Understanding pathogenesis of and BCG vaccine efficacy against high, moderate, and low transmissible Mycobacterium tuberculosis strains in mice.

The genetic diversity of Mycobacterium tuberculosis challenges Tuberculosis control and may contribute to variable protection by BCG. We evaluated pathogenesis and BCG efficacy against clinical Kenyan Mtb isolates grouped by epidemiological transmissibility. Forty-nine isolates were spoligotyped and classified as high (HT), moderate (MT), or low (LT) transmissibility. Representative HT, MT and LT isolates, together with HN878, were assessed for virulence and BCG-induced protection in CB6F1 and C57BL/6 mice. Endpoints included lung and spleen bacterial burden and lung immunopathology. The HT isolate CAS1-Kili (L3) induced pronounced lung pathology despite bacterial loads comparable to the LT T2 (L4) isolate, which caused less inflammation, indicating dissociation between burden and pathology. BCG reduced lung CFU at early timepoints in CB6F1 mice, but protection waned by 12 weeks, including against HN878. Splenic control differed by host: CB6F1 mice showed reduced dissemination at 12 weeks, whereas C57BL/6 mice showed limited systemic control. Dissemination kinetics also differed, with early splenic spread of T2 and delayed dissemination of CAS1-Kili. Notably, BCG consistently reduced lung pathology even when bacterial burden reductions were modest. Overall, BCG efficacy was strain-, host-, organ- and time-dependent, underscoring the need for durable vaccines protective across diverse lineages.