An intranasal stringent response vaccine targeting dendritic cells as a novel adjunctive therapy against tuberculosis

Lengthy tuberculosis (TB) treatment is required to overcome the ability of a subpopulation of persistent Mycobacterium tuberculosis (Mtb) to remain in a non-replicating, antibiotic-tolerant state characterized by metabolic remodeling, including induction of the Rel(Mtb)-mediated stringent response. We developed a novel therapeutic DNA vaccine containing a fusion of the rel(Mtb) gene with the gene encoding the immature dendritic cell-targeting chemokine, MIP-3 alpha/CCL20. To augment mucosal immune responses, intranasal delivery was also evaluated. We found that intramuscular delivery of the MIP-3 alpha/rel(Mtb) (fusion) vaccine or intranasal delivery of the rel(Mtb) (non-fusion) vaccine potentiate isoniazid activity more than intramuscular delivery of the DNA vaccine expressing rel(Mtb) alone in a chronic TB mouse model (absolute reduction of Mtb burden: 0.63 log(10) and 0.5 log(10) colony-forming units, respectively; P=0.0002 and P=0.0052), inducing pronounced Mtb-protective immune signatures. The combined approach involving intranasal delivery of the DNA MIP-3 alpha/rel(Mtb) fusion vaccine demonstrated the greatest mycobactericidal activity together with isoniazid when compared to each approach alone (absolute reduction of Mtb burden: 1.13 log(10), when compared to the intramuscular vaccine targeting rel(Mtb) alone; P<0.0001), as well as robust systemic and local Th1 and Th17 responses. This DNA vaccination strategy may be a promising adjunctive approach combined with standard therapy to shorten curative TB treatment, and also serves as proof of concept for treating other chronic bacterial infections.