An intramuscular prime-intranasal boost strategy for mRNA-LNP vaccine induces mucosal immune response against SARS-CoV-2 in murine model

BACKGROUND: Mucosal immunity constitutes the primary defense against pathogens. Vaccination strategies aimed at inducing mucosal immunity are therefore crucial for preventing viral infections. Lipid nanoparticle (LNP) delivery systems enhance mRNA vaccine stability, giving them the potential for mucosal delivery. METHODS: This study employed an mRNA-LNP vaccine candidate encoding the SARS-CoV-2 Spike protein, compatible with intranasal delivery, to evaluate immunization strategies aimed at inducing robust systemic and mucosal immunity. Antibody and T cell responses in both systemic and mucosal compartments, as well as protection against viral challenge, were assessed in mice following various regimens, including single-route and heterologous prime-boost strategies. Single B-cell immune repertoire analysis was performed to further elucidate the advantages of an optimized mucosal immunization approach. RESULTS: Intranasal immunization alone induced weak systemic antibody responses and failed to elicit mucosal immunity. In contrast, an "intramuscular prime and intranasal boost" regimen provoked strong systemic and mucosal immunity, marked by significantly elevated levels of antigen-specific T cells and mucosal IgA, which correlated with broader protection. Immunoprofiling revealed that intranasal boosting promoted IgA class switching in antigen-specific B cells and diversified the antigen-specific B cell receptor (BCR) repertoire. CONCLUSION: This study demonstrates that mRNA vaccines encapsulated in tailored LNPs can be effectively delivered via an "intramuscular prime and intranasal boost" strategy, establishing an efficacious approach for mRNA mucosal immunization.