Exogenous IFN-α delivered as an intranasal adjunct to systemic vaccination directs vaccine-specific T-cell responses to the upper respiratory tract.

Respiratory infectious diseases remain a major global health burden, sustained by ongoing community transmission. Licensed respiratory vaccines are predominantly systemically administered, which elicit vaccine-induced antigen-specific circulating immunity, but fail to protect the primary site of initial infection and onward transmission, the upper respiratory tract (URT). The URT is a highly compartmentalised anatomical site that is not directly accessed by systemic vaccination. Consequently, conventional systemic respiratory vaccines do not reliably prevent acquisition of infection or its onward transmission, allowing continued circulation and evolutionary pressure on respiratory pathogens, whilst vulnerable populations remain disproportionately affected. To overcome this critical limitation of respiratory vaccinology, we present a novel intervention that combines systemic vaccination with targeted non-antigenic immunomodulatory stimulation of the nasal mucosa to generate vaccine antigen-specific immunity in the URT. This approach may offer an easily deployable route for use across diverse vaccination programmes to interrupt respiratory infection and transmission chains at a population scale. Here, using SARS-CoV-2 vaccination as a test case, we demonstrate for the first time that intranasal exogenous IFN-α, when coadministered as an adjunct to systemic vaccination, provides local immune instruction without reliance on intranasal antigen delivery, and directs vaccine-specific T-cell responses to the URT.