Overcoming Genetic Variation in Vaccination

项目3：克服疫苗接种中的遗传变异 抽象的。对不同人群的研究得出了不同的对保护作用的估计 卡介苗抗结核。卡介苗在几个人群中的有效率为75%；相比之下，没有显著的保护作用 在结核病流行的地区检测到。许多研究发现，对分枝杆菌感染或 卡介苗是可遗传的；但宿主基因变异在疫苗接种成败中的作用更多。 很难量化。合作杂交(CC)是一大批重组近交系小鼠 来自8个遗传多样性的方正菌株，据报道捕获了近90%的变异 存在于实验室小鼠体内。我们用8个方正品系和3个CC品系进行的初步研究发现了寄主遗传 多样性是影响卡介苗能否诱导保护性免疫的关键因素。如中所示 人类对卡介苗疗效的荟萃分析，当这些遗传多样性的小鼠被认为是单个 对人群来说，卡介苗有适度的保护作用。然而，当按基因类型进行评估时，我们发现了一些 需要保护的品系，其他没有保护的品系，以及少数接种疫苗加剧了疾病的品系。 这些观察表明，宿主遗传变异限制了卡介苗的疗效，并表明目前的努力 开发对C57BL/6小鼠有效的疫苗(即单一基因)可能会在遗传上失败 不同的人群。这个项目将描述与以下因素相关的遗传和免疫因素 CC面板中BCG诱导的保护作用。Aim 1将把我们的初步研究扩展到55只独特的CC小鼠 台词。我们将定位与卡介苗诱导的保护相关的QTL，并在协作项目1中， 将结核分枝杆菌敏感性的QTL图谱扩展到气溶胶模型。除了使用细菌负荷作为 作为终点，将收集大量的免疫学数据。在目标2中，我们将评估3种不同的免疫 国家：a)幼稚；b)接种卡介苗；或c)接种疫苗并挑战结核分枝杆菌；通过经典免疫分析，RNA- SEQ，以及基于对感染细胞的识别的检测。有了这些数据，我们将确定候选人 与卡介苗诱导的保护相关的QTL相关的基因和免疫标记。在……里面 与Core B合作，我们将利用来自接种卡介苗的SATVI大队列的现有样本 以确定婴儿是否存在与卡介苗疗效相关的生物标记物或遗传变异 老鼠与儿童的结核病风险、卡介苗免疫原性或疗效也有类似的关联。目标3将决定 未受卡介苗保护的CC株能否用于其他疫苗的筛选。同样，我们也会 确定CC系是否具有更大的动态保护范围(超过C57BL/6小鼠) 可以用来区分不同的疫苗。因此，这个项目试图了解基因 和疫苗诱导免疫的免疫决定因素在遗传多样性的人群中 最终目标是改进结核病疫苗临床前开发的小鼠模型。

Project 3: Overcoming Genetic Variation in Vaccination Abstract. Studies in different human populations produce disparate estimates of protection conferred by BCG against TB. BCG efficacy is >75% in several populations; in contrast, no significant protection is detected in regions where TB is endemic. Many studies find that immunity to mycobacterial infection or BCG is heritable; but, the role of host genetic variation in the success or failure of vaccination is more difficult to quantify. The Collaborative Cross (CC) is a large panel of recombinant inbred mouse lines derived from 8 genetically diverse founder strains, and is reported to capture nearly 90% of the variation present in laboratory mice. Our preliminary study using 8 founder and 3 CC lines found host genetic diversity to be a crucial factor that affects whether BCG vaccination induces protective immunity. As in human meta-analyses of BCG efficacy, when these genetically diverse mice were considered as a single population, BCG has a modest protective effect. However, when assessed by genotype, we found some lines to be protected, others that were not protected, and a few in which vaccination exacerbated disease. These observations indicate that host genetic variation limits BCG efficacy, and suggests that current efforts to develop vaccines that are effective in C57BL/6 mice (i.e., a single genotype), could fail in genetically diverse populations. This project will characterize the genetic and immunological factors that correlate with BCG-induced protection in the CC panel. Aim 1 will extend our preliminary studies to 55 unique CC mouse lines. We will to map the QTLs associated with BCG-elicited protection and in collaboration Project 1, extend the QTL mapping of Mtb susceptibility to the aerosol model. In addition to using bacterial burden as an endpoint, extensive immunological data will be collected. In Aim 2, we will assess 3 different immune states: a) naïve; b) BCG vaccinated; or c) vaccinated and Mtb challenged; by classic immune assays, RNA- Seq, and assays based on the recognition of infected cells. With these data, we will identify candidate genes and immune markers that correlate with the QTLs that are associated with BCG-elicited protection. In collaboration with Core B, we will leverage existing samples from the large SATVI cohort of BCG-vaccinated infants to determine if the biomarker profiles or genetic variants that were associated with BCG-efficacy in mice are similarly associated with TB risk, BCG immunogenicity, or efficacy in children. Aim 3 will determine whether CC lines that are not protected by BCG can be used to screen other vaccines. Similarly, we will determine whether CC lines that have a greater dynamic range of protection (more than C57BL/6 mice) could be used to discriminate between different vaccines. Thus, this project seeks to understand the genetic and immunological determinants of vaccine-induced immunity in genetically diverse populations with the ultimate goal of improving the mouse model for pre-clinical development of TB vaccines.