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年全球结核病报告指出，有960万人，其中100万人 儿童，2014年患有结核病研究员。 于95年前引入，但仍在全球范围内占80％。 BCG非常有效 在防止婴儿中与结核病疾病有关的严重并发症以及引入BCG 疫苗导致整体儿童死亡率下降。那，BCG的有益影响远远超出了 防止婴儿中结核病感染。 在成年人中的最新研究表明，BCG诱导单核细胞的表观遗传变化 这导致功能能力提高，可以持续数月并扩展到与BCG无关的无关 病原体，一种称为“受过训练的免疫力”的现象。长期和改善的先天回应 朝向Th1和Th17响应的转移塑造了T细胞反应。尽管有这些优势，但新结核病 迫切需要疫苗以阻止结核病的全球扩散。随着时间的流逝，BCG诱导的免疫力逐渐减弱， 疫苗在成人中无效。此外，感染了艾滋病毒的婴儿的风险增加了局部或 传播BCG疾病。 考虑到结核病和艾滋病毒感染的高重叠，我们发展了小儿组合HIV-TB 基于相应营养的人适应的MTB突变体的疫苗。我们可以证明我们的MTB-SIV疫苗 在健康且感染了SIV的新生儿猕猴方面安全，可以诱导结核病和SIV特异性免疫 回答。我们介绍了我们的MTB疫苗应变增强的单核细胞功能的初步数据 几个月，与疫苗诱导的BCG训练的免疫力一致。同时，显示的CD4+ T细胞显示 持续性免疫激活的迹象可能在艾滋病毒高度患病率的地区有害，但 促进对细胞内病原体有利的Th1反应的潜力。 我们将使用衰减的MTB（AMTB）疫苗作为结核病疫苗候选者的模型来回答密钥 与受过训练和 异源免疫。首先，我们将确认BCG疫苗接种引起的表观遗传修饰 发生在马拉维婴儿。使用存档的婴儿恒河猕猴样品，我们将测试以下假设。 BCG或新型的型菌群MTB疫苗候选者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，并且疫苗诱导的训练的免疫学由组织保持 巨噬细胞和树突状细胞。最后，我们将测试先天印迹是否塑造CD4+T细胞 反应，与CD4+ T细胞的表观遗传变化有关。数据有望告知 预防性小儿结核病疫苗的设计。