Targeted delivery of the BCG vaccine to dendritic cells improves protective efficacy against Mycobacterium tuberculosis

Tuberculosis (TB) is the world's deadliest infectious disease, and the current vaccine, Bacillus Calmette-Guérin (BCG), is only partially effective. We hypothesised that BCG interacts sub-optimally with dendritic cells (DCs), key mediators of adaptive immunity. To improve BCG's efficacy, we engineered the vaccine to express a single-chain variable fragment (scFv) targeting the DEC-205 receptor on DCs (BCG:DEC). This modification enhanced BCG interaction with DEC-205-expressing cells, resulting in increased uptake into host cells and cytokine/chemokine secretion. After vaccination of mice, BCG:DEC increased MHC-II expression on vaccine-site myeloid cells, showed enhanced uptake by skin-resident DC subsets and generated higher frequencies of multifunctional, cytokine-secreting CD4 + T cell populations. Compared to BCG alone, BCG:DEC provided improved and sustained protection up to 20 weeks post-challenge against Mycobacterium tuberculosis in mice. Thus, DC-targeted BCG is a promising approach for TB control.