PROJECT ABSTRACT – PROJECT 2 SARS-CoV-2 and influenza A viruses are human pathogens with broad geographic range that cause pandemics and jeopardize human health. While the rapid deployment of vaccines against COVID-19 and annual campaigns with seasonally-matched inactivated, intramuscularly-delivered influenza vaccines have saved millions of human lives, it has become increasingly apparent that intramuscularly-delivered vaccines do not effectively induce mucosal immunity in the respiratory tract, which in theory, could better limit virus infection or transmission at the portal of entry or egress. Although vaccination of antigen-naïve populations provides benefit against SARS-CoV- 2 infection, the impacts of intramuscular boosting on protection from infection by recent circulating strains has been less impressive, in part due to the effects of immune imprinting. In Project 2 of this CCHI, we hypothesize that viral infection in the context of prior recent vaccination induces mucosal immune responses that functionally differ from those after infection or vaccination alone in the levels and types of cross-neutralizing and Fc effector functions of antibodies (Abs), and cross-reactive T cell responses. Project 2 will address key knowledge gaps as to the functional quality of infection- and vaccine-induced systemic and mucosal immunity. To achieve these goals, we will utilize ongoing human natural history cohorts of infected and vaccinated adults with unique clinical samples to study how vaccination impacts qualitative and quantitative systemic and mucosal antibody, B and T cell responses, and Fc effector functions seen after SARS-CoV-2 or IAV infection. We also will utilize samples from a unique influenza A virus human challenge cohort to assess how recent immunization with a quadrivalent influenza vaccine (Flucelvax®) modulates induction of mucosal immunity and control of infection. Our innovative studies on SARS-CoV-2 and influenza infection and vaccination will provide new information on human immune responses and inform evaluation of new mucosal vaccines targeting the human respiratory tract.