TY - JOUR
T1 - Antibodies targeting a quaternary site on SARS-CoV-2 spike glycoprotein prevent viral receptor engagement by conformational locking
AU - Liu, Lihong
AU - Casner, Ryan G.
AU - Guo, Yicheng
AU - Wang, Qian
AU - Iketani, Sho
AU - Chan, Jasper Fuk Woo
AU - Yu, Jian
AU - Dadonaite, Bernadeta
AU - Nair, Manoj S.
AU - Mohri, Hiroshi
AU - Reddem, Eswar R.
AU - Yuan, Shuofeng
AU - Poon, Vincent Kwok Man
AU - Chan, Chris Chung Sing
AU - Yuen, Kwok Yung
AU - Sheng, Zizhang
AU - Huang, Yaoxing
AU - Bloom, Jesse D.
AU - Shapiro, Lawrence
AU - Ho, David D.
N1 - Publisher Copyright:
© 2023 The Author(s)
PY - 2023/10/10
Y1 - 2023/10/10
N2 - SARS-CoV-2 continues to evolve, with many variants evading clinically authorized antibodies. To isolate monoclonal antibodies (mAbs) with broadly neutralizing capacities against the virus, we screened serum samples from convalescing COVID-19 patients. We isolated two mAbs, 12-16 and 12-19, which neutralized all SARS-CoV-2 variants tested, including the XBB subvariants, and prevented infection in hamsters challenged with Omicron BA.1 intranasally. Structurally, both antibodies targeted a conserved quaternary epitope located at the interface between the N-terminal domain and subdomain 1, uncovering a site of vulnerability on SARS-CoV-2 spike. These antibodies prevented viral receptor engagement by locking the receptor-binding domain (RBD) of spike in the down conformation, revealing a mechanism of virus neutralization for non-RBD antibodies. Deep mutational scanning showed that SARS-CoV-2 could mutate to escape 12-19, but such mutations are rarely found in circulating viruses. Antibodies 12-16 and 12-19 hold promise as prophylactic agents for immunocompromised persons who do not respond robustly to COVID-19 vaccines.
AB - SARS-CoV-2 continues to evolve, with many variants evading clinically authorized antibodies. To isolate monoclonal antibodies (mAbs) with broadly neutralizing capacities against the virus, we screened serum samples from convalescing COVID-19 patients. We isolated two mAbs, 12-16 and 12-19, which neutralized all SARS-CoV-2 variants tested, including the XBB subvariants, and prevented infection in hamsters challenged with Omicron BA.1 intranasally. Structurally, both antibodies targeted a conserved quaternary epitope located at the interface between the N-terminal domain and subdomain 1, uncovering a site of vulnerability on SARS-CoV-2 spike. These antibodies prevented viral receptor engagement by locking the receptor-binding domain (RBD) of spike in the down conformation, revealing a mechanism of virus neutralization for non-RBD antibodies. Deep mutational scanning showed that SARS-CoV-2 could mutate to escape 12-19, but such mutations are rarely found in circulating viruses. Antibodies 12-16 and 12-19 hold promise as prophylactic agents for immunocompromised persons who do not respond robustly to COVID-19 vaccines.
KW - N-terminal domain
KW - Omicron
KW - SARS-CoV-2
KW - broadly neutralizing antibody
KW - quaternary epitope
KW - subdomain 1
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U2 - 10.1016/j.immuni.2023.09.003
DO - 10.1016/j.immuni.2023.09.003
M3 - Article
C2 - 37776849
AN - SCOPUS:85173353376
SN - 1074-7613
VL - 56
SP - 2442-2455.e8
JO - Immunity
JF - Immunity
IS - 10
ER -