Publication date: Jul 07, 2025

Vaccines against coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), are highly effective in preventing severe disease but are less consistent in protecting against infection and transmission. Developing vaccines with enhanced immunogenicity that can provide protection in both the upper and lower respiratory tract (URT and LRT) is crucial. Mucosal immunization induces immunity at the site of initial infection, the respiratory tract, thereby preventing or mitigating infection. Here, we compared immune responses elicited by intramuscular mRNA vaccination alone with those elicited by intramuscular mRNA vaccination followed by intranasal administration of ChAdOx1 nCoV-19 vaccine in mice. Although both vaccination strategies induced strong systemic immunity, robust humoral and cellular mucosal immune responses, including spike-specific IgA and tissue-resident T cells, were only detected upon mucosal vaccination. Compared to unvaccinated animals, mucosal vaccination resulted in migration of T cells and macrophages into the nasal turbinates, as well as migration and proliferation of B and T cells in the nasal-associated lymphoid tissue. While both vaccination regimens provided protection across the entire respiratory tract at 2 weeks post-vaccination, at 12 weeks post-vaccination, only the mice that received a mucosal vaccination remained protected in the URT. Gene-expression profiling of the respiratory tract at 2 days post-infection revealed distinct clustering between groups. Enrichment of immune signaling pathways, including B and T cells receptor pathways, was significantly higher in intranasally vaccinated animals. Together, our study demonstrates that mucosal vaccination provides durable protection against SARS-CoV-2 than intramuscular vaccination alone.

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