• Carl Graham, Jeffrey Seow, Isabella Huettner, Hataf Khan, Neophytos Kouphou, Sam Acors, Helena Winstone, Suzanne Pickering, Rui Pedro Galao, Liane Dupont, Maria Jose Lista, Jose M Jimenez-Guardeño, Adam G Laing, Yin Wu, Magdalene Joseph, Luke Muir, Marit J van Gils, Weng M Ng, Helen M E Duyvesteyn, Yuguang Zhao, Thomas A Bowden, Manu Shankar-Hari, Annachiara Rosa, Peter Cherepanov, Laura E McCoy, Adrian C Hayday, NeilStuart J DSJDDepartment of Infectious Diseases, School of Immunology & Microbial Sciences, King's College London, London, UK; Genotype-to-Phenotype UK National Virology Consortium., Michael H Malim, and Katie J Doores.
• Department of Infectious Diseases, School of Immunology & Microbial Sciences, King's College London, London, UK.
• Immunity. 2021 Jun 8; 54 (6): 1276-1289.e6.

AbstractInteraction of the SARS-CoV-2 Spike receptor binding domain (RBD) with the receptor ACE2 on host cells is essential for viral entry. RBD is the dominant target for neutralizing antibodies, and several neutralizing epitopes on RBD have been molecularly characterized. Analysis of circulating SARS-CoV-2 variants has revealed mutations arising in the RBD, N-terminal domain (NTD) and S2 subunits of Spike. To understand how these mutations affect Spike antigenicity, we isolated and characterized >100 monoclonal antibodies targeting epitopes on RBD, NTD, and S2 from SARS-CoV-2-infected individuals. Approximately 45% showed neutralizing activity, of which ∼20% were NTD specific. NTD-specific antibodies formed two distinct groups: the first was highly potent against infectious virus, whereas the second was less potent and displayed glycan-dependant neutralization activity. Mutations present in B.1.1.7 Spike frequently conferred neutralization resistance to NTD-specific antibodies. This work demonstrates that neutralizing antibodies targeting subdominant epitopes should be considered when investigating antigenic drift in emerging variants.Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

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