Genetic Markers of Long-Term Mumps Vaccine Immunity

项目摘要/摘要 本申请是一项疫苗免疫遗传学研究项目的资金申请，该项目的重点是识别 长期流行性腮腺炎疫苗诱导免疫的关键遗传决定因素 吐温基因多态性与流行性腮腺炎疫苗免疫应答的变异。我们实验室已经做了 描述了基因多态对流行性腮腺炎、麻疹、风疹、流感和 天花免疫反应，并报告了新的发现表明，人类白细胞抗原，TLR，病毒受体，细胞- 因子/细胞因子受体、维生素A/D受体和其他多种免疫基因SNPs显著影响 这些疫苗后的体液和细胞免疫(CMI)反应。我们的研究表明 麻疹和风疹疫苗的免疫应答变化是多基因的，而不是单一的显性遗传。 Lele模型，以及基因对这种免疫反应变化的贡献可以被量化。在- 由近20年来这些研究的见解形成，并考虑到CON对公共卫生的重要性。 在美国、欧洲、太平洋岛国和亚洲爆发腮腺炎疫情后，我们现在将注意力转向 了解与流行性腮腺炎疫苗诱导的免疫反应的遗传关联。最彻底和最彻底的 对这种目的有效的研究是全面的发现/复制全基因组关联研究 (Gwas)，随后进行功能研究以验证哪些基因多态和途径具有最大 或对免疫受试者之间的免疫差异最关键的影响，以及通过 这些效应是如何发生的，支持了一种新的范式，通过这种范式，未来的疫苗开发努力可以 发生。在这一应用中，我们建议进行研究，以支持一种新的定向范式：发现-复制-- 验证-应用“，我们称之为疫苗组学。我们的研究集中在该范式的前两步。 我们的具体目标是1)执行两个阶段，发现/复制，全基因组关联研究，以 确定SNPs与体液和细胞免疫的个体间变异之间的新的遗传关联。 MUNE对腮腺炎疫苗的反应；以及2)验证我们已经复制的TLR4 SNP关联和新的 通过功能研究确定目标1的关联，这些研究将定义直接影响和/或向下- 已识别的多态的流免疫学后果。这些目标将使我们能够理解- 明确腮腺炎疫苗免疫反应的个体间差异如何受基因影响 多态现象。这种方法的合理性来自于我们的数据表明， 流行性腮腺炎疫苗的体液免疫率为40%，是免疫遗传学研究的合适靶点。尽管 对公共健康的影响，目前还没有基于人群的研究确定流行性腮腺炎与肺炎之间的联系。 电影免疫反应和全基因组SNPs，并验证这些多聚体的功能特征- 习语。我们的研究经过精心设计，以求严谨，并产生稳健、公正和可重现的结果。

PROJECT SUMMARY/ABSTRACT This application is a request for funding of a vaccine immunogenetics research program focused on identifying critical genetic determinants of long-term mumps vaccine-induced immunity by examining associations be- tween gene polymorphisms and variations in immune response to mumps vaccine. Our laboratory has done significant work delineating the effect of gene polymorphisms on mumps, measles, rubella, influenza and smallpox immune responses, and reported new findings demonstrating that HLA, TLR, viral receptor, cyto- kine/cytokine receptor, vitamin A/D receptor, and a variety of other immune gene SNPs significantly influence humoral and cell-mediated immune (CMI) responses following these vaccines. Our research demonstrates that variations in immune responses to measles and rubella vaccines are multigenic and not a single dominant al- lele model, and that the genetic contribution to such variations in immune responses can be quantified. In- formed by insights from these studies over almost 2 decades, and given the public health importance of con- tinued mumps outbreaks in the US, Europe, Pacific Island states, and Asia, we now turn our attention to understanding genetic associations with mumps vaccine-induced immune responses. The most thorough and efficient study for such purposes is a comprehensive discovery/replication genome-wide association study (GWAS), followed by functional studies to validate which gene polymorphisms and pathways have the largest or most critical impact on variations in immunity among immunized subjects, and the mechanism(s) through which these effects occur, supporting a new paradigm by which future efforts in vaccine development could occur. In this application, we propose studies supporting a new directed paradigm of “Discover – Replicate – Validate – Apply,” which we have called vaccinomics. Our studies focus on the first two steps of the paradigm. Our Specific Aims are to 1) perform a two-stage, discovery/replication, genome-wide association study to identify novel genetic associations between SNPs and inter-individual variations in humoral and cellular im- mune response to mumps vaccine; and 2) to validate our already-replicated TLR4 SNP associations and newly identified associations from Aim 1 through functional studies that will define the direct effects and/or down- stream immunologic consequences of the identified polymorphisms. These aims will allow us to comprehen- sively define how inter-individual variations in immune responses to mumps vaccine are influenced by gene polymorphisms. The justification for this approach comes from our data demonstrating that the heritability of mumps vaccine humoral immunity is 40%, and is an appropriate target for immunogenetic studies. Despite the public health implications, there are no population-based studies identifying associations between mumps vac- cine immune response and genome-wide SNPs and validating the functional characteristics of those polymor- phisms. Our study is carefully designed to be rigorous and produce robust, unbiased, and reproducible results.