Deriving correlates of protection from influenza-specific antibody and T cell receptor analysis.

项目总结 人类对流感疫苗接种和感染的适应性反应是复杂的，在 各种情况，包括怀孕和高龄，原因尚不清楚。我们将开展 广泛分析淋巴细胞表型谱系，包括NK细胞的表型谱，以及BCR和TCR 流感特异性B细胞和T细胞在临床队列中表达的序列谱系，旨在包括 已知对流感反应受损的主要弱势人群，即孕妇和老年人 接种疫苗或感染。评估生发中心反应阶段潜在的特定缺陷，以及 最终在血液中检测到的流感特异性淋巴细胞的增殖和选择，我们 将在接种疫苗后对引流淋巴结和扁桃体进行一系列细针抽吸(FNAs) 来自接受鼻腔疫苗接种的个人。配对的淋巴结和血液数据应该能够检测到 反应中的缺陷，以前无法在人类身上进行研究。我们将使用此方法来 确定老年人接种流感疫苗时使用佐剂(MF59)后免疫反应的主要变化，以及 将这些与所产生的抗体质量相关联。 该项目的另一个目标是利用先前广泛的针对流感的TCR和BCR 戴维斯、博伊德和罗宾逊实验室的测序工作，以及公共数据，以收集 确认流感特异性受体序列以检验特定假说。具有新的计算能力 方法，我们将识别和验证具有共同序列特征的汇聚或公共受体 它们结合了相似的表位。我们将测试这种基因的频率、多样性或特定的表位靶标 受体序列可以预测疫苗的反应，更重要的是，可以预防活的流感病毒 挑战。将使用两个不同的流感病毒挑战队列来验证我们的TCR和BCR预测因子 疫苗的保护性。 这个项目将更好地了解与年龄相关和与怀孕相关的变化 流感疫苗反应，以及关于次级淋巴组织中疫苗反应的新知识 包括淋巴结和扁桃体。从长远来看，在这个U19的范围内，项目2将为全球 努力改进对人类免疫系统的定量和预测性了解。这一知识 应有助于形成改进和测试下一代流感疫苗的战略，以防止 未来的流行病和大流行。这些新方法中的许多还可以为开发 一般来说，更有效的疫苗。

PROJECT SUMMARY Human adaptive responses to influenza vaccination and infection are complex, and can be impaired in a variety of conditions, including pregnancy and advanced age, for reasons that are still unclear. We will carry out extensive analyses of lymphocyte phenotypic repertoires, including those of NK cells, and the BCR and TCR sequence repertoires expressed by influenza-specific B cells and T cells, in clinical cohorts designed to include key vulnerable populations, pregnant women and the elderly, known to have impaired responses to influenza vaccination or infection. To evaluate potential specific defects in stages of germinal center reactions, and the proliferation and selection of influenza-specific lymphocytes that eventually become detectable in the blood, we will carry out serial fine-needle aspirations (FNAs) from draining lymph nodes after vaccination, and in tonsils from individuals receiving intranasal vaccine. Paired lymph node and blood data should enable detection of defects in responses that have previously not been accessible to study in humans. We will use this approach to identify key changes in immune responses with adjuvant (MF59) in influenza vaccination for the elderly, and correlate these with resultant antibody quality. An additional goal of this Project will be to leverage prior extensive influenza-specific TCR and BCR sequencing efforts in the Davis, Boyd and Robinson labs, as well as public data, to assemble databases of confirmed influenza-specific receptor sequences to test specific hypotheses. With new computational approaches, we will identify and validate convergent or public receptors that share sequence features indicating that they bind similar epitopes. We will test whether the frequency, diversity, or particular epitope targets of such receptor sequences can predict vaccine responses, and, more importantly, protection against live influenza viral challenge. Two different influenza viral challenge cohorts will be used to validate our TCR and BCR predictors of vaccine protection. This project will provide better understanding of age-related and pregnancy-related alterations in influenza vaccine responses, as well as new knowledge about vaccine responses in secondary lymphoid tissues including lymph nodes and tonsils. In the longer term, working within this U19, Project 2 will contribute to global efforts to improve quantitative and predictive understanding of the human immune system. This knowledge should help to shape strategies for improving and testing the next generation of influenza vaccines to prevent future epidemics and pandemics. Many of these new approaches may also provide a template for developing more effective vaccines in general.