The Pros and Cons of Trained Immunity Induced by Vaccines for Tuberculosis Prevention

摘要 2015年世卫组织全球结核病报告指出，960万人，其中100万人 2014年患结核病的儿童。预防结核病的卡介苗（BCG）疫苗 早在95年前就被引入，至今仍有超过80%的新生儿使用。BCG非常有效 在预防与婴儿结核病有关的严重并发症方面， 疫苗的使用降低了儿童死亡率。因此，BCG的有益效果远远超出了 保护婴儿免受结核病感染。 最近在成人中的研究表明，BCG诱导单核细胞群体的表观遗传变化 这导致改善的功能能力，可以持续数月，并延伸到BCG无关无关 病原体，这种现象被称为“训练免疫”。延长和改善先天反应也 使T细胞反应向Th 1和Th 17反应转变。尽管有这些优势， 迫切需要疫苗来阻止结核病的全球传播。BCG诱导的免疫力随着时间的推移而减弱， 疫苗对成人无效。此外，感染艾滋病毒的婴儿患局部或 传播性卡介苗病。 考虑到结核病和艾滋病毒感染的高度重叠，我们开发了一种儿科艾滋病毒-结核病联合治疗方案， 基于营养缺陷型人类适应性Mtb突变体的疫苗。我们可以证明我们的猪流感疫苗 在健康和SIV感染的新生猕猴中是安全的，并且可以诱导TB和SIV特异性免疫 应答我们目前的初步数据表明，我们的结核分枝杆菌疫苗株增强单核细胞功能高达5 月，与疫苗诱导的BCG训练免疫一致。同时，CD 4 + T细胞显示， 持续免疫激活的迹象可能在艾滋病毒高流行地区证明是有害的，但他们的 促进Th 1应答的潜力，这将有利于对抗细胞内病原体。 我们将使用我们的减毒结核分枝杆菌（AMtb）疫苗作为结核病候选疫苗的模型，以回答关键问题。 与BCG疫苗接种的有益（或有害）影响有关的问题，这些影响是由训练有素的 异种免疫首先，我们将证实卡介苗接种诱导的表观遗传修饰也 发生在马拉维的婴儿身上。使用存档的幼年恒河猴样本，我们将检验以下假设： 由BCG或新的营养缺陷型Mtb疫苗候选物诱导的表观遗传变化不限于 单核细胞，但也发生在树突状细胞中，疫苗诱导的训练免疫是由组织维持的。 巨噬细胞和树突细胞。最后，我们将测试先天印记是否塑造了CD 4 +T细胞 免疫应答，并与CD 4 + T细胞的表观遗传变化相关。预计这些数据将告知 预防性儿童结核病疫苗的设计。

ABSTRACT The 2015 WHO Global Tuberculosis Report states that 9.6 million people, among them 1 million children, fell ill with TB in 2014. The Bacille Calmette-Guérin (BCG) vaccine to prevent tuberculosis (TB) has been introduced 95 years ago and is still administered to >80% of newborns worldwide. BCG is highly effective in preventing severe complications associated with TB disease in infants, and the introduction of the BCG vaccine caused a drop in overall childhood mortality. Thus, the beneficial effects of BCG extend far beyond the protection against TB infection in infants. Recent studies in adults demonstrated that BCG induces epigenetic changes in monocyte populations that result in improved functional capacity that can persist for months and extends to BCG-unrelated unrelated pathogens, a phenomenon referred to as “trained immunity”. Prolonged and improved innate responses also shaped the T cell response with a shift towards Th1 and Th17 responses. Despite these advantages, a new TB vaccine is urgently needed to stop the global spread of TB. BCG-induced immunity wanes over time, and the vaccine is not effective in adults. Furthermore, HIV-infected infants have an increased risk to develop local or disseminated BCG disease. Considering the high overlap of TB and HIV infections, we developed a pediatric combination HIV-TB vaccine based on auxotroph human-adapted Mtb mutants. We could demonstrate that our Mtb-SIV vaccine was safe in healthy and SIV-infected newborn macaques and could induce TB and SIV-specific immune responses. We present preliminary data that our Mtb vaccine strain enhanced monocyte function for up to 5 months, consistent with vaccine-induced trained immunity by BCG. At the same time, CD4+ T cells, showed signs of persistent immune activation that could prove detrimental in areas with high HIV prevalence, but their potential to promote Th1 responses that would be advantageous against intracellular pathogens. We will use our attenuated Mtb (AMtb) vaccine as a model for TB vaccine candidates to answer key questions related to the beneficial (or detrimental) effects of BCG vaccination that are mediated by trained and heterologous immunity. First, we will confirm that epigenetic modifications induced by BCG vaccination also occur in Malawian infants. Using archived infant rhesus macaque samples, we will test the hypothesis that epigenetic changes induced by BCG or novel auxotroph Mtb vaccine candidates are not restricted to monocytes, but also occur in dendritic cells, and that vaccine-induced trained immunity is maintained by tissue macrophages and dendritic cells. Finally, we will test whether innate imprinting shapes the CD4+T cell response and is associated with epigenetic changes in CD4+ T cells. The data are expected to inform the design of preventative pediatric TB vaccines.