Immunogenetic Mechanisms of Vaccine Response

描述（由申请人提供）：本申请为风疹疫苗免疫遗传学研究项目11-15年级的2RO1 AI48793申请继续资助。风疹在世界大部分地区仍然是一种流行病毒，导致胎儿流产、畸形、先天性风疹综合征，目前的疫苗导致失败率高达5%。我们的研究重点是通过检查风疹疫苗的体液和细胞免疫反应异质性与基因多态性之间的关系，确定免疫的关键遗传决定因素。重要的是，我们的研究表明，风疹疫苗的体液和细胞免疫反应与HLA等位基因和候选免疫反应基因的snp显著相关，但这些关联并不能解释人群中所见的免疫反应的所有差异。我们将全面确定遗传决定因素，解释我们的发现，风疹疫苗诱导的体液免疫的遗传率接近50%。为此，我们提出了一个最先进的全基因组关联研究（GWAS）设计，然后是独立队列的复制研究，最后是验证研究，以确定复制snp的功能后果。我们研究的数据将通过定义风疹疫苗免疫反应的变化如何由基因多态性决定，为新疫苗开发提供新的疫苗组学“发现-复制-验证-应用”范式。为了实现这些目标，我们提出了以下具体目标：1)发现：执行GWAS以确定snp与多基因相互作用以及体液（中和抗体）和细胞介导的（IL-2, IL-6, IFN-3, TNF-1）免疫对风疹疫苗的标记之间的新遗传关联；在独立的、基于人群的受试者队列中，从我们目前资助的GWAS和候选基因snp中复制一组优先的最强关联。3)验证：确定所选复制遗传变异对免疫结果的直接影响和/或下游功能后果。这项应用具有创新性和重要意义，因为它将：检查基因多态性对风疹疫苗免疫反应异质性的影响，提供可能解释风疹疫苗免疫反应这些变异机制的数据，为新疫苗开发的发现-复制-验证-应用的新范式提供数据支持。这些研究将为了解风疹免疫提供具体知识，并为估计对病毒疫苗的免疫反应变异的遗传贡献提供模型框架。最后，我们的工作可能通过了解阻止对疫苗产生保护性免疫反应的遗传限制，为开发新的病毒疫苗（特别是针对风疹的疫苗）提供重要的知识。

DESCRIPTION (provided by applicant): This application is a request for continued funding of 2RO1 AI48793 for Years 11-15 of a rubella vaccine immunogenetics research program. Rubella remains an epidemic virus in much of the world, leading to fetal loss, malformation, congenital rubella syndrome, and current vaccines result in a failure rate of up to 5%. Our research is focused on identifying critical genetic determinates of immunity by examining associations between heterogeneity in humoral and cellular immune responses to rubella vaccine and gene polymorphisms. Importantly, our research demonstrates that humoral and cellular immune responses to rubella vaccine are significantly associated with HLA alleles and SNPs in candidate immune response genes, but these associations do not explain all of the variance in immune responses seen within the population. We will comprehensively identify the genetic determinants that explain our finding that the heritability of rubella vaccine-induced humoral immunity is nearly 50%. To do so, we propose a state-of-the-art genome-wide association study (GWAS) design, followed by replication studies in independent cohorts, and finally validation studies to determine the functional consequences of replicated SNPs. The data from our study will support a new vaccinomics "Discover - Replicate - Validate - Apply" paradigm for new vaccine development by defining how variations in rubella vaccine immune responses are determined by gene polymorphisms. To accomplish these goals, we propose the following Specific Aims: 1) Discover: To perform a GWAS to identify novel genetic associations between SNPs and multigenic interactions and markers of humoral (neutralizing antibody) and cell-mediated (IL-2, IL-6, IFN-3, TNF-1) immunity to rubella vaccine, 2) Replicate: To replicate a prioritized set of the strongest associations from both our GWAS and candidate gene SNPs from our currently funded grant in independent, population-based cohorts of subjects, and 3) Validate: To determine the direct effects and/or downstream functional consequences on immune outcomes of selected replicated genetic variants. This application is innovative and significant in that it will: examine the effect of gene polymorphisms on the heterogeneity of rubella vaccine immune responses, provide data that may explain mechanisms for these variations in rubella vaccine immune responses, provide data to support a novel paradigm of Discover - Replicate - Validate - Apply for new vaccine development. These studies will provide specific knowledge for understanding rubella immunity, and provide a model framework for estimating the genetic contribution on variations in immune responses to a viral vaccine. Lastly, our work may provide knowledge important to the development of new viral vaccines - particularly against rubella - by understanding genetic restrictions that prevent protective immune responses to vaccine.