The goal of our laboratory is to provide a scientific foundation for mucosal vaccines to prevent pneumococcal and influenza infections in the lung and transmission of HIV-1 in the intestine, reproductive tract and by breast milk. We integrate clinical and basic laboratory approaches to determine how pathogens interact with the host at the mucosal surface and how innate and humoral mechanisms, individually and in concert, serve to protect against infection. Our primary model for mucosal defense against HIV involves post-natal transmission of the virus by breast milk. We characterize mechanisms by which pathogen- specific antibodies in blood and milk from transmitting and non-transmitting mothers in Uganda neutralize autologous and heterlogous HIV isolates using cellular, molecular, and biochemical approaches. For S. pneumoniae and influenza, we characterize systemic and mucosal responses to natural infection and vaccine, the molecular basis for capsule-specific antibody responses, and the functional activity of these human antibodies. The goal is to develop effective vaccines against these pathogens to prevent infections where they begin, at the mucosa.