

Zost, Seth J., et al. "Potently Neutralizing and Protective Human Antibodies Against SARS-CoV-2." Nature, vol. 584, no. 7821, 2020, pp. 443-449.
Zost SJ, Gilchuk P, Case JB, et al. Potently neutralizing and protective human antibodies against SARS-CoV-2. Nature. 2020;584(7821):443-449.
Zost, S. J., Gilchuk, P., Case, J. B., Binshtein, E., Chen, R. E., Nkolola, J. P., Schäfer, A., Reidy, J. X., Trivette, A., Nargi, R. S., Sutton, R. E., Suryadevara, N., Martinez, D. R., Williamson, L. E., Chen, E. C., Jones, T., Day, S., Myers, L., Hassan, A. O., ... Crowe, J. E. (2020). Potently neutralizing and protective human antibodies against SARS-CoV-2. Nature, 584(7821), 443-449. https://doi.org/10.1038/s41586-020-2548-6
Zost SJ, et al. Potently Neutralizing and Protective Human Antibodies Against SARS-CoV-2. Nature. 2020;584(7821):443-449. PubMed PMID: 32668443.
* Article titles in AMA citation format should be in sentence-case
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,Jr Y1 - 2020/07/15/ PY - 2019/05/19/received PY - 2020/07/07/accepted PY - 2020/7/16/pubmed PY - 2020/8/28/medline PY - 2020/7/16/entrez SP - 443 EP - 449 JF - Nature JO - Nature VL - 584 IS - 7821 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. SN - 1476-4687 UR - https://www.unboundmedicine.com/medline/citation/32668443/Potently_neutralizing_and_protective_human_antibodies_against_SARS_CoV_2_ L2 - https://doi.org/10.1038/s41586-020-2548-6 DB - PRIME DP - Unbound Medicine ER -