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Mutations that arose in bacille Calmette-Guérin (BCG) daughter strains during decades of in vitro cultivation have long been suspected of reducing the efficacy of the BCG vaccine against pulmonary tuberculosis. Although concern was raised 6 decades ago that BCG had become overattenuated, preferential use of relatively virulent BCG vaccines has not restored efficacy. The recent discovery that as BCG evolved its production of antioxidants increased as a consequence of genomic duplications and other mutations suggests the alternative hypothesis that BCG became better at suppressing oxidant-dependent immune responses. This new model of BCG evolution is supported by evidence indicating that reducing BCG antioxidants enhances immunogenicity. Furthermore, some previously unexplained aspects of the performance of the BCG vaccine in clinical trials now make sense in the context of the new model. Finally, the model suggests that the risk of developing pulmonary tuberculosis is influenced by the balance between host-generated oxidants and microbial antioxidants that activate and suppress, respectively, the antigen-presentation pathways that protect the lungs.