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<p>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 <i>Mycobacterium tuberculosis (Mtb)</i> to mitigate oxidative stress, and in its absence <i>Mtb</i> is unable to scavenge host oxidative/nitrosative bursts. The <i>MtbΔsigH</i> (<i>ΔsigH</i>) isogenic mutant induces signatures of the innate immunity in macrophages and protects rhesus macaques from a lethal <i>Mtb challenge</i>. To understand the immune mechanisms of protection via mucosal vaccination with <i>ΔsigH</i>, we employed the resistant cynomolgus macaque model; and our results show that <i>ΔsigH</i> vaccination significantly protects against lethal <i>Mtb</i> challenge in this species. <i>ΔsigH</i>-vaccinated macaques are devoid of granulomas and instead generate inducible bronchus associated lymphoid structures, and robust antigen-specific CD4<sup>+</sup> and CD8<sup>+</sup> T cell responses, driven by a hyper-immune, trained immunity-like phenotype in host macrophages with enhanced antigen presentation. Correlates of protection in <i>ΔsigH</i>-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<sup>+</sup> Type I IFN-responsive macrophage recruitment. Thus, <i>ΔsigH</i> is a promising lead candidate for further development as an antitubercular vaccine.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年2月25日

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  • 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 Jr,
  • Chinnaswamy Jagannath,
  • Smriti Mehra,
  • Shabaana A. Khader,
  • Deepak Kaushal

摘要

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.