Post-exposure vaccination with an adjuvanted protein subunit vaccine, but not BCG, protects mice and guinea pigs against M. tuberculosis.

Tuberculosis (TB) remains a global health priority and vaccines targeting populations with prior Mycobacterium tuberculosis (Mtb) exposure are predicted to most rapidly impact epidemic control. Paradoxically, while efficacy trials are primarily targeting previously Mtb-exposed populations, preclinical testing largely relies on Mtb-naïve animal models. We introduce two post-exposure models, a murine reinfection model and a previously unreported guinea pig reactivation model, and evaluate the efficacy of the adjuvanted protein subunit vaccine H107/CAF®01 compared to Bacillus Calmette-Guérin (BCG). Consistent with clinical and human population data, we demonstrate that BCG fails to confer significant protection in these post-Mtb-exposed settings. In contrast, H107/CAF®01 imprints distinct Th17 responses and provides robust and consistent protection, reducing both the bacterial burden and infection-associated tissue pathology. These findings support the development of H107 as a vaccine candidate in previously Mtb-exposed and infected populations and underscores the importance of evaluating TB vaccines in animal models that reflect prior exposure.