Influenza responses and repertoire in vaccination, infection and tonsil organoids.

流感反应和疫苗接种、感染和扁桃体类器官的全部内容。

基本信息

批准号：
10265695
负责人：
Mark Morris Davis
金额：
$ 175.38万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-19 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10265695
关键词：
3-Dimensional Ablation Address Adjuvant Adult Alleles American Antibodies Antibody Affinity Antibody Response B cell repertoire B-Lymphocytes Blocking Antibodies Cells Centers for Disease Control and Prevention (U.S.)Cessation of life Characteristics Child Clinical Data Data Set Databases Development Disease Elderly Exposure to Fine needle aspiration biopsy Gene Expression Gene Targeting Genes Genetic Goals Grain Grant Grouping Health Hospitalization Human Immune response Immunity Immunologic Monitoring Immunologics In Vitro Infection Infectious Pregnancy Complications Inflammatory Response Influenza Influenza vaccination International Intervention Link Lymphocyte Methodology Methods Modeling Morbidity - disease rate Natural Killer Cells Neighborhoods Organoids Peptides Pregnancy Pregnant Women Proteins Reporter Resources Sampling Specificity System T cell receptor repertoire sequencing T cell response T-Cell Receptor T-Lymphocyte T-cell receptor repertoire Technology Testing Time Tissue Stains Tissue imaging Tonsil Twin Multiple Birth Uncertainty Vaccinated Vaccination Vaccines Woman Work adaptive immune response alpha-beta T-Cell Receptor analytical method base cytokine draining lymph node flu global health high dimensionality human imaging imprint in vivo individual variation influenza infection influenza virus vaccine influenzavirus interest live attenuated influenza vaccine lymph nodes member mortality neutralizing antibody novel novel vaccines pandemic disease response tool universal influenza vaccine universal vaccine vaccine evaluation vaccine response

项目摘要

Project Summary Influenza remains a continual threat to health of many Americans, resulting in 9.2-35.6 million illnesses, 140,000-710,000 hospitalizations, and 12,000-56,000 deaths annually since 2010 (CDC), as well as the ever-present likelihood of a devastating pandemic that could kill millions. Recent work has also suggested that a universal flu vaccine may be possible, although there is considerable uncertainty about how to achieve this. This renewal application seeks to leverage some of the important methodologies and data that we have developed in this past granting period to understand at a much deeper level what constitutes broad and effective B and T cell responses against influenza so as to better inform next generation vaccine efforts. Specifically, we have developed a unique tonsil organoid system that we can expose to a flu vaccine and produce high affinity antibodies several days to a week later. This gives us an ability to manipulate and test vaccine constructs and adjuvants in a fully human system in order to find the best way to trigger broadly neutralizing antibodies. In addition, we have developed powerful new T and B cell repertoire analysis methods that will allow us to productively analyze large flu- specific TCR and Ig data sets to identify which specificities or other correlates contribute the most to protection or amelioration of diseases in challenge studies. We also plan to further analyze influenza vaccine responses in pregnant women, the elderly and twins, to test various hypotheses that we have developed in our previous work in the CCHI. Lastly we will take advantage of recent advances by the Nolan lab in imaging tissue sections with large numbers of different antibodies to analyze the cellular organization the tonsil organoids with time during a flu vaccine response and after different interventions.

项目概要流感仍然对许多美国人的健康构成持续威胁，导致 9.2-3560 万人死亡自 2010 年以来，每年有 140,000-710,000 人患病，12,000-56,000 人死亡（疾病预防控制中心），以及可能导致数百万人死亡的毁灭性大流行的可能性始终存在。最近的研究还表明，通用流感疫苗可能是可能的，尽管存在如何实现这一目标存在很大的不确定性。此续订申请旨在利用我们过去开发的一些重要方法和数据更深入地了解什么构成了广泛且有效的 B 和 T 细胞流感应对措施，以便更好地为下一代疫苗工作提供信息。具体来说，我们开发了一种独特的扁桃体类器官系统，我们可以将其暴露于流感疫苗并几天到一周后产生高亲和力抗体。这使我们有能力在完全人体系统中操作和测试疫苗结构和佐剂，以便找到触发广泛中和抗体的最佳方法。此外，我们还开发了强大的新的 T 和 B 细胞库分析方法将使我们能够高效地分析大流感特定的 TCR 和 Ig 数据集，以确定哪些特异性或其他相关因素有助于大多数是在挑战研究中保护或改善疾病。我们还计划进一步分析孕妇、老年人和双胞胎的流感疫苗反应，以测试各种我们在 CCHI 之前的工作中提出了假设。最后我们将采取诺兰实验室在对大量组织切片进行成像方面取得的最新进展使用不同的抗体来分析流感期间扁桃体类器官随时间变化的细胞组织疫苗反应和不同干预措施后的反应。