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 6

mRNA-vaccinated serum antibody competition with S728-1157 neutralizing RBD-reactive mAbs and comparison of serum antibody response against 6P- versus 2P-stabilized spikes.

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mRNA-vaccinated serum antibody competition with S728-1157 neutralizing R...
Collection of sera and exposure history from vaccine groups (A). 2 × vacc, double vaccination (WA-1), (n = 20 participants); 3 × vacc., boosted or triple vaccination (WA-1) (n = 20 participants); conv. + 2 × vacc., convalescent plus double vaccination (WA-1) (n = 20 participants); conv. + 3 × vacc., convalescent plus boosted/triple vaccination (WA-1) (n = 10 participants); boosted breakthrough + bivalent vacc., after-boost infection followed by bivalent vaccination (WA-1/BA.5) (n = 9 participants). The model created with BioRender.com. Fold change of IC50 of antibody competing for binding to the S728-1157 epitope from 5 groups of individuals who received mRNA-based vaccine with variety type of exposure history (B). Dashed line in B indicates average of antibody titer that was found in convalescent individuals related to Figure 4. The statistical analysis in B was determined using Kruskal-Wallis with Dunn’s multiple comparison test. Comparison of the kinetics of serum antibodies to the S728-1157 epitope present in a given participant after completion of the primary vaccination regimen (2 × vacc.) and after boosted vaccination (3 × vacc.) divided by vaccine types (C and D). The connecting lines in C and D identify paired samples. Endpoint titer of mRNA-based vaccinated sera against SARS-CoV-2 spike WT substituted by 2P and 6P (E). Dashed line in E indicates limit of detection (LOD) of the analysis. Wilcoxon matched-pairs signed rank test was used to compare the antibody titer in C–E. Fold change indicated in B–D is defined as the mean fold change. Data in B–E are representative of 2 independent experiments performed in duplicate. *P ≤ 0.05; **P ≤ 0.01; ***P ≤ 0.001; ****P < 0.0001. Biorender.com was used to create panel A.