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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 Article has an altmetric score of 178

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

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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 1

Characterization of RBD-reactive mAbs isolated from COVID-19–convalescent individuals.

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Characterization of RBD-reactive mAbs isolated from COVID-19–convalescen...
(A and B) Uniform manifold approximation and projection (UMAP) of SARS-CoV-2 (A) spike RBD binding and (B) spike non-RBD binding B cells isolated from convalescent individuals that could be characterized into 3 groups (high, mid, and low responders) based on their serological response against SARS-CoV-2 spike13. (C) Proportion of spike non-RBD- and spike RBD–specific binding B cells in each responder group. Colors in A and B are representative of antigen-specific B cells from each responder group. (D–E) Number of somatic hypermutations in the IGHV in antibodies targeting (D) RBD and (E) non-RBD. Data in D–E represent mean ± SEM. (F) Binding profile of RBD-reactive mAbs against RBD mutants associated with different antibody classes, a combinatorial RBD mutant, and the RBDs of SARS-CoV-1 and MERS-CoV. Color gradients indicate relative binding percentage compared with RBD WT. (G) Neutralization potency measured by plaque assay (complete inhibitory concentration; IC99) and FRNT. IC50, half inhibitory concentration of RBD-reactive mAbs to SARS-CoV-2 variants and sarbecoviruses. The statistical analysis in C was determined using Tukey multiple pairwise-comparisons and in D and E was determined using Kruskal-Wallis with Dunn’s multiple comparison test. Data in F and G are representative of 2 independent experiments performed in triplicate. Genetic information for each antibody is in Supplemental Table 3. The SARS-CoV-2 viruses used in the neutralization assay are indicated in Supplemental Table 5. **P ≤ 0.01; ***P ≤ 0.001.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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