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

Carl Graham; Jeffrey Seow; Isabella Huettner; Hataf Khan; Neophytos Kouphou; Sam Acors; Helena Winstone; Suzy Pickering; Rui Pedro Ribeiro Galao; Liane Dupont; Maria Lista Brotos; Jose Jimenez Guardeno; Adam Laing; Yin Wu; Magdalene Joseph; Luke Muir; Marit J van Gils; Weng Ng; Helen  Duyvesteyn; Yuguang Zhao; Thomas A Bowden; Manu Shankar-Hari; Annachiara Rosa; Peter Cherepanov; Laura E McCoy; Adrian Hayday; Stuart Neil; Michael Malim; Katherine Doores

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

Carl Graham, Jeffrey Seow, Isabella Huettner, Hataf Khan, Neophytos Kouphou, Sam Acors, Helena Winstone, Suzy Pickering, Rui Pedro Ribeiro Galao, Liane Dupont, Maria Lista Brotos, Jose Jimenez Guardeno, Adam Laing, Yin Wu, Magdalene Joseph, Luke Muir, Marit J van Gils, Weng Ng, Helen Duyvesteyn, Yuguang ZhaoThomas A Bowden, Manu Shankar-Hari, Annachiara Rosa, Peter Cherepanov, Laura E McCoy, Adrian Hayday, Stuart Neil, Michael Malim, Katherine Doores

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Abstract

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.

Original language	English
Journal	Immunity
Publication status	Accepted/In press - 29 Mar 2021

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Neutralization potency of monoclonal_GRAHAM_Accepted29March2021_GREEN AAMAccepted author manuscript, 1.34 MBLicence: CC BY-NC-ND

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Graham, C., Seow, J., Huettner, I., Khan, H., Kouphou, N., Acors, S., Winstone, H., Pickering, S., Ribeiro Galao, R. P., Dupont, L., Lista Brotos, M., Jimenez Guardeno, J., Laing, A., Wu, Y., Joseph, M., Muir, L., van Gils, M. J., Ng, W., Duyvesteyn, H., ... Doores, K. (Accepted/In press). Neutralization potency of monoclonal antibodies recognizing dominant and subdominant epitopes on SARS-CoV-2 Spike is impacted by the B.1.1.7 variant. Immunity.

@article{9635c526a2304f7b8d844c8d955e57fd,

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

abstract = "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. ",

author = "Carl Graham and Jeffrey Seow and Isabella Huettner and Hataf Khan and Neophytos Kouphou and Sam Acors and Helena Winstone and Suzy Pickering and {Ribeiro Galao}, {Rui Pedro} and Liane Dupont and {Lista Brotos}, Maria and {Jimenez Guardeno}, Jose and Adam Laing and Yin Wu and Magdalene Joseph and Luke Muir and {van Gils}, {Marit J} and Weng Ng and Helen Duyvesteyn and Yuguang Zhao and Bowden, {Thomas A} and Manu Shankar-Hari and Annachiara Rosa and Peter Cherepanov and McCoy, {Laura E} and Adrian Hayday and Stuart Neil and Michael Malim and Katherine Doores",

year = "2021",

month = mar,

day = "29",

language = "English",

journal = "Immunity",

issn = "1074-7613",

publisher = "Cell Press",

}

Graham, C , Seow, J , Huettner, I , Khan, H , Kouphou, N , Acors, S , Winstone, H , Pickering, S , Ribeiro Galao, RP , Dupont, L , Lista Brotos, M , Jimenez Guardeno, J , Laing, A , Wu, Y , Joseph, M, Muir, L, van Gils, MJ, Ng, W, Duyvesteyn, H, Zhao, Y, Bowden, TA, Shankar-Hari, M, Rosa, A, Cherepanov, P, McCoy, LE, Hayday, A , Neil, S , Malim, M & Doores, K 2021, 'Neutralization potency of monoclonal antibodies recognizing dominant and subdominant epitopes on SARS-CoV-2 Spike is impacted by the B.1.1.7 variant', Immunity.

TY - JOUR

T1 - Neutralization potency of monoclonal antibodies recognizing dominant and subdominant epitopes on SARS-CoV-2 Spike is impacted by the B.1.1.7 variant

AU - Graham, Carl

AU - Seow, Jeffrey

AU - Huettner, Isabella

AU - Khan, Hataf

AU - Kouphou, Neophytos

AU - Acors, Sam

AU - Winstone, Helena

AU - Pickering, Suzy

AU - Ribeiro Galao, Rui Pedro

AU - Dupont, Liane

AU - Lista Brotos, Maria

AU - Jimenez Guardeno, Jose

AU - Laing, Adam

AU - Wu, Yin

AU - Joseph, Magdalene

AU - Muir, Luke

AU - van Gils, Marit J

AU - Ng, Weng

AU - Duyvesteyn, Helen

AU - Zhao, Yuguang

AU - Bowden, Thomas A

AU - Shankar-Hari, Manu

AU - Rosa, Annachiara

AU - Cherepanov, Peter

AU - McCoy, Laura E

AU - Hayday, Adrian

AU - Neil, Stuart

AU - Malim, Michael

AU - Doores, Katherine

PY - 2021/3/29

Y1 - 2021/3/29

N2 - 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.

AB - 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.

M3 - Article

SN - 1074-7613

JO - Immunity

JF - Immunity

ER -

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

Abstract

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