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

Abstract Lengthy tuberculosis (TB) treatment is required to address 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 construct involving fusion of the rel Mtb gene with the immature dendritic cell-targeting gene encoding chemokine MIP-3α/CCL20. To augment mucosal immune responses, intranasal delivery was also evaluated. We found that the intramuscular MIP-3α / rel Mtb (fusion) vaccine potentiates isoniazid activity more than a similar DNA vaccine expressing rel Mtb alone in a chronic TB mouse model (absolute reduction of Mtb burden: 0.63 log 10 colony-forming units, P=0.0001), inducing pronounced Mtb -protective immune signatures. The intranasal fusion vaccine, an approach combining rel Mtb fusion to MIP-3α and intranasal delivery, demonstrated the greatest therapeutic effect compared to each approach alone, as evidenced by robust Th1 and Th17 responses systemically and locally and the greatest mycobactericidal activity when combined with isoniazid (absolute reduction of Mtb burden: 1.13 log 10 , P<0.0001, when compared to the intramuscular vaccine targeting rel Mtb alone). This DNA vaccination strategy may be a promising adjunctive approach combined with standard therapy to shorten curative TB treatment, and also serve as proof-of-concept for treating other chronic infections.