N-terminal domain antigenic mapping reveals a site of vulnerability for SARS-CoV-2

Matthew McCallum; Anna De Marco; Florian A. Lempp; M. Alejandra Tortorici; Dora Pinto; Alexandra C. Walls; Martina Beltramello; Alex Chen; Zhuoming Liu; Fabrizia Zatta; Samantha Zepeda; Julia di Iulio; John E. Bowen; Martin Montiel-Ruiz; Jiayi Zhou; Laura E. Rosen; Siro Bianchi; Barbara Guarino; Chiara Silacci Fregni; Rana Abdelnabi; Shi Yan Caroline Foo; Paul W. Rothlauf; Louis Marie Bloyet; Fabio Benigni; Elisabetta Cameroni; Johan Neyts; Agostino Riva; Gyorgy Snell; Amalio Telenti; Sean P.J. Whelan; Herbert W. Virgin; Davide Corti; Matteo Samuele Pizzuto; David Veesler

doi:10.1016/j.cell.2021.03.028

N-terminal domain antigenic mapping reveals a site of vulnerability for SARS-CoV-2

Matthew McCallum, Anna De Marco, Florian A. Lempp, M. Alejandra Tortorici, Dora Pinto, Alexandra C. Walls, Martina Beltramello, Alex Chen, Zhuoming Liu, Fabrizia Zatta, Samantha Zepeda, Julia di Iulio, John E. Bowen, Martin Montiel-Ruiz, Jiayi Zhou, Laura E. Rosen, Siro Bianchi, Barbara Guarino, Chiara Silacci Fregni, Rana AbdelnabiShi Yan Caroline Foo, Paul W. Rothlauf, Louis Marie Bloyet, Fabio Benigni, Elisabetta Cameroni, Johan Neyts, Agostino Riva, Gyorgy Snell, Amalio Telenti, Sean P.J. Whelan, Herbert W. Virgin, Davide Corti, Matteo Samuele Pizzuto, David Veesler

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Abstract

The SARS-CoV-2 spike (S) glycoprotein contains an immunodominant receptor-binding domain (RBD) targeted by most neutralizing antibodies (Abs) in COVID-19 patient plasma. Little is known about neutralizing Abs binding to epitopes outside the RBD and their contribution to protection. Here, we describe 41 human monoclonal Abs (mAbs) derived from memory B cells, which recognize the SARS-CoV-2 S N-terminal domain (NTD) and show that a subset of them neutralize SARS-CoV-2 ultrapotently. We define an antigenic map of the SARS-CoV-2 NTD and identify a supersite (designated site i) recognized by all known NTD-specific neutralizing mAbs. These mAbs inhibit cell-to-cell fusion, activate effector functions, and protect Syrian hamsters from SARS-CoV-2 challenge, albeit selecting escape mutants in some animals. Indeed, several SARS-CoV-2 variants, including the B.1.1.7, B.1.351, and P.1 lineages, harbor frequent mutations within the NTD supersite, suggesting ongoing selective pressure and the importance of NTD-specific neutralizing mAbs for protective immunity and vaccine design.

Original language	English
Pages (from-to)	2332-2347.e16
Journal	Cell
Volume	184
Issue number	9
DOIs	https://doi.org/10.1016/j.cell.2021.03.028
State	Published - Apr 29 2021

Keywords

COVID-19
N-terminal domain
NTD
SARS-CoV-2
memory B cells
neutralizing antibody
spike glycoprotein

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10.1016/j.cell.2021.03.028

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McCallum, M., De Marco, A., Lempp, F. A., Tortorici, M. A., Pinto, D., Walls, A. C., Beltramello, M., Chen, A., Liu, Z., Zatta, F., Zepeda, S., di Iulio, J., Bowen, J. E., Montiel-Ruiz, M., Zhou, J., Rosen, L. E., Bianchi, S., Guarino, B., Fregni, C. S., ... Veesler, D. (2021). N-terminal domain antigenic mapping reveals a site of vulnerability for SARS-CoV-2. Cell, 184(9), 2332-2347.e16. https://doi.org/10.1016/j.cell.2021.03.028

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title = "N-terminal domain antigenic mapping reveals a site of vulnerability for SARS-CoV-2",

abstract = "The SARS-CoV-2 spike (S) glycoprotein contains an immunodominant receptor-binding domain (RBD) targeted by most neutralizing antibodies (Abs) in COVID-19 patient plasma. Little is known about neutralizing Abs binding to epitopes outside the RBD and their contribution to protection. Here, we describe 41 human monoclonal Abs (mAbs) derived from memory B cells, which recognize the SARS-CoV-2 S N-terminal domain (NTD) and show that a subset of them neutralize SARS-CoV-2 ultrapotently. We define an antigenic map of the SARS-CoV-2 NTD and identify a supersite (designated site i) recognized by all known NTD-specific neutralizing mAbs. These mAbs inhibit cell-to-cell fusion, activate effector functions, and protect Syrian hamsters from SARS-CoV-2 challenge, albeit selecting escape mutants in some animals. Indeed, several SARS-CoV-2 variants, including the B.1.1.7, B.1.351, and P.1 lineages, harbor frequent mutations within the NTD supersite, suggesting ongoing selective pressure and the importance of NTD-specific neutralizing mAbs for protective immunity and vaccine design.",

keywords = "COVID-19, N-terminal domain, NTD, SARS-CoV-2, memory B cells, neutralizing antibody, spike glycoprotein",

author = "Matthew McCallum and {De Marco}, Anna and Lempp, {Florian A.} and Tortorici, {M. Alejandra} and Dora Pinto and Walls, {Alexandra C.} and Martina Beltramello and Alex Chen and Zhuoming Liu and Fabrizia Zatta and Samantha Zepeda and {di Iulio}, Julia and Bowen, {John E.} and Martin Montiel-Ruiz and Jiayi Zhou and Rosen, {Laura E.} and Siro Bianchi and Barbara Guarino and Fregni, {Chiara Silacci} and Rana Abdelnabi and Foo, {Shi Yan Caroline} and Rothlauf, {Paul W.} and Bloyet, {Louis Marie} and Fabio Benigni and Elisabetta Cameroni and Johan Neyts and Agostino Riva and Gyorgy Snell and Amalio Telenti and Whelan, {Sean P.J.} and Virgin, {Herbert W.} and Davide Corti and Pizzuto, {Matteo Samuele} and David Veesler",

note = "Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",

year = "2021",

month = apr,

day = "29",

doi = "10.1016/j.cell.2021.03.028",

language = "English",

volume = "184",

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McCallum, M, De Marco, A, Lempp, FA, Tortorici, MA, Pinto, D, Walls, AC, Beltramello, M, Chen, A, Liu, Z, Zatta, F, Zepeda, S, di Iulio, J, Bowen, JE, Montiel-Ruiz, M, Zhou, J, Rosen, LE, Bianchi, S, Guarino, B, Fregni, CS, Abdelnabi, R, Foo, SYC, Rothlauf, PW, Bloyet, LM, Benigni, F, Cameroni, E, Neyts, J, Riva, A, Snell, G, Telenti, A, Whelan, SPJ, Virgin, HW, Corti, D, Pizzuto, MS & Veesler, D 2021, 'N-terminal domain antigenic mapping reveals a site of vulnerability for SARS-CoV-2', Cell, vol. 184, no. 9, pp. 2332-2347.e16. https://doi.org/10.1016/j.cell.2021.03.028

TY - JOUR

T1 - N-terminal domain antigenic mapping reveals a site of vulnerability for SARS-CoV-2

AU - McCallum, Matthew

AU - De Marco, Anna

AU - Lempp, Florian A.

AU - Tortorici, M. Alejandra

AU - Pinto, Dora

AU - Walls, Alexandra C.

AU - Beltramello, Martina

AU - Chen, Alex

AU - Liu, Zhuoming

AU - Zatta, Fabrizia

AU - Zepeda, Samantha

AU - di Iulio, Julia

AU - Bowen, John E.

AU - Montiel-Ruiz, Martin

AU - Zhou, Jiayi

AU - Rosen, Laura E.

AU - Bianchi, Siro

AU - Guarino, Barbara

AU - Fregni, Chiara Silacci

AU - Abdelnabi, Rana

AU - Foo, Shi Yan Caroline

AU - Rothlauf, Paul W.

AU - Bloyet, Louis Marie

AU - Benigni, Fabio

AU - Cameroni, Elisabetta

AU - Neyts, Johan

AU - Riva, Agostino

AU - Snell, Gyorgy

AU - Telenti, Amalio

AU - Whelan, Sean P.J.

AU - Virgin, Herbert W.

AU - Corti, Davide

AU - Pizzuto, Matteo Samuele

AU - Veesler, David

PY - 2021/4/29

Y1 - 2021/4/29

N2 - The SARS-CoV-2 spike (S) glycoprotein contains an immunodominant receptor-binding domain (RBD) targeted by most neutralizing antibodies (Abs) in COVID-19 patient plasma. Little is known about neutralizing Abs binding to epitopes outside the RBD and their contribution to protection. Here, we describe 41 human monoclonal Abs (mAbs) derived from memory B cells, which recognize the SARS-CoV-2 S N-terminal domain (NTD) and show that a subset of them neutralize SARS-CoV-2 ultrapotently. We define an antigenic map of the SARS-CoV-2 NTD and identify a supersite (designated site i) recognized by all known NTD-specific neutralizing mAbs. These mAbs inhibit cell-to-cell fusion, activate effector functions, and protect Syrian hamsters from SARS-CoV-2 challenge, albeit selecting escape mutants in some animals. Indeed, several SARS-CoV-2 variants, including the B.1.1.7, B.1.351, and P.1 lineages, harbor frequent mutations within the NTD supersite, suggesting ongoing selective pressure and the importance of NTD-specific neutralizing mAbs for protective immunity and vaccine design.

AB - The SARS-CoV-2 spike (S) glycoprotein contains an immunodominant receptor-binding domain (RBD) targeted by most neutralizing antibodies (Abs) in COVID-19 patient plasma. Little is known about neutralizing Abs binding to epitopes outside the RBD and their contribution to protection. Here, we describe 41 human monoclonal Abs (mAbs) derived from memory B cells, which recognize the SARS-CoV-2 S N-terminal domain (NTD) and show that a subset of them neutralize SARS-CoV-2 ultrapotently. We define an antigenic map of the SARS-CoV-2 NTD and identify a supersite (designated site i) recognized by all known NTD-specific neutralizing mAbs. These mAbs inhibit cell-to-cell fusion, activate effector functions, and protect Syrian hamsters from SARS-CoV-2 challenge, albeit selecting escape mutants in some animals. Indeed, several SARS-CoV-2 variants, including the B.1.1.7, B.1.351, and P.1 lineages, harbor frequent mutations within the NTD supersite, suggesting ongoing selective pressure and the importance of NTD-specific neutralizing mAbs for protective immunity and vaccine design.

KW - COVID-19

KW - N-terminal domain

KW - NTD

KW - SARS-CoV-2

KW - memory B cells

KW - neutralizing antibody

KW - spike glycoprotein

UR - http://www.scopus.com/inward/record.url?scp=85103091737&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2021.03.028

DO - 10.1016/j.cell.2021.03.028

M3 - Article

C2 - 33761326

AN - SCOPUS:85103091737

SN - 0092-8674

VL - 184

SP - 2332-2347.e16

JO - Cell

JF - Cell

IS - 9

ER -

N-terminal domain antigenic mapping reveals a site of vulnerability for SARS-CoV-2

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