ABSTRACT Tuberculosis due to Mycobacterium tuberculosis (MTB) is the leading cause of mortality due to infections today with more than 2 million deaths worldwide. BCG vaccine derived from Mycobacterium bovis is the only approved human vaccine although, it has a partial efficacy against childhood and adult tuberculosis. Since BCG lacks certain genes of wild type M. tuberculosis many recombinant BCG vaccine strains have been prepared and evaluated in animal models. Based on the observation that human neonates respond better to vaccine antigens when stimulated with Toll-like receptor (TLR) adjuvants, we constructed a novel recombinant BCG vaccine that expresses a peptide stimulating TLR-2 (TLR-BCG). This vaccine protected mice better than wild type BCG vaccine. We also developed a novel neonatal monkey model to evaluate vaccine effects against tuberculosis. This project will verify the hypothesis that, TLR-BCG vaccine will be more efficient than wild type BCG vaccine in generating stronger and longer lasting immune responses against tuberculosis in NHPs. Specific Aim-1A: We will evaluate TH1 immune responses induced by wild type BCG and recombinant TLR-BCG in the neonatal monkey model. We will determine if TLR-BCG induces qualitatively different primary T cell immune responses in NHPs compared with a natural infection with M. tuberculosis and correlate vaccine-induced protection against aerosol induced tuberculosis in NHPs. Specific Aim -2: We will evaluate long-term efficacy of TLR-BCG vaccines using a prime boost strategy with the neonatal monkey model. These studies are likely to lead to generate a better primary vaccine against tuberculosis, and a more efficient better booster vaccine for children already vaccinated with wt-BCG.