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

Dhiraj K. Singh, Mushtaq Ahmed, Sadia Akter, Vinay Shivanna, Allison N. Bucşan, Abhishek Mishra, Nadia A. Golden, Peter J. Didier, Lara A. Doyle, Shannan Hall-Ursone, Chad J. Roy, Garima Arora, Edward J. Dick, Chinnaswamy Jagannath, Smriti Mehra, Shabaana A. Khader () and Deepak Kaushal ()
Additional contact information
Dhiraj K. Singh: Texas Biomedical Research Institute
Mushtaq Ahmed: University of Chicago
Sadia Akter: University of Chicago
Vinay Shivanna: Texas Biomedical Research Institute
Allison N. Bucşan: Tulane University School of Medicine
Abhishek Mishra: Weill-Cornell Medicine
Nadia A. Golden: Tulane University School of Medicine
Peter J. Didier: Tulane University School of Medicine
Lara A. Doyle: Tulane University School of Medicine
Shannan Hall-Ursone: Texas Biomedical Research Institute
Chad J. Roy: Tulane University School of Medicine
Garima Arora: Texas Biomedical Research Institute
Edward J. Dick: Texas Biomedical Research Institute
Chinnaswamy Jagannath: Weill-Cornell Medicine
Smriti Mehra: Texas Biomedical Research Institute
Shabaana A. Khader: University of Chicago
Deepak Kaushal: Texas Biomedical Research Institute

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-57090-4

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