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

被引：616

作者：

Zost, Seth J. ^{[1
]}

Gilchuk, Pavlo ^{[1
]}

Case, James Brett ^{[2
]}

Binshtein, Elad ^{[1
]}

Chen, Rita E. ^{[2
,3
]}

Nkolola, Joseph P. ^{[4
]}

Schafer, Alexandra ^{[5
]}

Reidy, Joseph X. ^{[1
]}

Trivette, Andrew ^{[1
]}

Nargi, Rachel S. ^{[1
]}

Sutton, Rachel E. ^{[1
]}

Suryadevara, Naveenchandra ^{[1
]}

Martinez, David R. ^{[5
]}

Williamson, Lauren E. ^{[6
]}

Chen, Elaine C. ^{[6
]}

Jones, Taylor ^{[1
]}

Day, Samuel ^{[1
]}

Myers, Luke ^{[1
]}

Hassan, Ahmed O. ^{[2
]}

Kafai, Natasha M. ^{[2
,3
]}

Winkler, Emma S. ^{[2
,3
]}

Fox, Julie M. ^{[2
]}

Shrihari, Swathi ^{[2
]}

Mueller, Benjamin K. ^{[7
]}

Meiler, Jens ^{[7
,8
]}

Chandrashekar, Abishek ^{[4
]}

Mercado, Noe B. ^{[4
]}

Steinhardt, James J. ^{[9
]}

Ren, Kuishu ^{[10
]}

Loo, Yueh-Ming ^{[10
]}

Kallewaard, Nicole L. ^{[10
]}

McCune, Broc T. ^{[2
]}

Keeler, Shamus P. ^{[2
,11
]}

Holtzman, Michael J. ^{[2
,11
]}

Barouch, Dan H. ^{[4
]}

Gralinski, Lisa E. ^{[5
]}

Baric, Ralph S. ^{[5
]}

Thackray, Larissa B. ^{[2
]}

Diamond, Michael S. ^{[2
,3
,12
,13
]}

Carnahan, Robert H. ^{[1
,14
]}

Crowe, James E., Jr. ^{[1
,6
,14
]}

机构：

[1] Vanderbilt Univ, Med Ctr, Vanderbilt Vaccine Ctr, Nashville, TN 37232 USA

[2] Washington Univ, Sch Med, Dept Med, St Louis, MO 63110 USA

[3] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA

[4] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Ctr Virol & Vaccine Res, Boston, MA 02115 USA

[5] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27515 USA

[6] Vanderbilt Univ, Med Ctr, Dept Pathol Microbiol & Immunol, Nashville, TN 37232 USA

[7] Vanderbilt Univ, Dept Chem, Nashville, TN USA

[8] Univ Leipzig, Inst Drug Discovery, Sch Med, Leipzig, Germany

[9] AstraZeneca, BioPharmaceut R&D, Antibody Discovery & Prot Engn, Gaithersburg, MD USA

[10] AstraZeneca, BioPharmaceut R&D, Microbial Sci, Gaithersburg, MD USA

[11] Washington Univ, Sch Med, Div Pulm & Crit Care Med, St Louis, MO USA

[12] Washington Univ, Sch Med, Dept Mol Microbiol, St Louis, MO 63110 USA

[13] Washington Univ, Sch Med, Andrew M & Jane M Bursky Ctr Human Immunol & Immu, St Louis, MO USA

[14] Vanderbilt Univ, Med Ctr, Dept Pediat, Nashville, TN 37232 USA

来源：

NATURE | 2020年 / 584卷 / 7821期

关键词：

HUMAN MONOCLONAL-ANTIBODY; RESPIRATORY SYNDROME CORONAVIRUS; CRYO-EM STRUCTURE; SARS CORONAVIRUS; MERS-COV; STRUCTURAL DEFINITION; RECEPTOR; SPIKE; EPITOPE;

D O I：

10.1038/s41586-020-2548-6

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

An analysis identifies human monoclonal antibodies that potently neutralize wild-type SARS-CoV-2 and protect animals from disease, including two that synergize in a cocktail, suggesting that these could be candidates for use as therapeutic agents for the treatment of COVID-19 in humans. 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 limited(2,3). Moreover, we currently lack a thorough understanding of the mechanisms of humoral immunity to SARS-CoV-2(4). Here we analyse a large panel of human monoclonal antibodies that target the spike (S) glycoprotein(5), and identify several that exhibit potent neutralizing activity and fully block the receptor-binding domain of the S protein (S-RBD) 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 S-RBD, 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 S(RBD)and provide a structure-based framework for rational vaccine design and the selection of robust immunotherapeutic agents.

引用

页码：443 / +

页数：19

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