Oral BCG: Optimizing mucosal vaccination against tuberculosis

Tuberculosis is the second most common cause of infectious death worldwide and preventative efforts to develop a highly effective vaccine have been unsuccessful thus far. BCG (Bacille- Calmette-Guerin) vaccination remains the most widely available vaccine against TB, reducing severe disease in neonates, though its efficacy is only 50% for all forms of TB. We have shown that changing the route of BCG administration profoundly influences its protective efficacy. In the macaque model of TB, intravenous BCG provided 90% protection against Mtb challenge. Oral BCG was the first human vaccine given in infants against TB with good historical safety and efficacy. Here, we propose to optimize an oral BCG regimen (Aim 1), compare the efficacy of oral BCG to intravenous and intra-dermal BCG (current human standard) against Mtb challenge using modern imaging, immunologic (innate and adaptive lymphocyte function, systems serology, scRNA-seq) and molecular tools (Aim 2). Lastly, we will use computational systems modeling to identify correlates of vaccine-induced protection against Mtb infection (Aim 3). Data in this proposal will provide critical information about the efficacy of oral BCG and discover important measures that correlate with vaccine induced protection and failure. If successful, such measures could transform the TB field.