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

对老年人使用下一代流感疫苗的深入纵向分析

• 批准号: 10342393
• 负责人: Adolfo Garcia-Sastre
• 金额: $ 162.26万
• 依托单位: JACKSON LABORATORY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10342393
• 关键词: ATAC-seq; Adjuvant; Adult; Age; Aging; Antibodies; Antibody titer measurement; Antigen-Presenting Cells; Archives; B-Lymphocytes; Biological; Biological Assay; Blood; CD4 Positive T Lymphocytes; COVID-19 vaccine; Cell Nucleus; Cells; Cellular Immunology; Cellular Indexing of Transcriptomes and Epitopes by Sequencing; Cessation of life; Clinical assessments; Collaborations; Collection; Data; Dendritic Cells; Dose; Effectiveness; Elderly; Epitope Mapping; FDA approved; Failure; Feces; Fluzone; Future; Genetic Variation; Genome; Genomics; Goals; Helper-Inducer T-Lymphocyte; Hemagglutination; Humoral Immunities; Immune; Immunization Programs; Immunologic Memory; Individual; Influenza; Influenza A Virus, H7N9 Subtype; Influenza Hemagglutinin; Interferons; Lead; Leukocytes; Longevity; Longitudinal cohort; MF59; Messenger RNA; Molecular; Outcome Measure; Participant; Pathway interactions; Pattern; Phenotype; Production; Quantitative Trait Loci; RNA vaccine; Recording of previous events; Resources; Risk; Role; Sampling; Seasons; Specificity; Structure; Systems Biology; T-Lymphocyte; Technology; Time; Vaccinated; Vaccination; Vaccines; Virus Diseases; adaptive immunity; age related; base; cohort; cytokine; data resource; design; epigenome; epigenomics; follow-up; high risk population; immune function; immunogenic; immunological status; immunosenescence; improved; influenza epidemic; influenza virus strain; influenza virus vaccine; influenzavirus; longitudinal analysis; microbiome; multiple omics; nasal swab; next generation; novel strategies; predicting response; primary outcome; programs; recruit; responders and non-responders; response; sample collection; seasonal influenza; single-cell RNA sequencing; synergism; transcriptome; universal influenza vaccine; vaccination strategy; vaccine effectiveness; vaccine efficacy; vaccine response; volunteer

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.

项目摘要 世界卫生组织估计，每年流感流行导致300 - 500万例严重疾病和30万- 五十万人死亡。尽管有广泛的疫苗接种计划，但90%的流感相关死亡发生在老年人中 为这一高危人群量身定制的疫苗。美国流感疫苗的估计有效性。 2018-2019年流感季节的总体发病率为47%，但老年人仅为12-13%。因此， 迫切需要了解老年人中打开/关闭的机制，这些机制导致他们的有限 对最常用的流感疫苗Fluzone®高剂量的反应率。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细胞适应性免疫的下降有关，然而，我们的总体研究结果表明， 对免疫衰老机制的理解是不完整的。该提案的核心目标是 了解导致老年人对流感疫苗失去反应的机制， 建立健康老年人的3FluAging队列，这些老年人将接种三种不同的疫苗， 流感疫苗连续三年我们假设，衰老影响特定的调节机制， 体液免疫降低疫苗效力。在目标1中，我们将建立一个60名健康老年人的队列 （≥ 65岁），将连续接受三种不同的年度流感疫苗，连续血液和微生物组 在三年的随访期间收集样本。参与者将接受定期临床评估。在Aim中 2，我们将破译流感病毒的体液反应的大小和免疫优势模式， 健康的老年人接种疫苗。对于每种疫苗，我们将表征抗体滴度和质量， 将定义应答者和非应答者。在目标3中，我们将描述表观基因组，转录组， 细胞因子的产生和血液白细胞的细胞比例。我们将 鉴定与疫苗应答相关特异性（epi）基因组和功能标记及其寿命。 我们还将对所有参与者进行测序，以揭示遗传变异对流感疫苗反应的作用。在 目的4，我们将评估辅助性T细胞和抗原呈递细胞，特别是树突状细胞， 流感疫苗应答者和非应答者。通过识别每种药物的应答者和非应答者， 疫苗和整合这些数据与基线免疫状态多组学签名，我们将确定 免疫特征可以预测疫苗的反应性。我们希望能够确定体液免疫途径， 在衰老中改变，可用作设计新方法的基础，以提高大多数 常用的和新出现的流感疫苗。