Using mathematical modelling to estimate the efficacy of BCG vaccination on Mycobacterium tuberculosis dynamics and dissemination in ultra-low dose infected mice

BCG vaccine is the only licensed vaccine against tuberculosis (TB), a disease caused by Mycobacterium tuberculosis (Mtb). Even though billions of individuals have been vaccinated with BCG, efficacy of BCG vaccine and mechanisms by which it provides protection remain poorly understood. In a recent study, Plumlee et al. (Plos Pathogens, 19(11), e1011825, 2023) infected over a thousand mice, about half of which were vaccinated with BCG, with an ultra-low dose of Mtb (about 1 bacterium/mouse). We developed several alternative mathematical models describing Mtb dynamics in the initially infected lung (named Lung 1) and Mtb dissemination to the collateral lung (Lung 2) and fitted these models to the data from Plumlee et al. experiments.

Interestingly, proposed alternative models assuming direct or indirect Mtb dissemination describe the data on Mtb dynamics in unvaccinated mice with similar quality. Further, we predict that Mtb replicates rapidly early during the infection, is controlled 1-2 months post-infection, and resumes replication in the chronic phase. By fitting the models to Mtb dissemination data in BCG-vaccinated mice we found that the data are best explained if BCG reduces both the rate of Mtb replication in the lungs (by 9%) and the rate of Mtb dissemination between the lungs (by 89%).

Moreover, to investigate the large variability in CFUs found in murine lungs, we implemented stochastic simulations of Mtb dissemination in unvaccinated or BCG-vaccinated mice, but these simulations did not fully account for the observed variability. However, stochastically simulating Mtb infection of right and left lung and dissemination between the lungs over time could successfully explain large CFU variability. Overall, our mathematical modelling-based approach suggests that BCG reduces the net rate of Mtb replication and reduces the rate of

Mtb dissemination between the lungs. Our approach can be used to rigorously quantify efficacy of other TB vaccines in settings of ultra-low dose Mtb infection.