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A Multistage Subunit Vaccine Effectively Protects Mice Against Primary Progressive Tuberculosis, Latency and Reactivation

机译:多阶段亚单位疫苗有效保护小鼠免受原发性进行性肺结核,潜伏期和再激活。

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Adult tuberculosis (TB) is the main cause of TB epidemic and death. The infection results mainly by endogenous reactivation of latent TB infection and secondarily transmitted by exogenous infection. There is no vaccine for adult TB. To this end, we first chose antigens from a potential antigenic reservoir. The antigens strongly recognized T cells from latent and active TB infections that responded to antigens expressed by Mycobacterium tuberculosis cultured under different metabolic states. Fusions of single-stage polyprotein CTT3H, two-stage polyprotein A1D4, and multistage CMFO were constructed. C57BL/6 mice vaccinated with DMT adjuvant ed CMFO (CMFO-DMT) were protected more significantly than by CTT3H-DMT, and efficacy was similar to that of the only licensed vaccine, Bacillus Calmette-Guerin (BCG) and A1D4-DMT in the M. tuberculosis primary infection model. In the setting of BCG priming and latent TB infection, M. tuberculosis in the lung and spleen was eliminated more effectively in mice boosted with CMFO-DMT rather than with BCG, A1D4-DMT, or CTT3H-DMT. In particular, sterile immunity was only conferred by CMFO-DMT, which was associated with expedited homing of interferon-gamma^+CD4^+ T"E"M and interleukin-2^+ T"C"M cells from the spleen to the infected lung. CMFO-DMT represents a promising candidate to prevent the occurrence of adult TB through both prophylactic and therapeutic methods, and warrants assessment in preclinical and clinical trials.
机译:成人结核病(TB)是结核病流行和死亡的主要原因。感染主要由潜伏性结核感染的内源性再激活引起,其次是由外源性感染传播。没有针对成人结核病的疫苗。为此,我们首先从潜在的抗原库中选择了抗原。抗原强烈识别来自潜伏性和活动性TB感染的T细胞,这些T细胞对在不同代谢状态下培养的结核分枝杆菌表达的抗原有反应。构建了单阶段多蛋白CTT3H,两阶段多蛋白A1D4和多阶段CMFO的融合体。与CTT3H-DMT相比,接种了DMT佐剂CMFO(CMFO-DMT)的C57BL / 6小鼠受到的保护更大,其功效类似于唯一许可的疫苗,卡介苗-芽胞杆菌(BCG)和A1D4-DMT结核分枝杆菌原发感染模型。在BCG引发和潜在性TB感染的情况下,用CMFO-DMT增强的小鼠比用BCG,A1D4-DMT或CTT3H-DMT增强的小鼠更有效地消除了肺和脾结核分枝杆菌。特别地,仅通过CMFO-DMT赋予无菌免疫,这与从脾脏到细胞的干扰素-γ^ + CD4 ^ + T“ E” M和白介素-2 ^ + T“ C” M细胞的快速归巢有关。肺部感染。 CMFO-DMT代表了通过预防和治疗方法预防成人结核病发生的有前途的候选药物,并需要在临床前和临床试验中进行评估。

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