Prevention of tuberculosis in cynomolgus macaques by an attenuated Mycobacterium tuberculosis vaccine candidate

The need for novel vaccination strategies to control tuberculosis (TB) is underscored by the limited and variable efficacy of the currently licensed vaccine, Bacille 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 MtbΔsigH (ΔsigH) isogenic mutant induces signatures of the innate immunity in macrophages and protects rhesus macaques from a lethal Mtb challenge. To understand the immune mechanisms of protection via mucosal vaccination with ΔsigH, we employed the resistant cynomolgus macaque model; and our results show that ΔsigH vaccination significantly protects against lethal Mtb challenge in this species. ΔsigH-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 ΔsigH-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⁺ Type I IFN-responsive macrophage recruitment. Thus, ΔsigH is a promising lead candidate for further development as an antitubercular vaccine.