A Modular Vaccine Platform Against SARS‐CoV‐2 Based on Self‐Assembled Protein Nanoparticles

ABSTRACT The COVID‐19 pandemic has underscored the urgent need for deployable vaccine platforms capable of rapidly responding to emerging and re‐emerging variants of human coronaviruses. BP26, an outer membrane protein of the zoonotic bacterium Brucella , self‐assembles into a highly ordered, barrel‐like nanoparticle that can serve as a vaccine platform, demonstrating immunogenicity against the influenza virus and cancer when combined with specific antigens. Here, we expanded its versatility by incorporating the SpyTag/SpyCatcher pair, enabling modular and site‐specific antigen conjugation via simple mixing. SpyCatcher was genetically fused to BP26, and SpyTag to the receptor binding domain (RBD) of the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) spike protein, generating RBD‐displaying BP26 nanoparticles (BP26‐RBD). Immunization of mice with BP26‐RBD elicited strong RBD‐specific and neutralizing antibody responses and conferred protection against lethal SARS‐CoV‐2 challenge. This plug‐and‐play nanoparticle design supports antigen production in diverse expression systems, retains antigenic structure, and allows multivalent display, providing a cost‐effective and rapidly adaptable strategy for next‐generation vaccines targeting evolving viral threats.