Journal: J Clin Invest / Year: 2023 Title: Site of vulnerability on SARS-CoV-2 spike induces broadly protective antibody against antigenically distinct Omicron subvariants. Authors: Siriruk Changrob / Peter J Halfmann / Hejun Liu / Jonathan L Torres / Joshua J C McGrath / Gabriel Ozorowski / Lei Li / G Dewey Wilbanks / Makoto Kuroda / Tadashi Maemura / Min Huang / Nai- ...Authors: Siriruk Changrob / Peter J Halfmann / Hejun Liu / Jonathan L Torres / Joshua J C McGrath / Gabriel Ozorowski / Lei Li / G Dewey Wilbanks / Makoto Kuroda / Tadashi Maemura / Min Huang / Nai-Ying Zheng / Hannah L Turner / Steven A Erickson / Yanbin Fu / Atsuhiro Yasuhara / Gagandeep Singh / Brian Monahan / Jacob Mauldin / Komal Srivastava / Viviana Simon / Florian Krammer / D Noah Sather / Andrew B Ward / Ian A Wilson / Yoshihiro Kawaoka / Patrick C Wilson / Abstract: The rapid evolution of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variants has emphasized the need to identify antibodies with broad neutralizing capabilities to inform ...The rapid evolution of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variants has emphasized the need to identify antibodies with broad neutralizing capabilities to inform future monoclonal therapies and vaccination strategies. Herein, we identified S728-1157, a broadly neutralizing antibody (bnAb) targeting the receptor-binding site (RBS) that was derived from an individual previously infected with WT SARS-CoV-2 prior to the spread of variants of concern (VOCs). S728-1157 demonstrated broad cross-neutralization of all dominant variants, including D614G, Beta, Delta, Kappa, Mu, and Omicron (BA.1/BA.2/BA.2.75/BA.4/BA.5/BL.1/XBB). Furthermore, S728-1157 protected hamsters against in vivo challenges with WT, Delta, and BA.1 viruses. Structural analysis showed that this antibody targets a class 1/RBS-A epitope in the receptor binding domain via multiple hydrophobic and polar interactions with its heavy chain complementarity determining region 3 (CDR-H3), in addition to common motifs in CDR-H1/CDR-H2 of class 1/RBS-A antibodies. Importantly, this epitope was more readily accessible in the open and prefusion state, or in the hexaproline (6P)-stabilized spike constructs, as compared with diproline (2P) constructs. Overall, S728-1157 demonstrates broad therapeutic potential and may inform target-driven vaccine designs against future SARS-CoV-2 variants.
Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: COUNTING / Number real images: 1718 / Average exposure time: 9.0 sec. / Average electron dose: 50.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
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Image processing
Startup model
Type of model: INSILICO MODEL / In silico model: ab initio model generated in cryosparc
Initial angle assignment
Type: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 3.2)
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