Circulating SARS-CoV-2 spike N439K variants maintain fitness while evading antibody-mediated immunity

被引：425

作者：

Thomson, Emma C. ^{[1
,2
]}

Rosen, Laura E. ^{[3
]}

Shepherd, James G. ^{[1
]}

Spreafico, Roberto ^{[3
]}

Filipe, Ana da Silva ^{[1
]}

Wojcechowskyj, Jason A. ^{[3
]}

Davis, Chris ^{[1
]}

Piccoli, Luca ^{[4
]}

Pascall, David J. ^{[5
]}

Dillen, Josh ^{[3
]}

Lytras, Spyros ^{[1
]}

Czudnochowski, Nadine ^{[3
]}

Shah, Rajiv ^{[1
]}

Meury, Marcel ^{[3
]}

Jesudason, Natasha ^{[1
]}

De Marco, Anna ^{[4
]}

Li, Kathy ^{[1
]}

Bassi, Jessica ^{[4
]}

O'Toole, Aine ^{[6
]}

Pinto, Dora ^{[4
]}

Colquhoun, Rachel M. ^{[6
]}

Culap, Katja ^{[4
]}

Jackson, Ben ^{[6
]}

Zatta, Fabrizia ^{[4
]}

Rambaut, Andrew ^{[6
]}

Jaconi, Stefano ^{[4
]}

Sreenu, Vattipally B. ^{[1
]}

Nix, Jay ^{[7
]}

Zhang, Ivy ^{[8
,9
]}

Jarrett, Ruth F. ^{[1
]}

Glass, William G. ^{[8
]}

Beltramello, Martina ^{[4
]}

Nomikou, Kyriaki ^{[1
]}

Pizzuto, Matteo ^{[4
]}

Tong, Lily ^{[1
]}

Cameroni, Elisabetta ^{[4
]}

Croll, Tristan, I ^{[10
]}

Johnson, Natasha ^{[1
]}

Di Iulio, Julia ^{[3
]}

Wickenhagen, Arthur ^{[1
]}

Ceschi, Alessandro ^{[11
,12
,13
]}

Harbison, Aoife M. ^{[14
]}

Mair, Daniel ^{[1
]}

Ferrari, Paolo ^{[15
,16
]}

Smollett, Katherine ^{[1
]}

Sallusto, Federica ^{[17
,18
]}

Carmichael, Stephen ^{[1
]}

Garzoni, Christian ^{[19
]}

Nichols, Jenna ^{[1
]}

Galli, Massimo ^{[20
]}

机构：

[1] Univ Glasgow, MRC Univ Glasgow Ctr Virus Res, Glasgow G61 1QH, Lanark, Scotland

[2] London Sch Hyg & Trop Med, Dept Clin Res, London WC1 7HT, England

[3] Vir Biotechnol, San Francisco, CA 94158 USA

[4] Humabs Biomed SA, CH-6500 Bellinzona, Switzerland

[5] Univ Glasgow, Boyd Orr Ctr Populat & Ecosyst Hlth, Inst Biodivers Anim Hlth & Comparat Med, Glasgow G61 1QN, Lanark, Scotland

[6] Univ Edinburgh, Inst Evolutionary Biol, Edinburgh EH9 3FL, Midlothian, Scotland

[7] Lawrence Berkeley Natl Lab, Adv Light Source, Mol Biol Consortium, Berkeley, CA 94720 USA

[8] Mem Sloan Kettering Canc Ctr, Sloan Kettering Inst, Computat & Syst Biol Program, New York, NY 10065 USA

[9] Weill Cornell Grad Sch Med Sci, Triinst PhD Program Computat Biol & Med, New York, NY 10065 USA

[10] Univ Cambridge, Cambridge Inst Med Res, Dept Haematol, Cambridge CB2 0XY, England

[11] Univ Svizzera Italiana, Fac Biomed Sci, CH-6900 Lugano, Switzerland

[12] Ente Osped Cantonale, Div Clin Pharmacol & Toxicol, Inst Pharmacol Sci Southern Switzerland, CH-6900 Lugano, Switzerland

[13] Univ Hosp Zurich, Dept Clin Pharmacol & Toxicol, CH-8091 Zurich, Switzerland

[14] Maynooth Univ, Dept Chem & Hamilton Inst, Maynooth, Kildare, Ireland

[15] Ente Osped Cantonale, Osped Civ Lugano, Dept Nephrol, CH-6900 Lugano, Switzerland

[16] Univ New South Wales, Prince Wales Hosp, Clin Sch, Sydney, NSW 2052, Australia

[17] Univ Svizzera Italiana, Inst Res Biomed, CH-6500 Bellinzona, Switzerland

[18] Swiss Fed Inst Technol, ETH Inst Microbiol, CH-8093 Zurich, Switzerland

[19] Clin Luganese Moncucco, Clin Internal Med & Infect Dis, CH-6900 Lugano, Switzerland

[20] Luigi Sacco Hosp, Div Infect Dis 3, ASST Fatebenefratelli Sacco, I-20157 Milan, Italy

[21] Univ Liverpool, Fac Hlth & Life Sci, NIHR Hlth Protect Res Unit Emerging & Zoonot Infe, Inst Infect Vet & Ecol Sci, Liverpool L69 7BE, Merseyside, England

[22] Alder Hey Childrens Hosp, Resp Med, Liverpool L12 2AP, Merseyside, England

[23] Imperial Coll London, Natl Heart & Lung Inst, London SW3 6LY, England

[24] Univ Edinburgh, Roslin Inst, Edinburgh EH25 9RG, Midlothian, Scotland

[25] Royal Infirm Edinburgh NHS Trust, Intens Care Unit, Edinburgh EH16 4SA, Midlothian, Scotland

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

来源：

CELL | 2021年 / 184卷 / 05期

基金：

英国医学研究理事会; 英国惠康基金; 英国生物技术与生命科学研究理事会;

关键词：

RECEPTOR-BINDING DOMAIN; MUTATIONS; ESCAPE; SYSTEM;

D O I：

10.1016/j.cell.2021.01.037

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

SARS-CoV-2 canmutate and evade immunity, with consequences for efficacy of emerging vaccines and antibody therapeutics. Here, we demonstrate that the immunodominant SARS-CoV-2 spike (S) receptor binding motif (RBM) is a highly variable region of S and provide epidemiological, clinical, and molecular characterization of a prevalent, sentinel RBM mutation, N439K. We demonstrate N439K S protein has enhanced binding affinity to the hACE2 receptor, and N439K viruses have similar in vitro replication fitness and cause infections with similar clinical outcomes as compared to wild type. We show the N439K mutation confers resistance against several neutralizing monoclonal antibodies, including one authorized for emergency use by the US Food and Drug Administration (FDA), and reduces the activity of some polyclonal sera from persons recovered from infection. Immune evasion mutations that maintain virulence and fitness such as N439K can emerge within SARS-CoV-2 S, highlighting the need for ongoing molecular surveillance to guide development and usage of vaccines and therapeutics.

引用

页码：1171 / +

页数：37

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