A novel vaccination strategy induces vaccine-specific mucosal responses at port of viral entry and exit: using systemic SARS-CoV-2 vaccination as a test case

Respiratory infectious diseases are associated with substantial morbidity and mortality rates worldwide, especially at the extremes of age and in immunocompromised individuals. Over the past two decades, respiratory viruses have driven nine epidemics and pandemics (including the COVID-19 pandemic); and their ongoing emergence, persistence and evolution continue to threat global health security. The upper respiratory tract (URT) represents the primary access point for respiratory viruses, where initial host infection occurs. Vaccine-mediated URT mucosal memory responses can control infection, prevent transmission and limit viral evolution. However, vaccines against respiratory viruses predominantly have systemic administration routes that elicit strong responses in the circulation to prevent severe respiratory disease, but do not effectively block infection and onward community transmission. To overcome the limitations of systemic vaccination alone, we present a novel intervention combining systemic vaccination with targeted non-antigenic inflammatory stimulation of the URT, to induce vaccine-specific immune responses in the URT mucosa. Using SARS-CoV-2 vaccination as a test case, we demonstrate for the first time, that intranasal coadministration of exogenous IFN-alpha; as a targeted inflammatory URT signal, alongside systemic vaccination, induces vaccine-specific T-cell responses in the URT.