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

TitleSite of vulnerability on SARS-CoV-2 spike induces broadly protective antibody to antigenically distinct Omicron subvariants.
Publication TypeJournal Article
Year of Publication2023
AuthorsChangrob S, Halfmann PJ, Liu H, Torres JL, McGrath JJC, Ozorowski G, Li L, G Wilbanks D, Kuroda M, Maemura T, Huang M, Zheng N-Y, Turner HL, Erickson SA, Fu Y, Yasuhara A, Singh G, Monahan B, Mauldin J, Srivastava K, Simon V, Krammer F, D Sather N, Ward AB, Wilson IA, Kawaoka Y, Wilson PC
JournalJ Clin Invest
Date Published2023 Mar 02
ISSN1558-8238
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 wildtype 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 wildtype, Delta, and BA.1 viruses. Structural analysis showed that this antibody targets a class 1/RBS-A epitope in the receptor binding domain (RBD) via multiple hydrophobic and polar interactions with its heavy chain complementarity determining region 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 to diproline (2P) constructs. Overall, S728-1157 demonstrates broad therapeutic potential, and may inform target-driven vaccine design against future SARS-CoV-2 variants.

DOI10.1172/JCI166844
Custom 1

https://www.ncbi.nlm.nih.gov/pubmed/36862518?dopt=Abstract

Alternate JournalJ Clin Invest
PubMed ID36862518

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