Characteristics and protective efficacy of human antibodies against M. tuberculosis

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Abstract Active tuberculosis (TB), a transmissible uncontrolled respiratory infection caused by Mycobacterium tuberculosis (Mtb), is a global public health problem and one of the top 10 causes of death worldwide. More effective vaccines for the protection against TB 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 specific protective antibody responses that could be induced in humans 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 a several microbial pathogens, including those with intracellular location such as Mtb. Human antibody levels to Mtb capsular polysaccharides are not only greatly variable, they are also tremendously heterogeneous in their binding specificity to oligosaccharide motifs within the polysaccharide. Our published and preliminary data suggest that protection is due to IgG reactivity to specific oligosaccharide motifs. Based on these novel data, our overarching hypotheses are: 1) Human antibodies to specific capsular polysaccharides are protective against Mtb; and 2) protection by these antibodies arises from reactivity to specific oligosaccharide motifs within the polysaccharide. 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 determine the oligosaccharide epitopes of Mtb surface carbohydrates that are most relevant for protection Although some of our most successful vaccines are based on inducing antibodies to capsular polysaccharides, the field has started to move to oligosaccharide-conjugate vaccines, which, in addition to targeting the most relevant epitopes, have the advantage of greater product consistency compared to the heterogeneous preparations of purified polysaccharides of most marketed glycoconjugate vaccines. The knowledge gained could inform new strategies for developing both vaccines and Ab-based immunotherapies against TB.