| Summary: | <i>Mycobacterium abscessus</i> is a nontuberculous mycobacterium (NTM) of particular concern in individuals with obstructive lung diseases such as cystic fibrosis (CF). Treatment requires multiple drugs and is characterised by high rates of relapse; thus, new strategies to limit infection are urgently required. This study sought to determine how Bacille Calmette-Guérin (BCG) vaccination may impact NTM infection, using a murine model of <i>Mycobacterium abscessus</i> infection and observational data from a non-BCG vaccinated CF cohort in Sydney, Australia and a BCG-vaccinated CF cohort in Cape Town, South Africa. In mice, BCG vaccination induced multifunctional antigen-specific CD4<sup>+</sup> T cells circulating in the blood and was protective against dissemination of bacteria to the spleen. Prior infection with <i>M. abscessus</i> afforded the highest level of protection against <i>M. abscessus</i> challenge in the lung, and immunity was characterised by a greater frequency of pulmonary cytokine-secreting CD4<sup>+</sup> T cells compared to BCG vaccination. In the clinical CF cohorts, the overall rates of NTM sampling during a three-year period were equivalent; however, rates of NTM colonisation were significantly lower in the BCG-vaccinated (Cape Town) cohort, which was most apparent for <i>M. abscessus</i>. This study provides evidence that routine BCG vaccination may reduce <i>M. abscessus</i> colonisation in individuals with CF, which correlates with the ability of BCG to induce multifunctional CD4<sup>+</sup> T cells recognising <i>M. abscessus</i> in a murine model. Further research is needed to determine the optimal strategies for limiting NTM infections in individuals with CF.
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