EMD-29531
SARS-CoV-2 BQ.1.1 spike RBD bound to the human ACE2 ectodomain and the S309 neutralizing antibody Fab fragment
EMD-29531
Single-particle3.2 Å
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Map released: 04/10/2023
Last modified: 16/10/2024
Sample Organism:
Severe acute respiratory syndrome coronavirus 2,
Homo sapiens
Sample: SARS-CoV-2 BQ.1.1 spike RBD bound to the human ACE2 ectodomain and the S309 neutralizing antibody Fab fragment
Fitted models: 8fxc (Avg. Q-score: 0.507)
Deposition Authors: Park YJ
,
Seattle Structural Genomics Center for Infectious Disease (SSGCID),
Veesler D
Sample: SARS-CoV-2 BQ.1.1 spike RBD bound to the human ACE2 ectodomain and the S309 neutralizing antibody Fab fragment
Fitted models: 8fxc (Avg. Q-score: 0.507)
Deposition Authors: Park YJ
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Neutralization, effector function and immune imprinting of Omicron variants.
Addetia A,
Piccoli L
,
Case JB
,
Park YJ
,
Beltramello M,
Guarino B,
Dang H,
de Melo GD
,
Pinto D,
Sprouse K
,
Scheaffer SM,
Bassi J
,
Silacci-Fregni C,
Muoio F
,
Dini M
,
Vincenzetti L,
Acosta R,
Johnson D,
Subramanian S,
Saliba C
,
Giurdanella M,
Lombardo G,
Leoni G,
Culap K
,
McAlister C,
Rajesh A
,
Dellota Jr E
,
Zhou J
,
Farhat N,
Bohan D
,
Noack J,
Chen A
,
Lempp FA
,
Quispe J,
Kergoat L
,
Larrous F
,
Cameroni E,
Whitener B,
Giannini O
,
Cippa P,
Ceschi A
,
Ferrari P
,
Franzetti-Pellanda A,
Biggiogero M,
Garzoni C,
Zappi S,
Bernasconi L,
Kim MJ,
Rosen LE
,
Schnell G,
Czudnochowski N,
Benigni F,
Franko N
,
Logue JK
,
Yoshiyama C,
Stewart C
,
Chu H
,
Bourhy H
,
Schmid MA
,
Purcell LA
,
Snell G
,
Lanzavecchia A,
Diamond MS
,
Corti D
,
Veesler D
(2023) Nature , 621 , 592 - 601
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(2023) Nature , 621 , 592 - 601
Abstract:
Currently circulating SARS-CoV-2 variants have acquired convergent mutations at hot spots in the receptor-binding domain1 (RBD) of the spike protein. The effects of these mutations on viral infection and transmission and the efficacy of vaccines and therapies remains poorly understood. Here we demonstrate that recently emerged BQ.1.1 and XBB.1.5 variants bind host ACE2 with high affinity and promote membrane fusion more efficiently than earlier Omicron variants. Structures of the BQ.1.1, XBB.1 and BN.1 RBDs bound to the fragment antigen-binding region of the S309 antibody (the parent antibody for sotrovimab) and human ACE2 explain the preservation of antibody binding through conformational selection, altered ACE2 recognition and immune evasion. We show that sotrovimab binds avidly to all Omicron variants, promotes Fc-dependent effector functions and protects mice challenged with BQ.1.1 and hamsters challenged with XBB.1.5. Vaccine-elicited human plasma antibodies cross-react with and trigger effector functions against current Omicron variants, despite a reduced neutralizing activity, suggesting a mechanism of protection against disease, exemplified by S309. Cross-reactive RBD-directed human memory B cells remained dominant even after two exposures to Omicron spikes, underscoring the role of persistent immune imprinting.
Currently circulating SARS-CoV-2 variants have acquired convergent mutations at hot spots in the receptor-binding domain1 (RBD) of the spike protein. The effects of these mutations on viral infection and transmission and the efficacy of vaccines and therapies remains poorly understood. Here we demonstrate that recently emerged BQ.1.1 and XBB.1.5 variants bind host ACE2 with high affinity and promote membrane fusion more efficiently than earlier Omicron variants. Structures of the BQ.1.1, XBB.1 and BN.1 RBDs bound to the fragment antigen-binding region of the S309 antibody (the parent antibody for sotrovimab) and human ACE2 explain the preservation of antibody binding through conformational selection, altered ACE2 recognition and immune evasion. We show that sotrovimab binds avidly to all Omicron variants, promotes Fc-dependent effector functions and protects mice challenged with BQ.1.1 and hamsters challenged with XBB.1.5. Vaccine-elicited human plasma antibodies cross-react with and trigger effector functions against current Omicron variants, despite a reduced neutralizing activity, suggesting a mechanism of protection against disease, exemplified by S309. Cross-reactive RBD-directed human memory B cells remained dominant even after two exposures to Omicron spikes, underscoring the role of persistent immune imprinting.