Protein subunit vaccines form a key pipeline for developing novel tuberculosis (TB) vaccines. Mycobacterium tuberculosis (Mtb) contains approximately 4000 individual proteins. However, only approximately 100 have been evaluated as antigens in the clinical and preclinical stages of vaccine development. Trained immunity-targeting vaccines induce innate immune memory against heterologous infections and enhance antigen-specific adaptive immune responses. However, no trained immunity-targeting subunit TB vaccine has been reported yet. This study tested Rv1471, a thioredoxin secreted by Mtb, as a candidate TB vaccine antigen due to its capacity to stimulate mouse bone marrow-derived macrophages (BMDMs). Rv1471 induced functional and phenotypic maturation of BMDMs in vitro, reflected by the increased production of inflammatory cytokines and surface expression of co-stimulatory molecules. Transcription analysis of Rv1471-trained BMDMs indicated that innate immune memory was activated through pathways of Akt-mTOR-HIF-1α and aerobic glycolysis. Rv1471 also enhanced innate immune memory responses and protection against intracellular infections of different mycobacteria. In a murine model of TB, immunization with Rv1471 formulated with liposomal DDA/MPLA adjuvant produced robust antigen-specific multi-functional CD4+ and CD8+ T-cell immune responses and had substantial protective efficacy against Mtb challenge. Analysis of recall immunity showed that the Rv1471 subunit vaccine triggered robust T-cell immunity post Mtb infection. These findings support the development of an innate immune memory-targeting subunit TB vaccine to increase TB vaccine efficacy.

中文翻译：

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结核分枝杆菌抗原 Rv1471 诱导先天免疫记忆和对感染的适应性免疫


蛋白亚单位疫苗是开发新型结核病 （TB） 疫苗的关键管道。结核分枝杆菌 （Mtb） 包含大约 4000 种单独的蛋白质。然而，在疫苗开发的临床和临床前阶段，只有大约 100 种被评估为抗原。训练有素的免疫靶向疫苗可诱导针对异源感染的先天免疫记忆，并增强抗原特异性适应性免疫反应。然而，目前还没有经过训练的免疫靶向亚单位结核病疫苗的报道。本研究测试了 Rv1471，一种由 Mtb 分泌的硫氧还蛋白，由于其能够刺激小鼠骨髓来源的巨噬细胞 （BMDM） 作为候选结核病疫苗抗原。Rv1471 在体外诱导 BMDM 的功能和表型成熟，这反映在炎性细胞因子的产生和共刺激分子的表面表达增加上。Rv1471 训练的 BMDM 的转录分析表明，先天免疫记忆通过 Akt-mTOR-HIF-1α 和有氧糖酵解途径被激活。Rv1471 还增强了先天免疫记忆反应和对不同分枝杆菌细胞内感染的保护。在结核病小鼠模型中，用脂质体 DDA/MPLA 佐剂配制的 Rv1471 免疫产生强大的抗原特异性多功能 CD4 + 和 CD8 + T 细胞免疫反应，并且对 Mtb 攻击具有显着的保护功效。回忆免疫分析表明，Rv1471 亚单位疫苗在 Mtb 感染后触发了强大的 T 细胞免疫。这些发现支持开发先天免疫记忆靶向亚单位结核病疫苗以提高结核病疫苗的效力。