Efficacy of intranasal adenovirus vector vaccine is attenuated by type I IFN-induced NK cell activation

Adenovirus vector (Adv)-based intranasal (i.n.) vaccines induce mucosal immunity and are thus a promising strategy against various infectious diseases. To improve the safety and efficacy of Adv vaccines, it is essential to clarify the mechanisms underlying the induction of immune responses. We focused on type I interferons (IFNs), which play a crucial role in the antiviral response. To elucidate the mechanisms behind i.n. Adv vaccination, we intranasally administered antigen (Ag)-expressing Adv to type I IFN receptor-deficient (Ifnar1 ^-/-) mice. Our findings indicated that type I IFN signaling specifically suppresses Ag-specific antibody production at the airway mucosal surface. Depletion of NK cells revealed that low Ag expression results from enhanced NK cell activity, which eliminates Adv-infected cells, thereby reducing Ag-specific antibody production at the airway mucosal surface. Together, these results suggest that type I IFN signaling decreases Ag expression by promoting the elimination of Adv-infected cells via NK cell activation, which attenuates Ag-specific antibody production during i.n. Adv vaccination. Our findings contribute to the development of more potent and optimized Adv vaccines.