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 5

Convalescent serum antibody competition with broadly neutralizing RBD-reactive mAbs and comparison of serum antibody response against 6P- versus 2P-stabilized spikes.

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Convalescent serum antibody competition with broadly neutralizing RBD-re...
Schematic diagram for experimental procedure of serum competitive ELISA (A). The model created with BioRender.com. IC50 of polyclonal antibody serum from convalescent individuals (high responder, n = 15 donors; moderate responder, n = 16 donors; low responder, n = 16 donors) that could compete with broadly neutralizing mAbs (competitor mAb) S728-1157 (B), S451-1140 (C), and S626-161 (D), as well as therapeutic mAbs LY-CoV555 (E), REGN-10933 (F), nonneutralizing mAb CR3022 (G), and well-defined RBS-A/class 1 mAb CC12.3 (H). The reciprocal serum dilutions in B–H are showed as Log1P of the IC50 of serum dilution that can achieve 50% competition with the competitor mAb of interest. The statistical analysis in B–H was determined using Kruskal-Wallis with Dunn’s multiple comparison test. Representative 3 conformations of prefusion spike trimer antigen observed in the previous structural characterization of SARS-CoV-2 stabilized by 2P and 6P (33, 49) (I). Endpoint titer of convalescent sera against SARS-CoV-2 spike WT (J) and Omicron BA.1 (K) in 2 versions of spike substituted by 2P and 6P. Data in B–H and J–K are representative of 2 independent experiments performed in duplicate. Wilcoxon matched-pairs signed rank test was used to compare the anti-spike antibody titer against 2P and 6P in J and K. Fold change indicated in J and K is defined as the mean fold change.*P ≤ 0.05; **P ≤ 0.01; ***P ≤ 0.001; ****P < 0.0001. Biorender.com was used to create panel A.