Induction and maintenance of SARS-CoV-2 mRNA vaccine-specific memory across tissues

跨组织的 SARS-CoV-2 mRNA 疫苗特异性记忆的诱导和维持

• 批准号: 10751246
• 负责人: Julia Meghan Davis-Porada
• 金额: $ 4.92万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10751246
• 关键词: 2019-nCoV; Adult; Affect; Age; Antibody Formation; Antibody titer measurement; Attenuated; Authorization documentation; B-Lymphocytes; Blood; Blood specimen; COVID-19 pandemic; COVID-19 vaccine; Cell physiology; Cells; Child; Clinical; Collaborations; Communities; Data; Development; Enzyme-Linked Immunosorbent Assay; Event; Exhibits; Flow Cytometry; Frequencies; Future; Goals; Health; Human; Humoral Immunities; Immune; Immune response; Immune system; Immunity; Immunologic Memory; Individual; Infection; Inflammatory; Integration Host Factors; Interferons; Investigation; Knowledge; Laboratories; Life; Lung; Lymphocyte; Lymphoid; Lymphoid Tissue; Macrophage; Maintenance; Measures; Mediating; Medical; Memory; Memory B-Lymphocyte; Modeling; Moderna COVID-19 vaccine; Monitor; Mononuclear; Morbidity - disease rate; Mucous Membrane; Natural Immunity; Organ Donor; Organ Procurements; Outcome; Persons; Phenotype; Population; Prevention strategy; Production; Property; Proteins; RNA vaccine; Residencies; Resources; Role; Serology; Site; Spatial Distribution; T memory cell; T-Lymphocyte; Time; Tissue Donors; Tissues; Vaccinated; Vaccination; Vaccine Design; Vaccinee; Vaccines; Variant; Viral; Virus; Virus Diseases; Work; adaptive immunity; authority; coronavirus disease; current pandemic; cytokine; frontier; high dimensionality; human tissue; improved; lymph nodes; lymphoid organ; manufacture; mortality; neutralizing antibody; novel; novel vaccines; pandemic disease; pathogen; prevent; quantitative imaging; respiratory virus; response; severe COVID-19; tissue resource; unvaccinated; vaccine development; vaccine distribution; vaccine efficacy; vaccine formulation; vaccine response; vaccine strategy; vaccine trial; vaccine-induced immunity; vaccinology

PROJECT SUMMARY Vaccines save lives, and the rapid development of novel vaccines against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) was a triumph for the medical community. While the rapid deployment of these vaccines has undoubtedly attenuated the severe morbidity and mortality induced by the virus, their efficacy is decreased against variant strains, in children, and with increasing time post-administration. These clinical findings highlight our lack of understanding of how durable, protective immunity is induced by vaccination and how this varies across the population. Studying vaccine induced memory in humans has two major challenges. First, viral exposures over life confound the identification of vaccine-specific memory; second, the stores of memory lymphocytes reside in the tissues, which makes monitoring the vaccine response in healthy individuals challenging. The SARS-CoV-2 pandemic affords us the unique opportunity to study the response to a novel vaccine formulation without confounding natural antigenic exposure and the ability to distinguish infection from vaccination by serology. Additionally, our unique organ donor tissue resource provides a validated model to investigate tissue-localized vaccine-specific immunity. The goal of this proposal is to understand how vaccine- induced immune memory is distributed across tissue and affected by host factors such as age. The central hypothesis of this proposal is that induction and maintenance of vaccine-specific memory is controlled in lymph nodes, and specific early induction events directly impact immune memory development and vary with age. I will address this hypothesis and meet the goals of the study by using flow cytometry and high- dimensional sequencing to evaluate the relationship between circulating and tissue-localized vaccine memory and how they differ in phenotype, function, and across age. I will also investigate how the initial, inflammatory host-specific response to the mRNA-1273 vaccine differs across age and correlates to the quantity of immune memory induced. The results of this study will elucidate the importance of lymph nodes in the vaccine response and highlight the benefits and downfalls of mRNA vaccines across various host factors. These results will have implications for future vaccine design and may play a role in managing both the SARS-CoV-2 pandemic and any future ones.

项目总结 疫苗拯救生命，以及针对严重急性呼吸综合征的新型疫苗的快速开发 冠状病毒-2(SARS-CoV-2)是医学界的胜利。虽然这些设备的快速部署 疫苗无疑减轻了病毒引起的严重发病率和死亡率，其疗效是 在儿童中，随着给药后时间的增加，对变种菌株的抵抗力下降。这些临床 这些发现突显了我们对接种疫苗和接种疫苗如何诱导持久的保护性免疫缺乏了解 这在不同的人群中是如何变化的。研究疫苗诱导的人类记忆有两个主要挑战。 首先，在生活中接触病毒扰乱了疫苗特有记忆的识别；其次，疫苗的存储 记忆淋巴细胞驻留在组织中，这使得监测健康个体的疫苗反应 很有挑战性。SARS-CoV-2大流行为我们提供了一个独特的机会来研究对一种新的 疫苗配方不混淆自然抗原暴露和区分感染和 通过血清学接种疫苗。此外，我们独特的器官捐赠者组织资源提供了一个经过验证的模型 研究组织定位的疫苗特异性免疫。这项提案的目标是了解疫苗是如何- 诱导免疫记忆是跨组织分布的，受年龄等宿主因素的影响。中环 这一提议的假设是，疫苗特异性记忆的诱导和维持在 淋巴结和特定的早期诱导事件直接影响免疫记忆的发育和 随着年龄的增长而变化。我将解决这一假设，并通过使用流式细胞术和高密度脂蛋白来实现研究目标。 维度测序评估循环和组织定位疫苗记忆之间的关系 以及它们在表型、功能和年龄上的差异。我还将调查最初的、炎症性的 宿主对mRNA-1273疫苗的特异性反应因年龄而异，并与免疫量有关 诱发的记忆。这项研究的结果将阐明淋巴结在疫苗中的重要性 并强调不同宿主因素下信使核糖核酸疫苗的利弊。这些 研究结果将对未来的疫苗设计产生影响，并可能在管理SARS-CoV-2病毒方面发挥作用 大流行和任何未来的大流行。