Potent Neutralizing Antibodies from COVID-19 Patients Define Multiple Targets of Vulnerability

The rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has had a large impact on global health, travel, and economy. Therefore, preventative and therapeutic measures are urgently needed. Here, we isolated monoclonal antibodies from three convalescent coronavirus disease 2019 (COVID-19) patients using a SARS-CoV-2 stabilized prefusion spike protein. These antibodies had low levels of somatic hypermutation and showed a strong enrichment in VH1-69, VH3-30-3, and VH1-24 gene usage. A subset of the antibodies was able to potently inhibit authentic SARS-CoV-2 infection at a concentration as low as 0.007 micrograms per milliliter. Competition and electron microscopy studies illustrate that the SARS-CoV-2 spike protein contains multiple distinct antigenic sites, including several receptor-binding domain (RBD) epitopes as well as non-RBD epitopes. In addition to providing guidance for vaccine design, the antibodies described here are promising candidates for COVID-19 treatment and prevention.

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References

Pallesen J, Wang N, Corbett K, Wrapp D, Kirchdoerfer R, Turner H . Immunogenicity and structures of a rationally designed prefusion MERS-CoV spike antigen. Proc Natl Acad Sci U S A. 2017; 114(35):E7348-E7357. PMC: 5584442. DOI: 10.1073/pnas.1707304114. View

Lander G, Stagg S, Voss N, Cheng A, Fellmann D, Pulokas J . Appion: an integrated, database-driven pipeline to facilitate EM image processing. J Struct Biol. 2009; 166(1):95-102. PMC: 2775544. DOI: 10.1016/j.jsb.2009.01.002. View

Wang N, Rosen O, Wang L, Turner H, Stevens L, Corbett K . Structural Definition of a Neutralization-Sensitive Epitope on the MERS-CoV S1-NTD. Cell Rep. 2019; 28(13):3395-3405.e6. PMC: 6935267. DOI: 10.1016/j.celrep.2019.08.052. View

Jiang S, Hillyer C, Du L . Neutralizing Antibodies against SARS-CoV-2 and Other Human Coronaviruses. Trends Immunol. 2020; 41(5):355-359. PMC: 7129017. DOI: 10.1016/j.it.2020.03.007. View

Shang J, Ye G, Shi K, Wan Y, Luo C, Aihara H . Structural basis of receptor recognition by SARS-CoV-2. Nature. 2020; 581(7807):221-224. PMC: 7328981. DOI: 10.1038/s41586-020-2179-y. View

Ter Meulen J, van den Brink E, Poon L, Marissen W, Leung C, Cox F . Human monoclonal antibody combination against SARS coronavirus: synergy and coverage of escape mutants. PLoS Med. 2006; 3(7):e237. PMC: 1483912. DOI: 10.1371/journal.pmed.0030237. View

Chen X, Li R, Pan Z, Qian C, Yang Y, You R . Human monoclonal antibodies block the binding of SARS-CoV-2 spike protein to angiotensin converting enzyme 2 receptor. Cell Mol Immunol. 2020; 17(6):647-649. PMC: 7167496. DOI: 10.1038/s41423-020-0426-7. View

van Griensven J, Edwards T, de Lamballerie X, Semple M, Gallian P, Baize S . Evaluation of Convalescent Plasma for Ebola Virus Disease in Guinea. N Engl J Med. 2016; 374(1):33-42. PMC: 5856332. DOI: 10.1056/NEJMoa1511812. View

Sanders R, Derking R, Cupo A, Julien J, Yasmeen A, de Val N . A next-generation cleaved, soluble HIV-1 Env trimer, BG505 SOSIP.664 gp140, expresses multiple epitopes for broadly neutralizing but not non-neutralizing antibodies. PLoS Pathog. 2013; 9(9):e1003618. PMC: 3777863. DOI: 10.1371/journal.ppat.1003618. View

10.

Sandritter T . Palivizumab for respiratory syncytial virus prophylaxis. J Pediatr Health Care. 2000; 13(4):191-5; quiz 196-7. DOI: 10.1016/S0891-5245(99)90039-1. View

11.

Ko J, Seok H, Cho S, Ha Y, Baek J, Kim S . Challenges of convalescent plasma infusion therapy in Middle East respiratory coronavirus infection: a single centre experience. Antivir Ther. 2018; 23(7):617-622. DOI: 10.3851/IMP3243. View

12.

Okba N, Muller M, Li W, Wang C, GeurtsvanKessel C, Corman V . Severe Acute Respiratory Syndrome Coronavirus 2-Specific Antibody Responses in Coronavirus Disease Patients. Emerg Infect Dis. 2020; 26(7):1478-1488. PMC: 7323511. DOI: 10.3201/eid2607.200841. View

13.

Briney B, Inderbitzin A, Joyce C, Burton D . Commonality despite exceptional diversity in the baseline human antibody repertoire. Nature. 2019; 566(7744):393-397. PMC: 6411386. DOI: 10.1038/s41586-019-0879-y. View

14.

van Gils M, van den Kerkhof T, Ozorowski G, Cottrell C, Sok D, Pauthner M . An HIV-1 antibody from an elite neutralizer implicates the fusion peptide as a site of vulnerability. Nat Microbiol. 2016; 2:16199. PMC: 5372380. DOI: 10.1038/nmicrobiol.2016.199. View

15.

Gibson D, Young L, Chuang R, Venter J, Hutchison 3rd C, Smith H . Enzymatic assembly of DNA molecules up to several hundred kilobases. Nat Methods. 2009; 6(5):343-5. DOI: 10.1038/nmeth.1318. View

16.

Hershberger E, Sloan S, Narayan K, Hay C, Smith P, Engler F . Safety and efficacy of monoclonal antibody VIS410 in adults with uncomplicated influenza A infection: Results from a randomized, double-blind, phase-2, placebo-controlled study. EBioMedicine. 2019; 40:574-582. PMC: 6412085. DOI: 10.1016/j.ebiom.2018.12.051. View

17.

Zhao J, Yuan Q, Wang H, Liu W, Liao X, Su Y . Antibody Responses to SARS-CoV-2 in Patients With Novel Coronavirus Disease 2019. Clin Infect Dis. 2020; 71(16):2027-2034. PMC: 7184337. DOI: 10.1093/cid/ciaa344. View

18.

Robinson J, Hastie K, Cross R, Yenni R, Elliott D, Rouelle J . Most neutralizing human monoclonal antibodies target novel epitopes requiring both Lassa virus glycoprotein subunits. Nat Commun. 2016; 7:11544. PMC: 4866400. DOI: 10.1038/ncomms11544. View

19.

Tian X, Li C, Huang A, Xia S, Lu S, Shi Z . Potent binding of 2019 novel coronavirus spike protein by a SARS coronavirus-specific human monoclonal antibody. Emerg Microbes Infect. 2020; 9(1):382-385. PMC: 7048180. DOI: 10.1080/22221751.2020.1729069. View

20.

Wrapp D, Wang N, Corbett K, Goldsmith J, Hsieh C, Abiona O . Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science. 2020; 367(6483):1260-1263. PMC: 7164637. DOI: 10.1126/science.abb2507. View