Prevention of TB in nonhuman primates by a stress-response deficient mutant of Mycobacterium tuberculosis via induction of classical T cell immunity

The need for novel vaccination strategies to control tuberculosis (TB) is underscored by the limited and variable efficacy of the currently licensed vaccine, Bacillar Calmette-Guerin (BCG). SigH is critical for Mycobacterium tuberculosis (Mtb) to mitigate oxidative stress, and in its absence Mtb is unable to scavenge host oxidative/nitrosative bursts. The MtbDsigH (DsigH) isogenic mutant induced signatures of the innate immune response in macrophages, and protected rhesus macaques from a lethal Mtb challenge. To understand the immune mechanisms of protection via mucosal vaccination with DsigH, we employed the resistant cynomolgus macaques; and our new results show that DsigH vaccination significantly protected against lethal Mtb challenge in this species. DsigH­-vaccinated macaques are devoid of granulomas and instead generate inducible bronchus associated lymphoid structures, and robust antigen-specific CD4⁺ and CD8⁺ T cell responses, driven by a hyper-immune, trained immunity-like phenotype in host macrophages with enhanced antigen presentation. Correlates of protection in DsigH­-vaccinated macaques include gene signatures of T cell activation, IFNG production, including IFN-responsive, activated T cells, concomitant with IFNG production, and suppression of IDO⁺ IFN-responsive macrophage recruitment. Thus, ΔsigH is a promising lead candidate for further development as an antitubercular vaccine.