Abstract Active tuberculosis (TB), a transmissible respiratory infection caused by uncontrolled Mycobacterium tuberculosis (Mtb) infection, is worldwide one of the top 10 causes of death. To control this major global public health problem alternative therapies and a more effective vaccine are urgently needed. The currently available Bacillus Calmette-Guerin (BCG) vaccine has been in use for almost a century but provides insufficient protection against TB. A major obstacle in the TB vaccine field is the limited understanding of the full breadth of the immune components involved in the protection against TB. Currently, TB vaccine development is focused on eliciting or boosting cell-mediated immunity, but increasing evidence suggests that antibodies also have a role in the protection against TB. To gain a better understanding of the epitopes involved in human protection and inducible by vaccination, detailed characterization and functional studies of human polyclonal and monoclonal Abs (mAbs) to potentially protective epitopes are required. Antibodies to capsular and other surface polysaccharides are protective against several microbial pathogens, including those with intracellular location. Using novel glycan arrays our published and preliminary data show that human Abs to Mtb surface glycans are highly heterogeneous in their binding specificity and differ in both their reactivity to oligosaccharide motifs and their functions between BCG vaccination and/or controlled (latent) versus uncontrolled (TB) Mtb infection. Our overarching hypotheses are: 1) Human Abs to AM are protective against Mtb, and 2) protection by these Abs arises from reactivity to specific OS motifs within AM. Our specific aims are: 1. To generate and characterize human polyclonal and mAbs to Mtb surface glycans; 2. To determine the effects of Mtb surface- specific human Abs on macrophage functions; and 3. To establish the protective efficacy of Mtb surface- specific human Abs in vivo. Our overarching goal is to identify key immunogenic Mtb glycotopes that render Ab-mediated protection in humans. The information gained could fill a critical gap in the current knowledge of TB immunity and inform new strategies for developing both vaccines and Ab-based immunotherapies against TB.