PreprintCited by 901SARS-CoV-2 and COVID-19 Researchvaccines and immunoinformatics approachesAnimal Virus Infections Studies

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

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McCallum, Matthew, Marco, Anna De, Lempp, Florian, Tortorici, M. Alejandra, Pinto, Dora, Walls, Alexandra C., Beltramello, Martina, Chen, Alex, Liu, Zhuoming, Zatta, Fabrizia, Zepeda, Samantha, di Iulio, Julia, Bowen, John E., Montiel-Ruiz, Martin, Zhou, Jiayi, Rosen, Laura E., Bianchi, Siro, Guarino, Barbara, Fregni, Chiara Silacci, Abdelnabi, Rana, Caroline Foo, Shi-Yan, Rothlauf, Paul W., Bloyet, Louis-Marie, Benigni, Fabio, Cameroni, Elisabetta, Neyts, Johan, Riva, Agostino, Snell, Gyorgy, Telenti, Amalio, Whelan, Sean P.J., Virgin, Herbert W., Corti, Davide, Pizzuto, Matteo Samuele, Veesler, David·2021·Cell

DOI 10.1101/2021.01.14.426475PMC PMC7814825

Preprint — published as 10.1016/j.cell.2021.03.028 · Paper page

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Abstract

SARS-CoV-2 entry into host cells is orchestrated by the spike (S) glycoprotein that contains an immunodominant receptor-binding domain (RBD) targeted by the largest fraction of 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 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. SARS-CoV-2 variants, including the 501Y.V2 and B.1.1.7 lineages, harbor frequent mutations localized in the NTD supersite suggesting ongoing selective pressure and the importance of NTD-specific neutralizing mAbs to protective immunity.

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“The NTD, particularly the NTD supersite, is also a strong target for antibodies(29,30,32).”
Influential
Antigenic landscape of a highly mutated SARS-CoV-2 Spike in ongoing viral evolution
Turelli, P., Eray, E., Raclot, C., et al. (2026) · bioRxiv · doi:10.64898/2026.02.27.708159
“Some potent NTD-targeting nAbs are public antibodies ( 12 , 13 ) that bind a common antigenic supersite spanning residues Q14-T20, F140-R158 and H245-A264 in the NTD loops N1, N3 and N5, respectively ( 13 ).”
Structure-guided design of a bivalent SARS-CoV-2 mRNA vaccine with NTD stabilizing mutations enhances broad immunity
Yeo, J., Yun, M.-R., Kim, S.-Y., Seok, J.-H., Jeon, J. H., Lee, T., Kim, J., Kim, K., Park, M., Kim, D., et al. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1718740
pH-induced structural changes in SARS-CoV-2 spike variantsPreprint
Oliveira, A. S. F., Tulli, L., Kearns, F. L., Casalino, L., Rosenfeld, M. A., Berger, I., Schaffitzel, C., Davidson, A. D., Haddrell, A. E., Reid, J. P., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.11.17.688702 · Cited by 1
“Residues L210-I216 are part of a flexible peripheral loop, located near the NTD antigenic supersite (147-151).”
Tracking down the origin and subsequent spread of SARS-CoV-2 lineage B.1.619
Bollen, N., Hong, S. L., Potter, B. I., Lienhard, R., Tritten, M.-L., Sierro, N., Guedj, E., Dulize, R., Bornand, D., Auberson, M., et al. (2025) · Virus Evolution · doi:10.1093/ve/veaf017
“McCallum et al. (2021) found that H146Y reduced binding of various antibodies (S2M28, S2X28, and in particular of 4A8), indicating a higher chance of immune escape.”
A cost-effective approach for comprehensive analysis of human memory B Cell repertoire: fast isolation of broad neutralizing mAbs to SARS-CoV-2 variants
Conde, L., Oliveira, D., Maciel, G., et al. (2025) · medRxiv · doi:10.1101/2025.01.14.25320505
“Similarly, the NTD plays a multifaceted role in viral attachment and entry but is also prone to mutations and deletions that alter antigenicity and enable immune evasion [42].”
Etiological and immunopathogenetic aspects of multiorgan failure development in coronavirus disease (COVID-19)
Ащеулова, Т. В., Herasymchuk, N. M., Kochubiei, O., & Herasymchuk, U. S. (2024) · Zaporozhye Medical Journal · doi:10.14739/2310-1210.2024.4.302379
“Домен CD RBD S-білка HCoV розпізнає як конкретний для кожного виду HCoV специфічний рецептор кліти-ни-хазяїна, який є основною мішенню для антитіл, що нейтралізують вірус [12,13].”
Research progress in Fc‐effector functions against SARS‐CoV‐2
Gao, R., Feng, C., Sheng, Z., Li, F., & Wang, D. (2024) · Journal of Medical Virology · doi:10.1002/jmv.29638 · Cited by 1
Broadly neutralizing antibodies against emerging delta-coronavirusesPreprint
Rexhepaj, M., Park, Y., Perruzza, L., Asarnow, D. E., McCallum, M., Culap, K., Saliba, C., Leoni, G., Balmelli, A., Yoshiyama, C. N., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.03.27.586411
Self-citation
Screening Peptide Drug Candidates to Neutralize Whole Viral Agents : A Case study with SARS-CoV-2 VirusPreprint
Özçelik, C. E., Araz, C. Z., Yılmaz, Ö., Gülyüz, S., Özkul, A., & Şeker, U. Ö. Ş. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.10.22.563490
Surrogate virus neutralisation test based on nanoluciferase-tagged antigens to quantify inhibitory antibodies against SARS-CoV-2 and characterise Omicron-specific reactivity
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Ensemble-Based Modeling of the SARS-CoV-2 Omicron BA.1 and BA.2 Spike Trimers and Systematic Characterization of Cryptic Binding Pockets in Distinct Functional States : Emergence of Conformation-Sensitive and Variant-Specific Allosteric Binding SitesPreprint
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Background
Rapid emergence of transmissible SARS-CoV-2 variants in mild community cases
Crone, M., Hakki, S., Zhou, J., et al. (2023) · medRxiv · doi:10.1101/2023.02.15.23285923
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BackgroundSelf-citation
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Infectivity and immune escape of the new SARS-CoV-2 variant of interest Lambda
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Authors: McCallum, M., Marco, A. D., Lempp, F., 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., Abdelnabi, R., Caroline Foo, S.-Y., Rothlauf, P. W., Bloyet, L.-M., Benigni, F., Cameroni, E., Neyts, J., Riva, A., Snell, G., Telenti, A., Whelan, S. P. J., Virgin, H. W., Corti, D., Pizzuto, M. S., & Veesler, D.
Affiliations: University of Washington (US)
Vir Biotechnology (Switzerland) (CH)
VIR Biotechnology (United States) (US)
Centre National de la Recherche Scientifique (FR)
Washington University in St. Louis (US)
Rega Institute for Medical Research (BE)
University of Milan (IT)
Corresponding author: Corti, Davide
Pizzuto, Matteo Samuele
Veesler, David
ORCID: McCallum, Matthew
Marco, Anna De
Lempp, Florian
Tortorici, M. Alejandra
Pinto, Dora
Walls, Alexandra C.
Beltramello, Martina
Chen, Alex
Liu, Zhuoming
Zatta, Fabrizia
Zepeda, Samantha
Bowen, John E.
Montiel-Ruiz, Martin
Zhou, Jiayi
Rosen, Laura E.
Bianchi, Siro
Guarino, Barbara
Abdelnabi, Rana
Rothlauf, Paul W.
Bloyet, Louis-Marie
Benigni, Fabio
Cameroni, Elisabetta
Neyts, Johan
Riva, Agostino
Snell, Gyorgy
Telenti, Amalio
Whelan, Sean P.J.
Virgin, Herbert W.
Corti, Davide
Pizzuto, Matteo Samuele
Veesler, David
Venue: Cell
Publisher: openRxiv
Published: 2021-01-14
Volume: 184
Issue: 9
Pages: 2332-2347.e16
ISSN: 0092-8674 (ISSN-L)
DOI: 10.1101/2021.01.14.426475
PMC: PMC7814825
OpenAlex: W3136616180
Cited by: 901
References: 0
Citations by year: 2026: 38 · 2025: 64 · 2024: 92 · 2023: 154 · 2022: 270 · 2021: 269
FWCI: 62.32
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Cell (publishedVersion)
bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Lirias (acceptedVersion, other-oa)
PubMed Central (submittedVersion)
HAL (submittedVersion)
Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
Lirias (submittedVersion, other-oa)
Funders: Burroughs Wellcome Fund
University of Washington
Fast Grants
National Institutes of Health (1s10od023476-01)
Natural Sciences and Engineering Research Council of Canada (HHSN272201700059C)
National Institute of General Medical Sciences (R01GM120553, T32GM008268)
National Institute of Allergy and Infectious Diseases (HHSN272201700059C, DP1AI158186)
Topics: Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › vaccines and immunoinformatics approaches
Life Sciences › Agricultural and Biological Sciences › Animal Science and Zoology › Animal Virus Infections Studies
Keywords: SARS-CoV-2, spike protein, N-terminal domain, neutralizing antibodies, monoclonal antibodies, antigenic mapping, receptor binding domain, SARS-CoV-2 variants, Alpha variant, Beta variant, P.1 lineage, vaccine design

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

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