The Francis Crick Institute
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Neutralization potency of monoclonal antibodies recognizing dominant and subdominant epitopes on SARS-CoV-2 Spike is impacted by the B.1.1.7 variant.

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journal contribution
posted on 2021-06-16, 10:33 authored by 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 ME Duyvesteyn, Yuguang Zhao, Thomas A Bowden, Manu Shankar-Hari, Annachiara Rosa, Peter Cherepanov, Laura E McCoy, Adrian C Hayday, Stuart JD Neil, Michael H Malim, Katie J Doores
Interaction 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.


Crick (Grant ID: 10093, Grant title: Hayday FC001093) Crick (Grant ID: 10061, Grant title: Cherepanov FC001061)