Abstract The goal of this FOA is “to improve our understanding of how vaccines against infectious agents lead to durable protective immunity.” This project seeks to address this objective through a detailed characterization of immune responses in the early phase post-vaccination to identify components that distinguish durable from non-durable responses to vaccination with a live attenuated vaccine against dengue virus (DENV). To date, a single dengue vaccine (CYD-TDV) has reached licensure and others have shown promising efficacy data, but there remain important gaps in the safety and efficacy of these vaccines, particularly around the issue of the durability of protective immunity. This project leverages blood samples available from dengue vaccine trials, in particular a longitudinal study of participants from a phase III trial of CYD-TDV that has been ongoing since 2011. The project addresses the overall hypothesis that functional, transcriptomic, and epigenetic profiles of DENV-specific T and B lymphocytes early post-vaccination predict the establishment of long-lasting DENV-specific serologic immunity through the following Specific Aims: 1) Identify T and B cell functional responses to DENV associated with the long-term persistence of binding and neutralizing antibodies after receipt of CYD-TDV; 2) Identify gene expression and epigenetic profile(s) in DENV-specific T and B lymphocytes associated with the persistence of antibodies after receipt of CYD-TDV; and 3) Validate the immunological signature of durable antibody responses in recipients of CYD-TDV and compare this signature to other dengue vaccines and to natural and experimental DENV infection.