Targeted FcRn to deliver epitope-optimized RBD confers broad-spectrum mucosal protection against SARS-CoV-2.

Current respiratory vaccines face two major obstacles: limited breadth of protection and insufficient induction of mucosal immunity. Here, we present a neonatal Fc receptor (FcRn)-targeted mucosal delivery strategy integrating computational antigen design to address both challenges. Using severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as a model virus, we employed Epigraph to generate T cell epitope-optimized consensus sequences for the receptor-binding domain (RBD) and incorporated them into a modified human IgG1 Fc framework engineered for enhanced FcRn binding, yielding a single fusion antigen. In vitro, this antigen efficiently binds FcRn, facilitating epithelial transcytosis and prolonging mucosal retention. In vivo, it elicits robust cellular, humoral, and mucosal immune responses against SARS-CoV-2 and its major variants in both respiratory and systemic compartments, with evidence of tissue-resident memory responses. Following intranasal administration, the antigen conferred complete cross-protection against lethal challenge with representative SARS-CoV-2 and its variants. Notably, a low antigen dose of 0.2 μg in a two-dose regimen achieved full protection. Immunomics further revealed that this design induces a broader T and B cell repertoire. Collectively, this study establishes a generalizable framework that combines epitope-optimized antigen design with FcRn-mediated mucosal delivery, providing a promising strategy for broad-spectrum vaccine development against rapidly evolving respiratory viruses.