Autophagy enhances the Efficacy of BCG Vaccine

Tuberculosis caused by Mycobacterium tuberculosis kills around 1.5 million people per year and infects a third of mankind. Bacillus Calmette–Guérin (BCG) is a live attenuated vaccine widely used to prevent tuberculosis in humans. BCG activates CD4 and CD8 T cell-dependent Th1 immunity and protects partially against childhood disease but is poorly effective against adult tuberculosis. The efficacy of BCG vaccine has been increased by the addition of Mycobacterium tuberculosis-derived antigens and listeriolysin through genetic manipulation. Such recombinant vaccines leak more antigens across phagosome membranes into the cytosol of macrophages and dendritic cells (APCs). An intriguing property of intracellular BCG is the maturation arrest, where the vaccine is sequestered within an immature phagosome, which does not fuse with lysosomes. This affects the ability of APCs to produce peptide epitopes from BCG and reduces CD4 T cell responses. We describe here novel strategies to enhance the sorting of intracellular BCG vaccine and vaccine-derived soluble antigens into proteolytic lysosome compartments of APCs. Thus, rapamycin-induced autophagy in APCs enhanced the localization of both BCG vaccine and its secreted Ag85B to autophagosomes and lysosomes, increasing peptide presentation to CD4 T cells. Over-expression of secreted Ag85B in recombinant BCG led to aggresome formation in the cytosol of APCs, which triggered autophagosomes and boosted antigen presentation. Consistent with intracellular effects, rapamycin-activated dendritic cells containing BCG were more effective as vaccines in mice against tuberculosis. Finally, co-administration of rapamycin with BCG given to mice enhanced both CD4 and CD8 T cell responses, which protected better against a challenge with tuberculosis. Since BCG is a widely used and safe vaccine for humans, we propose that newer autophagy-inducing BCG vaccines can generate better protection against tuberculosis.