Intranasal administration of spike-specific mRNA-LNP confers more protection than the intramuscular route against SARS-CoV-2

Abstract

Objective(s): Intranasal vaccination mimics natural infection and induces mucosal immunity against respiratory viruses. This study compared the immunogenicity and protective efficacy of a nucleoside-modified messenger RNA (mRNA) encoding the SARS-CoV-2 spike protein, encapsulated in lipid nanoparticles (LNPs), administered via intranasal (I.N) versus intramuscular (I.M) routes. Materials and Methods: BALB/c mice received mRNA-LNP vaccines at 1, 5, or 10 µg doses intramuscularly. Antibody responses (Immunoglobulin G/IgA [IgG/IgA]), neutralization titers (conventional virus neutralization test [cVNT]), and interferon-gamma (IFN-γ) responses were assessed to select the optimal dose. The selected 5 µg dose was then administered to mice and Syrian hamsters via I.N or I.M routes. Post-challenge, lung viral loads (50% Tissue Culture Infectious Dose [TCID50]/ml) and weight changes were evaluated. Results: The 5 µg dose induced robust humoral and cellular immunity (cVNT >5 log₂). Intranasal delivery elicited strong spike-specific IgA in nasal washes. Although I.M vaccination produced higher serum neutralizing titers (51.2 vs. 22.0), I.N vaccination conferred superior protection with a 4-log reduction in lung viral load (~10¹ TCID50/ml) versus I.M and controls (~10² TCID50/ml). I.N-vaccinated hamsters were completely protected from weight loss, whereas I.M-vaccinated animals showed mild weight reduction (~1%). Conclusion: Intranasal mRNA-LNP administration elicits potent mucosal and systemic immunity and provides superior protection against SARS-CoV-2 challenge compared to I.M vaccination, underscoring its promise as a transformative strategy for respiratory virus vaccines.