Immunogenetic Mechanisms of Vaccine Response

描述（由申请人提供）：本申请是风疹疫苗免疫遗传学研究计划11-15年2 RO 1 AI 48793的持续资助请求。风疹在世界上许多地方仍然是一种流行病毒，导致胎儿丢失、畸形、先天性风疹综合征，目前的疫苗导致高达5%的失败率。我们的研究重点是确定免疫力的关键遗传决定因素，通过检查风疹疫苗的体液和细胞免疫反应的异质性和基因多态性之间的关联。重要的是，我们的研究表明，风疹疫苗的体液和细胞免疫应答与候选免疫应答基因中的HLA等位基因和SNP显著相关，但这些关联并不能解释人群中免疫应答的所有差异。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力是近50%。为此，我们提出了最先进的全基因组关联研究（GWAS）设计，然后在独立队列中进行复制研究，最后进行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基因多态性如何决定风疹疫苗免疫应答的变化来支持新疫苗开发的新疫苗组学“发现-复制-复制-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：进行GWAS以确定SNP与多基因相互作用和体液免疫标记之间的新的遗传关联。（中和抗体）和细胞介导的（IL-2、IL-6、IFN-3、TNF-1）风疹疫苗免疫，2）重复：为了在独立的、基于人群的受试者队列中复制来自我们的GWAS和来自我们目前资助的资助的候选基因SNP的最强关联的优先级集合，以及3）重复：确定选定复制遗传变异对免疫结果的直接影响和/或下游功能后果。该应用是创新的和重要的，因为它将：检查基因多态性对风疹疫苗免疫应答的异质性的影响，提供可以解释风疹疫苗免疫应答中这些变化的机制的数据，提供数据以支持发现-复制-复制-应用的新范式用于新疫苗开发。这些研究将为理解风疹免疫提供具体的知识，并提供一个模型框架，用于估计对病毒疫苗免疫反应变化的遗传贡献。最后，我们的工作可能会提供重要的知识，以开发新的病毒疫苗-特别是对风疹-通过了解遗传限制，防止保护性免疫反应的疫苗。

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.