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

The BCG vaccine remains the only licensed vaccine against tuberculosis (TB), yet the mechanisms behind BCG-induced protection remain poorly understood. Plumlee et al. (PLOS Pathogens 2023) infected over 1,000 mice, half of which were vaccinated with BCG, with an ultra-low dose (ULD) of Mycobacterium tuberculosis (Mtb); the authors found that BCG vaccination resulted in fewer infected mice, lower CFU lung burden, and more frequent unilateral lung infection. We have developed several mathematical models of Mtb dynamics and dissemination between murine right and left lungs and fit these models to the CFU data from unvaccinated or BCG-vaccinated mice. Alternative mathematical models incorporating either direct (lung-to-lung) or indirect (lung-intermediate-tissue-lung) dissemination pathways fit the unvaccinated data equally well, suggesting multiple plausible routes of Mtb spread. Yet, irrespective of the dissemination route, the models predicted rapid Mtb replication during early infection, transient control within 1-2 months after infection, and continued bacterial growth in the chronic phase. Fitting models to the data from BCG-vaccinated animals revealed that BCG reduces the rate of Mtb dissemination between the lungs by 89% while having a more modest effect on the replication rate within the lung, reducing it by 9%. We found that the dominant effect of BCG in curbing lung dissemination arises from its ability to reduce Mtb replication resulting in fewer infected mice, lower lung CFU, and decreased bilateral infection of the lung. We used our parameterized mathematical models to calculate the number of mice needed to detect the efficacy of a hypothetical vaccine on the probability of Mtb clearance or dissemination between murine lungs that extends previously provided estimates. Taken together, our novel mathematical modeling-based framework provides a rigorous way of quantifying vaccine efficacy in ULD-infected mice, paving the way for the pre-clinical evaluation of next-generation TB vaccines. Author summaryThe Bacillus Calmette-Guerin (BCG) vaccine remains the only licensed vaccine against tuberculosis (TB), a disease caused by Mycobacterium tuberculosis (Mtb) bacteria. BCG is clearly protective for several years when given at birth but the mechanisms by which it provides protection remain incompletely understood. By combining analysis of Mtb dynamics in over 1,000 control and BCG-vaccinated mice, infected with an ultra low dose of Mtb, with mathematical models we show that BCG reduces both the rate of Mtb replication in the lung and the rate of Mtb dissemination between the lungs. Importantly, our model suggests that BCG may thus reduce a chance of being infected and that BCG-mediated prevention of disseminated TB in humans could be due vaccines ability to block Mtb dissemination out of the lung. Our novel framework thus will allow to predict efficacy of the next generation TB vaccines in settings of infection at doses that humans are thought to be typically exposed to.