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

项目摘要 疫苗拯救生命，新型疫苗的快速发展，以防止严重急性呼吸道综合征 冠状病毒2型（SARS-CoV-2）是医学界的一个胜利。虽然快速部署这些 疫苗无疑减轻了病毒引起的严重发病率和死亡率，其效力 在儿童中，随着给药后时间的增加，对变异株的耐药性降低。这些临床 研究结果突出表明，我们缺乏对疫苗接种如何诱导持久的保护性免疫的理解， 这在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，一生中的病毒暴露混淆了疫苗特异性记忆的识别;其次， 记忆淋巴细胞存在于组织中，这使得监测健康个体的疫苗反应成为可能。 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 没有混淆天然抗原暴露的疫苗制剂和区分感染与 通过血清学进行接种。此外，我们独特的器官供体组织资源提供了一个经过验证的模型， 研究组织定位疫苗特异性免疫。这项计划的目的是了解疫苗- 诱导的免疫记忆分布在整个组织中，并受宿主因素如年龄的影响。中央 这一建议的假设是疫苗特异性记忆的诱导和维持是由 淋巴结和特异性早期诱导事件直接影响免疫记忆的发展， 随年龄而变化。我将通过使用流式细胞术和高- 三维测序，以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。我还将研究最初的，煽动性的 宿主对mRNA-1273疫苗的特异性应答在不同年龄段不同，并与免疫应答的量相关。 记忆诱导这项研究的结果将阐明淋巴结在疫苗中的重要性 反应，并强调mRNA疫苗在各种宿主因素中的益处和缺点。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和 大流行病和任何未来的。

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.