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

结核病预防疫苗诱导的训练免疫的利与弊

• 批准号: 9207318
• 负责人: Kristina De Paris
• 金额: $ 19万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-08 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9207318
• 关键词: Activities of Daily Living; Address; Adolescent; Adult; African; Antigens; Archives; Area; Attenuated; Attenuated Live Virus Vaccine; Birth; Blood; Blood specimen; CD4 Positive T Lymphocytes; Calmette-Guerin Bacillus; Cells; Child; Childhood; Country; Data; Dendritic Cell Vaccine; Dendritic Cells; Disease; Drops; Effectiveness; Epigenetic Process; Fatality rate; Genus Mycobacterium; HIV; HIV Infections; HIV Seropositivity; Human; Immune response; Immunity; Infant; Infection; Infection prevention; Macaca; Macaca mulatta; Maintenance; Mediating; Modeling; Modification; Molecular; Mycobacterium tuberculosis; Neonatal; Newborn Infant; Population; Prevalence; Prevention; Preventive vaccine; Reporting; Resources; Risk; SIV; SIV Vaccines; Safety; Sampling; Shapes; Subunit Vaccines; T cell response; T-Lymphocyte; Target Populations; Testing; Time; Tissue Sample; Tissues; Training; Tuberculosis; Tuberculosis Vaccines; Vaccinated; Vaccine Design; Vaccines; Viral Vector; adaptive immunity; base; cell type; clinically relevant; combat; design; immune activation; immunogenic; immunogenicity; imprint; improved; innate immune function; insight; macrophage; monocyte; mortality; mutant; neglect; novel; pathogen; peripheral blood; preclinical study; prevent; response; vaccination against tuberculosis; vaccine candidate; vaccine-induced immunity

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.

抽象的 2015 年世界卫生组织全球结核病报告指出，960 万人患有结核病，其中 100 万人患有结核病。 儿童于 2014 年患上结核病。用于预防结核病 (TB) 的卡介苗 (BCG) 疫苗已 该药物于 95 年前推出，至今仍用于全球 80% 以上的新生儿。卡介苗非常有效 预防婴儿结核病相关的严重并发症，以及卡介苗的引入 疫苗导致儿童总体死亡率下降。因此，BCG 的有益作用远远超出了 预防婴儿结核感染。 最近对成人的研究表明，卡介苗可诱导单核细胞群的表观遗传变化 这会导致功能能力的提高，这种能力可以持续数月，并扩展到与 BCG 无关的不相关的领域 病原体，这种现象被称为“训练有素的免疫力”。还延长和改善了先天反应 塑造了 T 细胞反应，转向 Th1 和 Th17 反应。尽管有这些优点，新的 TB 迫切需要疫苗来阻止结核病的全球传播。 BCG 诱导的免疫力会随着时间的推移而减弱，并且 疫苗对成人无效。此外，感染艾滋病毒的婴儿发生局部或 播散性卡介苗疾病。 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-结核病联合用药 基于营养缺陷型人类适应 Mtb 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 的新生猕猴中是安全的，并且可以诱导 TB 和 SIV 特异性免疫 回应。我们提供的初步数据表明，我们的 Mtb 疫苗株可增强单核细胞功能长达 5 年 几个月，与 BCG 疫苗诱导的训练免疫力一致。与此同时，CD4+T细胞显示 持续免疫激活的迹象可能对艾滋病毒高流行地区有害，但它们 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 Mtb (AMtb) 疫苗作为候选结核病疫苗的模型来回答关键问题 与 BCG 疫苗接种的有益（或有害）影响相关的问题由经过培训的和 异源免疫。首先，我们将确认卡介苗疫苗接种诱导的表观遗传修饰也 发生于马拉维婴儿。使用存档的恒河猴幼崽样本，我们将检验以下假设： BCG 或新型营养缺陷型 Mtb 候选疫苗引起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，疫苗诱导的训练有素的免疫力是由组织维持的 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CD4+T细胞 反应并与 CD4+ T 细胞的表观遗传变化相关。这些数据预计将告知 预防性儿童结核病疫苗的设计。