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

项目摘要 人类对流感疫苗接种和感染的适应性反应是复杂的，并且可以在一段时间内受损。 各种条件，包括怀孕和高龄，原因尚不清楚。开展严厉 广泛分析淋巴细胞表型库，包括NK细胞、BCR和TCR 流感特异性B细胞和T细胞表达的序列库，在设计为包括 已知对流感的反应受损的主要脆弱人群，孕妇和老年人 接种疫苗或感染。评价各阶段生发中心反应的潜在特异性缺陷， 增殖和选择流感特异性淋巴细胞，最终成为血液中检测，我们 将在接种疫苗后对引流淋巴结和扁桃体进行连续细针抽吸（FNA） 接受鼻内疫苗的个体。配对淋巴结和血液数据应能够检测 以前无法在人类中进行研究的反应缺陷。我们将使用这种方法来 确定老年人流感疫苗接种中佐剂（MF59）免疫应答的关键变化， 将这些与产生的抗体质量相关联。 本项目的另一个目标是利用先前广泛的流感特异性TCR和BCR 在戴维斯，博伊德和罗宾逊实验室的测序工作，以及公共数据，组装数据库， 确认流感特异性受体序列，以测试特定的假设。新的计算 方法，我们将确定和验证趋同或公共受体，共享序列特征，表明 它们结合相似的表位。我们将测试是否频率，多样性，或特定的表位目标，这样的 受体序列可以预测疫苗的反应，更重要的是， 挑战.两个不同的流感病毒攻毒队列将用于验证我们的TCR和BCR预测因子 疫苗保护。 该项目将使人们更好地了解与年龄和怀孕有关的变化， 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内工作，项目2将有助于全球 努力提高对人类免疫系统的定量和预测性理解。这些知识 应该有助于制定改进和测试下一代流感疫苗的战略， 未来的流行病和大流行病。这些新方法中的许多方法也可以为开发 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.