Immune signatures of vaccine responses in vulnerable populations

摘要 我们提出了一个深入的询问和系统的方法，将确定分子签名， 在三个易受伤害的患者群体中进行疫苗接种：B细胞耗竭的自身免疫患者， 年老体弱的个体和功能性无脾的镰状细胞病患者。这些不同 这些人群都有一个失调的炎症环境，这与疫苗接种反应不良有关。我们有 组建了一个跨学科的调查小组， 合作使用一种系统方法，将明确定义和研究不足的队列与无偏见的 大规模分析以阐明定义疫苗应答性的特征。这一目标将通过以下方式实现： 1)检查了三个用不同疫苗（包括新型mRNA疫苗）攻击的脆弱患者队列， 和一种共享疫苗; 2）使用共享平台，深入询问来自血液的免疫反应， 限制访问的隔间;和3）改进新的数学工具，用于数据的多维分析， 识别活跃的通路和模块，并确定免疫系统中组分之间的特定连接， 网络，有助于差异疫苗的有效性。这项工作利用了最近在单- 细胞和空间免疫分析方法沿着共享的免疫学和蛋白质组学平台， 为弱势群体提供新的公共资源，以人类免疫系统的不同状态为特征。 我们的队列整合将支持疫苗接种反应的分子特征的开发 并确定与潜在治疗策略相关的关键途径。

ABSTRACT We propose a deep interrogation and a systems approach that will identify molecular signatures to vaccination across three cohorts of vulnerable patient populations: autoimmune patients with B cell depletion, aged and frail individuals, and patients with sickle cell disease who are functionally asplenic. These distinct populations share a dysregulated inflammatory milieu that is linked to poor vaccination responsiveness. We have assembled an interdisciplinary team of investigators with a track record of longstanding and productive collaborations to use a systems approach that combines well-defined and understudied cohorts with unbiased large-scale profiling to elucidate signatures defining vaccine responsiveness. This goal will be accomplished by: 1) examining three vulnerable patient cohorts challenged with different vaccines, including novel mRNA vaccines and one shared vaccine; 2) using shared platforms that deeply interrogate immune responses from blood and limited-access compartments; and 3) refining new mathematical tools for multidimensional analysis of data to identify active pathways and modules and to determine specific connections among components in the immune network that contribute to differential vaccine effectiveness. This effort capitalizes on recent advances in single- cell and spatial immune profiling methods along with shared immunologic and proteomic platforms to create a novel public resource for vulnerable populations that characterizes diverse states of the human immune system. Integration across our cohorts will support the development of molecular signatures of vaccination responses and identify critical pathways relevant for potential therapeutic strategies.