Site of vulnerability on SARS-CoV-2 spike induces broadly protective antibody against antigenically distinct Omicron subvariants
Siriruk Changrob, … , Yoshihiro Kawaoka, Patrick C. Wilson
Siriruk Changrob, … , Yoshihiro Kawaoka, Patrick C. Wilson
Published March 2, 2023
Citation Information: J Clin Invest. 2023;133(8):e166844. https://doi.org/10.1172/JCI166844.
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Research Article Immunology

Site of vulnerability on SARS-CoV-2 spike induces broadly protective antibody against antigenically distinct Omicron subvariants

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 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.

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

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Figure 3

Mechanism of broad neutralization of S728-1157.

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Mechanism of broad neutralization of S728-1157. (A) Epitope binning of b...
(A) Epitope binning of broadly neutralizing RBD-reactive mAbs. Heatmap demonstrating the percentage of competition between each RBD-reactive mAb from previous studies (15, 23, 36-38) with 3 broadly neutralizing mAbs, S728-1157, S451-1140, and S626-161. Data are representative of 2 independent experiments performed in triplicate. (B) Surface representation of the model derived from the cryoEM map of spike WT-6P-Mut7 in complex with IgG S728-1157. The heavy chain is shown in dark purple, light chain in light purple, and the spike protein in gray. Although we observe full mAb occupancy in the cryo-EM map, only 1 Fv is shown here. (C) Structural comparison of S728-1157 to other RBS-A/class 1 antibodies such as CC12.1 (PDB ID: 6XC2, blue), CC12.3 (PDB ID: 6XC4, green), B38 (PDB ID: 7BZ5, red), and C105 (PDB ID: 6XCN, orange). The heavy chains are in a darker shade, and the light chains in a lighter shade of their respective colors. Omicron BA.1 mutations near the epitope interface are shown as red spheres. (D) CDR-H3 forms distinct interactions with SARS-CoV-2 RBD between S728-1157 and CC12.3. Sequence alignment of CDR-H3 of the 2 antibodies are shown in the middle with nonconserved residues shown in orange.