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称，960万人，其中100万人 2014年，儿童患上了结核病。卡介苗(BCG)预防结核病的疫苗 该药于95年前推出，目前仍在全球80%的新生儿身上使用。卡介苗非常有效 在预防婴儿结核病相关严重并发症方面，以及卡介苗的引入 疫苗导致了儿童总死亡率的下降。因此，卡介苗的有益影响远远超出了 预防婴儿感染结核病的措施。 最近在成人中的研究表明，卡介苗诱导单核细胞群体的表观遗传学变化 这导致功能能力得到改善，可持续数月，并延伸至与卡介苗无关的无关功能 病原体，一种被称为“训练免疫”的现象。延长和改善的先天反应也 通过向Th1和Th17反应转变来塑造T细胞反应。尽管有这些优势，一种新的结核病 迫切需要疫苗来阻止结核病的全球传播。卡介苗诱导的免疫力随着时间的推移而减弱， 疫苗对成年人无效。此外，感染艾滋病毒的婴儿患上局部或 播散性卡介苗病。 考虑到结核病和HIV感染的高度重叠，我们开发了一种儿科组合HIV-TB 基于营养缺陷型人类适应的结核分枝杆菌突变体的疫苗。我们可以证明我们的Mtb-SIV疫苗 在健康和感染SIV的新生儿猕猴中是安全的，并可以诱导结核病和SIV特异性免疫 回应。我们提供的初步数据表明，我们的结核分枝杆菌疫苗株可使单核细胞功能增强多达5 几个月，与卡介苗疫苗诱导的训练免疫一致。与此同时，CD4+T细胞，显示出 持续免疫激活的迹象可能会在艾滋病毒高发地区被证明是有害的，但他们的 促进Th1反应的潜力，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)疫苗作为结核病疫苗候选者回答关键问题的模型 关于卡介苗接种的有益(或有害)影响的问题，由训练有素的和 异种免疫。首先，我们将确认卡介苗接种引起的表观遗传修饰也 发生在马拉维的婴儿中。使用存档的幼年恒河猴样本，我们将检验这一假设 卡介苗或新型Mtb缺陷型候选疫苗引起的表观遗传学变化并不局限于 单核细胞，但也存在于树突状细胞中，疫苗诱导的训练性免疫由组织维持 巨噬细胞和树突状细胞。最后，我们将测试先天印记是否塑造了CD4+T细胞 并与CD4+T细胞的表观遗传学变化有关。预计这些数据将向 儿童结核病预防性疫苗的设计。

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.