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保护估计， 卡介苗对抗结核病。BCG在几个人群中的疗效>75%;相比之下， 在结核病流行的地区发现。许多研究发现，对分枝杆菌感染或 卡介苗具有遗传性;但是，宿主遗传变异在疫苗接种成功或失败中的作用更大 难以量化。协作杂交（CC）是一个重组近交系小鼠的大面板 来源于8个遗传多样性的创始人菌株，据报道捕获了近90%的变异 存在于实验室小鼠中。我们对8个建群种和3个CC系的初步研究发现， 多样性是影响卡介苗接种是否诱导保护性免疫的关键因素。如在 BCG疗效的人类荟萃分析，当这些遗传多样性小鼠被视为单一的 在人群中，BCG具有适度的保护作用。然而，当通过基因型进行评估时，我们发现一些 一些品系需要保护，另一些品系没有保护，还有一些品系的疫苗接种加剧了疾病。 这些观察结果表明，宿主的遗传变异限制了卡介苗的功效，并表明目前的努力， 为了开发在C57 BL/6小鼠中有效的疫苗（即，单一基因型），可能会在遗传上失败， 不同的人群。该项目将描述与癌症相关的遗传和免疫因素， CC组中BCG诱导的保护作用。目的1将我们的初步研究扩展到55个独特的CC小鼠 线我们将与项目1合作，定位与BCG诱导的保护相关的QTL， 将Mtb易感性的QTL定位扩展到气溶胶模型。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 说明：a）未经处理; B）接种BCG;或c）接种疫苗和Mt B攻击;通过经典免疫测定，RNA- Seq和基于感染细胞识别的测定。通过这些数据，我们将确定候选人 与BCG诱导的保护相关的QTL相关的基因和免疫标记。在 通过与核心B的合作，我们将利用来自BCG疫苗接种的大型SATVI队列的现有样本 婴儿，以确定是否与BCG疗效相关的生物标志物谱或遗传变异， 小鼠与儿童中的TB风险、BCG免疫原性或功效类似地相关。目标3将决定 不受BCG保护的CC系是否可用于筛选其他疫苗。同样，我们将 确定是否具有更大的动态保护范围的CC系（超过C57 BL/6小鼠） 可以用来区分不同的疫苗。因此，该项目旨在了解基因 和免疫决定因素的疫苗诱导的免疫力在遗传多样性的人口与 最终目标是改进用于结核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.