SUMMARY: Role of Pre-existing Immunity on Airborne Transmission of Influenza A Viruses Influenza viruses pose a major public health threat through both seasonal epidemics and sporadic pandemics. The epidemiological success of influenza viruses relies on its ability to spread efficiently through the air and navigate three distinct spaces: 1) the donor, 2) the environment and 3) the recipient (Lakdawala and Subbarao Nature Medicine 2012). The first infection with influenza viruses leaves a long-lasting immunity, which can be evaded by the virus through antigenic drift and shift. Our published data using the ferret model shows that pre-existing immunity from the 2009 H1N1 pandemic virus infection protects recipient animals from airborne transmission of a seasonal H3N2 influenza virus (Le Sage et al PLoS Pathogens 2021). We hypothesize that pre-existing immunity can influence susceptibility to circulating influenza strains independent of neutralizing antibody. To understand the role of pre-existing immunity in protection against airborne transmission, Aim 1 will identify immunological and viral factors underlying susceptibility to airborne transmission. Each influenza season, population-wide immunity triggers viral antigenic evolution, Aim 2 will determine the impact of antigenic drift on the susceptibility to influenza virus transmission. Aim 3 will examine the impact of different vaccine platforms on susceptibility to drifted influenza virus strains. This proposal will provide a better understanding of the immune protection needed to dampen influenza virus transmission and inform effective universal vaccine strategies.