Systems Biology of Mumps Vaccine Response

项目总结/摘要 这项申请是一项研究计划的资金请求，该计划的重点是了解与腮腺炎疫苗免疫反应减弱相关的因素。腮腺炎免疫力下降是一个公共卫生问题 也是控制和消除腮腺炎疾病的主要障碍。美国和欧洲的疫情主要发生在十几岁和二十出头的高度接种疫苗的人群中。这些爆发是 主要是由于腮腺炎疫苗诱导的免疫力减弱。腮腺炎免疫力下降的定义是 随着时间的推移，抗体滴度降低，老年受试者中疫苗有效性降低，以及随着接种疫苗时间的增加，对疾病的易感性增加;然而，几乎没有关于疫苗接种后抗体滴度的定性信息。 腮腺炎特异性记忆B细胞的特征，关于长期T细胞免疫的数据甚至更少。 对腮腺炎的反应我们的目标是研究第一个因素（随着时间的推移免疫反应下降）。对腮腺炎持久免疫的建立可能受多种免疫途径控制， 网络和以协调和交互方式起作用的小区类型。我们建议表征B细胞， CD 4 + T细胞对第3剂MMR的应答。然后，我们将研究基线特征（例如，既往抗体 反应和性别）和遗传因素（mRNA和miRNA）使用系统生物学方法和介导分析来影响这些免疫反应。为了实现这一目标，我们提出以下建议 具体目标：1）进行早期体液（B细胞）免疫应答的系统生物学研究; 2）进行早期CD 4 + T辅助细胞应答的系统生物学研究; 3）表征T辅助细胞和体液免疫应答之间的相互关系。这些目标将使我们能够全面评估 基线免疫力、对第3剂MMR的早期主要应答以及MMR疫苗接种后记忆的建立和体内平衡的恢复如何以及在多大程度上有助于观察到的临床 腮腺炎免疫力下降。反过来，这些知识可以用来通知腮腺炎的机制研究 疫苗诱导的免疫持久性，在未来开发更有效的腮腺炎疫苗和佐剂， 以确定可能的早期生物标志物，以检测那些对腮腺炎保护作用减弱的风险最大的人。

PROJECT SUMMARY/ABSTRACT This application is a request for funding of a research program focused on understanding the factors associated with waning immune response to mumps vaccine. Waning immunity to mumps is a public health concern and a major obstacle in the control and elimination of mumps disease. Outbreaks in the US and Europe primarily occur among highly vaccinated populations in their late teens and early twenties. These outbreaks are primarily due to the waning of mumps vaccine-induced immunity. Waning immunity to mumps is defined by decrease in antibody titer over time, decreased vaccine effectiveness in older subjects, and increased susceptibility to disease as time since vaccination increases; however, little information is available on the qualitative characteristics of mumps-specific memory B cells, and even less data is available regarding long-term T cell responses to mumps. Our goal is to study the first factor (decrease in immune responses over time). The establishment of long-lasting immunity to mumps is likely to be controlled by multiple immunologic pathways, networks, and cell types acting in a coordinated and interactive manner. We propose to characterize B cell and CD4+ T cell responses to a 3rd dose of MMR. We will then examine how baseline characteristics (e.g., prior Ab response and sex) and genetic factors (mRNA and miRNA) influence those immune responses using a systems-biology approach and mediation analysis. In order to accomplish this objective, we propose the following Specific Aims: 1) To conduct a systems biology study of early humoral (B cell) immune responses; 2) To conduct a systems biology study of early CD4+ T helper responses; and 3) To characterize interrelationships between T helper cell and humoral immune responses. These aims will allow us to comprehensively assess how— and to what degree—baseline immunity, the early primary response to a 3rd dose of MMR, and the establishment of memory and return to homeostasis after MMR vaccination contribute to the observed clinical waning of mumps immunity. In turn, this knowledge can be utilized to inform mechanistic studies of mumps vaccine-induced immune persistence, develop more effective mumps vaccines and adjuvants in the future, and to identify possible early biomarkers to detect those at greatest risk of waning protection against mumps.