We have identified several new TB vaccine candidate antigens based on human T cell responses and animal protection. Priority has been given to those that both elicit a Th1 response from PBMC from PPD positive healthy donors and protect in rodent models. Several animal models have been developed to evaluate vaccine efficacy and are currently being used to further characterize vaccine candidates and adjuvant/delivery systems. We propose to expand the evaluation of candidate vaccine antigens through extensive testing in clinically and geographically diverse populations, using state of the art immunological assays. This section will provide important information on conservation of antigens in genetically diverse populations infected with diverse isolates. These studies will also lay the foundation for definition of key immunological correlates of protection. In parallel, we will perform immunogenicity studies using priority antigens and vaccine formulations in rodent models. We will also perform detailed analysis of the immune responses of human volunteers immunized with Mtb72f in AS02A, the first defined TB vaccine to enter clinical trials. Finally, we will test antigens/vaccine formulations in rodent models of infection and disease. By the end of the funding period, we will have defined a second vaccine candidate for entry into clinical trials.