Improving the efficacy of bacillus calmette guerin vaccine by concomitant inhibition of T regulatory and T helper 2 cells.

Abstract

Tuberculosis (TB) remains a major threat to human population as currently Mycobacterium tuberculosis (MTB) infects nearly 33% of the global population. Annually, about one and a half million deaths are caused by tuberculosis (TB). Current reports suggest that approximately nine million new TB cases are reported every year. There is an available therapy for TB, however it is quite lengthily and consists of numerous antibiotics leading to treatment dropout. This treatment incompletion has been linked to the major cause for the appearance of drug-resistant species of MTB. Consequently, alternate therapies to treat TB are needed. Bacillus Calmette-Guerin (BCG) remains the only vaccine of choice since its inception in 1921. Although BCG mounts host protective T helper1 (Th1) cell activation, which plays a pivotal role in host protection against TB, its efficacy is inadequate, suggesting that additional methods to enhance protective immune responses are needed. We have also shown that simultaneous inhibition of Th2 cells and Tregs by using pharmacological inhibitors (suplatasttosylate and D4476, respectively) dramatically enhance MTB clearance and induces a superior Th1 response. Here we show that treatment with these two immuno-modulators during BCG vaccination dramatically improves vaccine efficacy. Furthermore, we demonstrate that these drugs induce a shift in T cell memory development, towards central memory T (Tcm) cell responses. Collectively, our findings provide evidence that concurrent inhibition of T helper cells type 2 and Tregs during BCG vaccination promotes vaccine efficacy.