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

• DOI: 10.1016/j.immuni.2021.03.023
• Publication Date: 2021-04-02T02:02:57Z
• Authors: 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-G...; Adam G. Laing; Yin Wu; Magdalene Joseph; Luke Muir; Marit J. van Gils; Weng M. Ng; Helen M.E. Duyves...; Yuguang Zhao; Thomas A. Bowden; Manu Shankar-Hari; Annachiara Rosa; Peter Cherepanov; Laura E. McCoy; Adrian C. Hayday; Stuart J.D. Neil; Michael H. Malim; Katie J. Doores
• Keywords: Models, Molecular; 0301 basic medicine; 570; COVID-19/diagnosis; Protein Conformation; 610; Antibodies, Monoclonal/chemistry; Cross Reactions; Antibodies, Viral; Epitopes/chemistry; SARS-CoV-2/immunology; Article; Epitopes; Structure-Activity Relationship; 03 medical and health sciences; Neutralization Tests; antibody; Virology; Antibodies, Viral/chemistry; Humans; B.1.1.7; Spike Glycoprotein, Coronavirus/chemistry; Protein Binding/immunology; SARS-CoV-2; immune escape; Antibodies, Monoclonal; COVID-19; neutralization; Antibodies, Neutralizing/immunology; Antibodies, Neutralizing; neutralizing epitope; Virus; 3. Good health; Angiotensin-Converting Enzyme 2/chemistry; Mutation; Spike Glycoprotein, Coronavirus; Angiotensin-Converting Enzyme 2; Cross Reactions/immunology; variant of concern; Virología; Protein Binding

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.