Genetic Markers of Long-Term Mumps Vaccine Immunity

项目总结/摘要 该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 关键的遗传决定因素的长期腮腺炎疫苗诱导的免疫力，通过检查协会是， Tween基因多态性与腮腺炎疫苗免疫应答变异我们的实验室 描述基因多态性对腮腺炎、麻疹、风疹、流感和 天花免疫反应，并报道了新的发现，表明HLA，TLR，病毒受体，细胞， 细胞因子/细胞因子受体、维生素A/D受体和多种其他免疫基因SNP显著影响 体液和细胞介导的免疫（CMI）应答。我们的研究表明， 对麻疹和风疹疫苗的免疫反应的变异是多基因的，而不是单一的显性al- Lele模型，并且可以量化对免疫应答中的这种变化的遗传贡献。在- 从这些研究的见解形成了近20年来，并考虑到公共卫生的重要性， 在美国、欧洲、太平洋岛国和亚洲持续爆发腮腺炎后，我们现在将注意力转向 了解流行性腮腺炎疫苗诱导的免疫反应的遗传关联。最彻底的， 一个有效的研究，为这些目的是一个全面的发现/复制全基因组关联研究 （GWAS），其次是功能研究，以验证哪些基因多态性和途径具有最大的 或对免疫受试者免疫力变化的最关键影响，以及通过 这些影响发生的原因，支持了一个新的范式，未来疫苗开发的努力可以 发生.在这个应用程序中，我们提出了研究支持一个新的定向范式“发现-复制- 我们称之为疫苗组学。我们的研究集中在范式的前两个步骤。 我们的具体目标是1）进行两阶段，发现/复制，全基因组关联研究， 确定SNPs与体液和细胞免疫中个体间变异之间的新遗传关联， 对腮腺炎疫苗的免疫应答; 2）验证我们已经复制的TLR 4 SNP相关性和新的 通过功能研究确定目标1中的关联，这些研究将定义直接影响和/或降低- 所鉴定的多态性的免疫学后果。这些目标将使我们能够- 全面定义腮腺炎疫苗免疫应答中个体间差异如何受基因影响 多态性这种方法的合理性来自于我们的数据表明， 腮腺炎疫苗的体液免疫为40%，是免疫遗传学研究的适当靶点。尽管 公共卫生的影响，没有基于人口的研究确定腮腺炎疫苗之间的关联， 电影免疫应答和全基因组SNP，并验证这些多聚体的功能特征， phisms。我们的研究经过精心设计，严格，并产生稳健，无偏倚和可重复的结果。

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.