Tuberculosis (TB) is a global infectious threat caused by Mycobacterium tuberculosis, for which the only licensed vaccine available to date is derived from an attenuated Mycobacterium bovis strain known as Bacille Calmette-Guerin (BCG). BCG effectiveness varies depending on age and geographic location, and although effective against TB meningitis, it is only partially protective against pulmonary TB. Alternative vaccine candidates have been proposed, but with limited protection rates. One approach to developing an effective TB vaccine would be to improve the existing BCG for better administration and TB control. Furthermore, the testing of novel vaccine candidates could be accelerated by developing an attenuated and safe M. tuberculosis (Mtb) strain, for use in a controlled human infection model study, to complement animal studies. In one of two recently published back-to-back papers, Smith, Su, Wallach et al. developed a safer engineered version of BCG with robust protection against Mtb infection. In the other study, Wang, Su, Wallach, Wagner et al. obtained a promising engineered Mtb strain as a candidate for human challenge studies.

In the other study, Wang, Su, Wallach, Wagner et al. designed an Mtb strain with three kill switches: two mycobacteriophage lysin operons negatively regulated by aTc or doxy and a degron domain–NadE fusion that induces ClpC1-dependent degradation of the essential enzyme NadE, negatively regulated by trimethoprim (TMP). This triple-kill switch (TKS) Mtb strain grows in the present of aTc and TMP and does not grow in their absence. The TKS Mtb strain had growth kinetics and antibiotic susceptibility comparable to the wild-type strain in vitro, with an escape rate that was below the lower limit of detection. In vivo, TKS Mtb enabled infection comparable to the wild type in mice receiving aTc and TMP antibiotics, and was rapidly eradicated in their absence, with no relapse observed. TKS Mtb showed a low escape rate (less than 10–10 per genome per generation) and rapid elimination kinetics, both of which are critical safety factors for an Mtb strain intended to be used in TB human challenge studies.