A deep longitudinal analysis of next generation influenza vaccines in older adults

项目总结 世界卫生组织估计，每年流感的流行导致300-500万例严重疾病和30万人- 50万人死亡。90%的流感相关死亡发生在老年人身上，尽管疫苗接种计划广泛开展 为这一高危人群量身定做的疫苗。流感疫苗在美国的估计效果。 2018-2019年流感季节的总体比例为47%，但老年人的比例仅为12%-13%。因此，有一种 迫切需要了解老年人开启/关闭导致其功能受限的机制 对最常用的流感疫苗--福来宗®大剂量的应答率。此外，还需要 了解下一代流感疫苗是否以及为什么可能更有效。免疫衰老 已知与最佳B细胞和T细胞获得性免疫能力下降有关，然而，我们的总体 对免疫衰老机制的了解还不完全。这项提议的中心目标是 了解导致老年人对流感疫苗失去反应的机制 将接种三种不同疫苗的健康老年人3Fluage队列的建立 连续三年接种流感疫苗。我们假设衰老影响特定的调控机制。 体液免疫降低疫苗效力。在目标1中，我们将建立一个由60名健康老年人组成的队列 (≥65年)世卫组织将先后接种三种不同的年度流感疫苗，并提供连续血液和微生物组 在三年的跟踪调查中收集样本。参与者将接受定期的临床评估。在AIM 2，我们将破译对流感病毒的体液反应的幅度和免疫优势模式 接种疫苗后健康的老年人。对于每种疫苗，我们将表征抗体效价和质量，并 将定义响应者和非响应者。在目标3中，我们将描述表观基因组、转录组、 在接种疫苗的健康老年参与者中，细胞因子的产生和白细胞的细胞比例。我们会 确定与疫苗反应相关的特定(Epi)基因组和功能特征及其寿命。 我们还将对所有参与者进行排序，以揭示基因变异对流感疫苗反应的作用。在……里面 目的4，我们将评估T辅助细胞和抗原提呈细胞，特别是树突状细胞的功能。 流感疫苗应答者和无应答者。通过分别确定应答者和非应答者 疫苗，并将这些数据与基线免疫状态多组体签名相结合，我们将确定 免疫功能可以预测疫苗的反应性。我们希望确定体液免疫途径是 在老化过程中发生改变，可用作设计新方法的基础，以提高MOST 通常使用的以及正在出现的流感疫苗。

PROJECT SUMMARY The WHO estimates that annual epidemics of influenza result in 3-5 million cases of severe illness and 300,000- 500,000 deaths. 90% of influenza-related deaths occur in older adults despite widespread vaccination programs with vaccines tailored for this high-risk group. The estimated effectiveness of the influenza vaccine in the U.S. for the 2018-2019 influenza season overall was 47%, but only 12-13% in older adults. There is therefore an urgent need to understand the mechanisms that are turned on/off in older adults that result in their limited response rate to the most commonly used influenza vaccine, Fluzone® High-Dose. There is also a need to understand whether and why next-generation influenza vaccines might be more efficacious. Immunosenescence is known to be associated with declines in optimal B cell and T cell adaptive immunity, however, our overall understanding of the mechanisms of immunosenescence is incomplete. The central goal of this proposal is to understand the mechanisms that lead to a loss of response to influenza vaccine in older adults through establishment of the 3FluAging cohort of healthy older adults who will be vaccinated with three different influenza vaccines three years in a row. We hypothesize that aging impacts specific regulatory mechanisms of humoral immunity to reduce vaccine effectiveness. In Aim 1, we will establish a cohort of 60 healthy older adults (≥65yrs) who will sequentially receive three different annual influenza vaccines, with serial blood and microbiome sample collection during three years of follow-up. Participants will undergo regular clinical assessments. In Aim 2, we will decipher the magnitude and immunodominance pattern of the humoral response to influenza virus in healthy older individuals upon vaccination. For each vaccine, we will characterize antibody titer and quality and will define responders and non-responders. In Aim 3, we will characterize the epigenome, transcriptome, cytokine production, and cell proportions of blood leukocytes in vaccinated healthy older participants. We will identify specific (epi)genomic and functional signatures, and their longevity, associated with vaccine response. We will also sequence all participants to uncover the role of genetic variation on influenza vaccine responses. In Aim 4, we will assess the function of T helper cells and antigen presenting cells, specifically dendritic cells, in influenza vaccine responders and non-responders. By identifying responders and non-responders for each vaccine and integrating these data with baseline immune status multi-omic signatures, we will determine which immune features can predict vaccine responsiveness. We expect to identify humoral immunity pathways that are altered in aging that can be used as the basis for designing novel approaches to boost efficacy of the most commonly used, as well as emerging, influenza vaccines.