BCG vaccination reduces the rate of Mycobacterium tuberculosis dissemination between murine lungs

The BCG vaccine remains the only licensed defense against tuberculosis (TB), yet its protective mechanisms are poorly understood. Utilizing data from a study of over 1,000 mice infected with an ultra-low dose (ULD) of Mycobacterium tuberculosis (Mtb), we developed mathematical models to quantify Mtb dynamics and dissemination in the murine lungs. Our models, incorporating both direct (lung-lung) and indirect dissemination(lung-intermediate tissue-lung) pathways, fit data from unvaccinated mice equally well, suggesting multiple plausible routes of Mtb spread; the models predicted rapid early Mtb replication, transient control within 1–2 months, and continued growth in chronic infection. Crucially, fitting these models to the data from BCG-vaccinated animals revealed that the vaccine reduces the inter-lung dissemination rate by 89%, while only modestly reducing the Mtb replication rate in the lung by 9%. Stochastic simulations demonstrated that growth-reducing vaccines, even at moderate efficacy decrease the number of infected mice, CFU levels, and bilateral spread. Finally, we used these parameterized models to calculate the sample sizes required to detect vaccine efficacy regarding Mtb clearance or dissemination. This framework quantifies vaccine efficacy in ULD-infected mice and supports preclinical evaluation of next-generation TB vaccines.