Abstract Respiratory viruses spread from host to host as they are shed from mucosal surfaces and can transmit through the air or via surface contact. Therefore, it is believed that the induction of a strong mucosal immune defense cannot only prevent from infection at the port of virus entry, but also affect virus transmission, thereby preventing new infections. In this proposal, we will address the impact of mucosal adjuvanted vaccination on the outcome of disease, host immune responses to and transmission events after experimental respiratory infection with influenza virus and SARS-CoV-2. We will use the guinea pig (influenza) and Syrian golden hamster (SARS-CoV- 2), two established models for vaccination, infection and transmission studies with respiratory viruses. Intranasal virus inoculation will result in replication mainly in the upper respiratory tract for guinea pigs, whereas SARS- CoV-2 will replicate in both upper and lower respiratory tract. We will compare protection provided by mucosal adjuvanted vaccination via the intranasal route to parenteral vaccination via the intramuscular route and will investigate the impact of induction of protective immune responses at mucosal sites on host immune responses to infection in vaccinated hosts (hybrid immunity) and virus transmission between vaccinated infected animals and naïve receiver animals. Despite being vaccine-preventable diseases, transmission of influenza and SARS- CoV-2 occurs frequently after breakthrough infection of antigenically drifted virus variants in vaccinated people. For this R21, three principal investigators with complementary expertise in preclinical animal models for respiratory virus transmission, mucosal adjuvanted vaccines and immune profiling will continue to build on their previous collaborative efforts and expertise to investigate the potential of an intranasal mucosal adjuvanted vaccine strategy previously validated in mice. The mucosal adjuvant consists of a nanoemulsion with TLR- agonistic properties combined with a RIG-I agonist. This combination adjuvant is currently being tested and compared to other licensed intramuscular adjuvants by us in mice for its suitability as a mucosal adjuvanted vaccination strategy for universal and supraseasonal influenza and SARS-CoV-2 vaccine antigens. The efficiency of inhibition of transmission by mucosal vaccination will be compared to parenteral vaccination with the current standards of care for populations at risk (split inactivated influenza virus vaccine or recombinant hemagglutinin for influenza and mRNA or adjuvanted recombinant SARS-CoV-2 spike protein-based COVID-19 vaccines). We will correlate induced mucosal and systemic immune responses after vaccination with protection from experimental infection, reduction in transmission to naive receiver animals and enhancement of hybrid immunity (immunity as a result of vaccination and infection).