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

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.