Sublingual vaccination by chitosan-based patch protected aged mice from influenza virus infection

Abstract Background Influenza remains a major global health threat, particularly for the elderly, who exhibit reduced vaccine efficacy. While mucosal vaccination offers a promising strategy to enhance immune protection, the sublingual (SL) route has been underutilized, despite its potential to induce both systemic and mucosal immunity. In this study, we evaluated the protective efficacy of a chitosan-based sublingual mucoadhesive patch delivering a subunit influenza vaccine (PLA-based nanoparticles adjuvanted with a TLR7/8 agonist and functionalized with hemagglutinin) in young (2–3 months) and aged (16–18 months) mice. Results Strikingly, the SL patch provided 100% protection in aged mice against an influenza challenge, outperforming injected formulations (75–80% protection), despite lower IgG antibody levels, limited secretory IgA or cytotoxic T cell responses. Conversely, the patch failed to protect young mice, suggesting age-dependent immune mechanisms, possibly linked to IL-6 levels and chronic mucosal inflammation. Mechanistic investigations after vaccination by the chitosan-based patch revealed enhanced B cell activation and neutrophil recruitment in the draining lymph nodes, potentially driven by chitosan, which may contribute to improved antibody affinity. Conclusions These findings underscore the potential of chitosan-based SL patches to overcome age-related immune decline and improve vaccine responses in the elderly.