Immunological memory confers long term protection against pathogens and is the basis of successful vaccination.Following antigenic stimulation long lived plasma cells and memory B cells are maintained for a lifetime,conferring immediate protection and enhanced responsiveness to the eliciting antigen. However, in the case ofvariable pathogens such as influenza virus, B cell memory is only partially effective, depending on the extent ofsimilarity between the preceding and the new viruses. The B cell response is dominated by serotype-specificantibodies and heterosubtypic antibodies capable of neutralizing several serotypes appear to be extremely rare.Understanding the basis of broadly neutralizing antibody responses is a critical aspect for the developmentof more effective vaccines. In this project we will explore the specificity and dynamics of human antibodyresponses to influenza virus by using newly developed technological platforms to culture human B cells and plasmacells and to analyze the repertoire of human naïve and memory T cells. High throughput functional screenings,structural analysis and testing in animal models will provide a thorough characterization of the human immuneresponse. The B cell and T cell analysis aims at understanding fundamental aspects of the immune response suchas: the selection and diversification of memory B cells; the individual variability of the antibody response, themechanisms of T-B cooperation and the consequences of the original antigenic sin and of aging on the immuneresponse. This analysis will be complemented by a translational approach whereby broadly neutralizing humanmonoclonal antibodies will be developed and used: i) for passive vaccination against highly variable viruses; ii) forvaccine design through the identification and production of recombinant antigens to be used as effective vaccines;and iii) for active vaccination in order to facilitate T cell priming and jump start the immune responses.