Abstract
BCG is the oldest vaccine in continuous use. While current intradermal vaccination regimens confer limited protection outside the context of pediatric extrapulmonary tuberculosis (TB), promising new data indicate that when administered mucosally or intravenously at a higher dose, BCG can induce sterilizing immunity against pulmonary TB in nonhuman primates. BCG is also known to promote nonspecific host resistance against a variety of unrelated infections and is a standard immunotherapy for bladder cancer, suggesting that this innate immune function may contribute to its protective role against TB. Here, we propose that both the mycobacterial-specific and off-target effects of BCG depend on the interplay of adaptive and innate cells and the cytokines they produce, and that the elucidation of this interaction should be a major strategy in the development of more effective BCG-based vaccines and immunotherapies.