Engineering a SARS-CoV-2 Vaccine Targeting the Receptor-Binding Domain Cryptic-Face Via Immunofocusing

Overview

Journal ACS Cent Sci

Specialty Chemistry

Date 2024 Oct 28

PMID 39463836

Authors

Theodora U J Bruun

Jonathan Do

Payton A-B Weidenbacher

Ashley Utz

Peter S Kim

Affiliations

Soon will be listed here.

Abstract

The receptor-binding domain (RBD) of the SARS-CoV-2 spike protein is the main target of neutralizing antibodies. Although they are infrequently elicited during infection or vaccination, antibodies that bind to the conformation-specific cryptic face of the RBD display remarkable breadth of binding and neutralization across . Here, we employed the immunofocusing technique PMD (protect, modify, deprotect) to create RBD immunogens (PMD-RBD) specifically designed to focus the antibody response toward the cryptic-face epitope recognized by the broadly neutralizing antibody S2X259. Immunization with PMD-RBD antigens induced robust binding titers and broad neutralizing activity against homologous and heterologous strains. A serum-depletion assay provided direct evidence that PMD successfully skewed the polyclonal antibody response toward the cryptic face of the RBD. Our work demonstrates the ability of PMD to overcome immunodominance and refocus humoral immunity, with implications for the development of broader and more resilient vaccines against current and emerging viruses with pandemic potential.

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