Intranasal administration of split-inactivated influenza virus vaccine mixed with a novel adjuvant elicits protective antibodies against seasonal influenza viruses.

Seasonal influenza remains a persistent global health concern, and despite the availability of vaccines, there are both limitations in vaccine effectiveness and needle-associated hesitancy that reduce vaccine uptake. To address these challenges, this study evaluated the intranasal delivery of Fluzone, a commercially licensed split-inactivated influenza vaccine, formulated with or without adjuvant. Mice were vaccinated intranasally with Fluzone alone or combined with either Infectimune, a cationic lipid nanoparticle adjuvant, or TRAC478, a synthetic dual toll-like receptor liposome adjuvant containing TLR4 and TLR7/8 agonists. In immunologically naive mice, a higher inoculation volume was more effective at eliciting protective antibody responses even though the same dose of vaccine antigen was used for vaccination. Fluzone mixed with adjuvant enhanced hemagglutination-inhibition (HAI) titers and all mice were protected against influenza virus challenge. Mice with pre-existing anti-influenza virus immunity that was elicited by prior infection with historical influenza strains had modest antibody responses and full protection following immunization with unadjuvanted vaccine. However, the inclusion of an adjuvant with Fluzone significantly raised HAI titers and HA-specific IgG levels. Pre-immune mice vaccinated with Fluzone mixed with either adjuvant had low to undetectable viral lung titers following challenge. Overall, intranasally delivered split-inactivated influenza vaccines paired with a mucosal adjuvant is a promising strategy to enhance vaccine effectiveness.