PROJECT SUMMARY Dengue viruses cause more human morbidity than any other arbovirus, underscoring the public health urgency of making safe and effective dengue vaccines available in endemic settings, in alignment with NIAID priorities. This critical need will be addressed by testing the safety and protective efficacy of NIAID's lead tetravalent, live attenuated dengue vaccine candidate, TV005, in adults in dengue-endemic Bangladesh through a vaccine-challenge trial based on the Dengue Controlled Human Infection Model (D-CHIM). Our central hypothesis is that vaccination with TV005 will protect against infection with a live, recombinant dengue 2 challenge virus (DENV-2), with DENV-2 viremia following challenge as the primary efficacy endpoint. In addition to extensive Phase I and II trials leading to the development of TV005, our team has used a similar vaccine-challenge design to evaluate the safety and efficacy of TV005 in dengue-naïve U.S. adults, which was well-tolerated and >99% efficacious in preventing viremia. The next critical step for NIAID's promising vaccine is to test its safety and efficacy in a dengue-endemic setting. In this study, 224 healthy adult volunteers, both dengue-exposed and -naïve, will be enrolled and randomized 1:1 (vaccine: placebo) to receive TV005 followed by inpatient challenge with DENV-2 at 6 or 24 months post-vaccination. To test our central hypothesis, we will pursue the following Specific Aims: Aim 1A) Determine, in a dengue endemic population, the protective efficacy of TV005 vaccine against dengue infection induced by a live, recombinant DENV-2 challenge virus (rDEN2∆30-7169) administered 6 or 24 months after vaccination; Aim 1B) Evaluate the safety of TV005 and the DEN-2 challenge virus in a dengue endemic population; and Aim 2) Use predictive modeling to identify baseline and post-vaccination immune phenotype(s) that predict TV005 efficacy and safety to better understand response to vaccination and protective immunity, and to inform future study design for dengue vaccine development in endemic settings. In contrast to large-scale field trails, the D-CHIM will provide early vaccine efficacy and safety signals while enrolling a minimal number of volunteers, and contribute to our understanding of the immune response to both vaccination and challenge in an endemic setting through statistical modeling of vaccine impact.