Immunotherapy targeting drug-tolerant Mycobacterium tuberculosis persisters accelerates tuberculosis cure in preclinical models.

Mycobacterium tuberculosis remains a global health crisis, ranking among the deadliest infectious diseases worldwide. In response to the WHO's call for therapeutic vaccines to complement antibiotic regimens and reduce tuberculosis (TB) treatment duration, we developed an intranasal DNA vaccine fusing the M. tuberculosis stringent response gene relMtb with the gene encoding the DC-targeting chemokine Mip3a (also known as CCL20). Administered alongside the first-line regimen, this vaccine accelerated a stable cure in immunocompetent murine TB models, reducing lung inflammation and eliciting robust and sustained RelMtb-stimulated T cell responses systemically and locally. The Mip3a/relMtb vaccine enhanced DC recruitment, activation, and spatial coordination with T cells, suggesting improved innate-adaptive immune synergy. Notably, it augmented the efficacy of a novel drug-resistant TB regimen as well. Critically, the vaccine induced analogous antigen-stimulated T cell immunity in nonhuman primates, the gold standard for preclinical TB vaccine evaluation, with responses detected in blood and bronchoalveolar lavage mirroring those observed in the murine models. These findings underscore the potential of this strategy to advance therapeutic TB vaccine development targeting M. tuberculosis persisters while providing a framework to define correlates of vaccine-mediated protection.