N-terminal Domain Antigenic Mapping Reveals a Site of Vulnerability for SARS-CoV-2

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2021 Mar 24

PMID 33761326

Citations 581

Authors

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

Affiliations

Soon will be listed here.

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.

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