| Izvleček: | <p>Human tuberculosis (TB) is caused by various members of the <em>Mycobacterium tuberculosis</em> (Mtb) complex. Differences in host response to infection have been reported, illustrative of a need to evaluate efficacy of novel vaccine candidates against multiple strains in preclinical studies. We previously showed that the murine lung and spleen direct mycobacterial growth inhibition assay (MGIA) can be used to assess control of <em>ex vivo</em> mycobacterial growth by host cells. The number of mice required for the assay is significantly lower than <em>in vivo</em> studies, facilitating testing of multiple strains and/or the incorporation of other cellular analyses. Here, we provide proof-of-concept that the murine MGIA can be applied to evaluate vaccine-induced protection against multiple Mtb clinical isolates. Using an ancient and modern strain of the Mtb complex, we demonstrate that <em>ex vivo</em> bacillus Calmette–Guérin (BCG)-mediated mycobacterial growth inhibition recapitulates protection observed in the lung and spleen following <em>in vivo</em> infection of mice. Further, we provide the first report of cellular and transcriptional correlates of BCG-induced growth inhibition in the lung MGIA. The <em>ex vivo</em> MGIA represents a promising platform to gain early insight into vaccine performance against a collection of Mtb strains and improve preclinical evaluation of TB vaccine candidates.</p>
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