New Tuberculosis Vaccine Strategies: Taking Aim at Un-Natural Immunity

Despite some major progress made in developing tuberculosis (TB) vaccine strategies, with a dozen novel vaccines currently in the clinical pipeline, the world is still missing an effective TB vaccine. This questions whether any major breakthroughs can be achieved without making a drastic departure from the current strategy, which creates a state of 'near-natural immunity', imitating the natural immunity developed after Mycobacterium tuberculosis (Mtb) infection. Here, we argue instead that mounting evidence suggests an effective strategy ought to induce a state of all-around 'un-natural' immunity comprising trained innate immunity (TII), tissue-resident memory T cells (T_RM), and anti-Mtb surface antibodies in the lung. Thus, here we summarize the latest information, thinking, and development in the field of TB and vaccines.