Mapping Immune Responses to CMV in Renal Transplant Recipients - Transplant Supplement

SARS-CoV-2病毒感染和相关的新冠肺炎疾病造成了前所未有的全球发病率和 以前健康的患者的死亡率，仅在美国就有超过400万例和15万人死亡。更老的 经历与衰老相关的免疫功能障碍的患者，以及有潜在健康问题的患者， 如慢性肾脏疾病，已经不公平地背负了新冠肺炎的负担。了解以下方面的关联 对SARS-CoV-2感染的保护以及为什么这些免疫功能低下的患者明显拥有 在产生这些保护性免疫反应方面的缺陷对于开发针对这些疾病的临床实践至关重要 高危人群。为了解决这个基本的知识鸿沟，这项研究将描述自然免疫的特征 免疫低下患者对SARS-CoV-2病毒感染的反应 持久的。具体地说，我们将评估SARS-CoV-2抗体的数量和质量以及他们的 与SARS-CoV-2特异性T细胞频率和功能的关系，从而产生完整的 免疫低下患者对SARS-CoV-2的适应性免疫反应图。 为了实现我们的目标，我们利用加州大学内的四个肾脏移植中心建立了 2500例等待移植的终末期肾病患者和2000例肾移植患者的队列 接受新冠肺炎大流行前和后血清储存的人，种族和民族高度多样化 人口，其中40%来自少数群体，他们不公平地承受着新冠肺炎的负担。我们 将在4500名患者中进行暴露于SARS-CoV-2的筛查，包括100名ESRD和76名 肾移植受者有SARS-CoV-2特异性抗体的证据，基于最近的人群 洛杉矶的血清阳性率估计为4%。我们将额外招募没有证据的匹配患者 SARS-CoV-2特异性抗体。抗体效价、同型、亚类、亲和力、感染中和能力和 与细胞免疫的界面将在基线时确定，纵向随访3-6个月和9-6个月 12个月后评估对SARS-CoV-2的体液免疫应答的寿命。同样，我们将描述 SARS-CoV-2特异性细胞免疫反应的频率、表型和寿命。 这项研究将产生一个广泛的临床表型、结果和高维血液资料库 和尿液样本的纵向样本的SARS-CoV-2暴露和不暴露的数据 加州移植人口，为研究界了解 对SARS-CoV-2的免疫力。利用最先进的生物统计学和计算方法，我们将把 体液和细胞免疫反应的高维数据用于建立联合适应性模型 SARS-CoV-2暴露后的免疫状况，并评估它们的寿命和保护 重新曝光。

SARS-CoV-2 virus infection and associated COVID-19 disease has caused unparalleled global morbidity and mortality in previously healthy patients, with over 4 million cases and 150,000 deaths in the US alone. Older patients, who experience immune dysfunction associated with aging, and patients with underlying health issues, such as chronic kidney disease, have been inequitably burdened by COVID-19. Understanding correlates of protection against SARS-CoV-2 infection and why these immunocompromised patients apparently possess deficiencies in generating these protective immune responses is critical to developing clinical practices for these at-risk populations. To address this fundamental knowledge gap, this study will characterize the natural immune response to SARS-CoV-2 virus infection in immunocompromised patients and determine whether immunity is long-lasting. Specifically, we will evaluate the quantity and quality of antibodies against SARS-CoV-2 and their relationship to frequency and functionality of SARS-CoV-2-specific T cells, therefore generating a complete picture of the adaptive immune response to SARS-CoV-2 in immunocompromised patients. To achieve our goal, we have utilized four kidney transplant centers within the University of California to establish a cohort of 2500 patients with end-stage renal disease (ESRD) awaiting transplant and 2000 renal transplant recipients with banked pre- and post-COVID-19 pandemic sera across a highly racially and ethnically diverse population, of which 40% are from minority populations that have been inequitably burdened by COVID-19. We will screen for exposure to SARS-CoV-2 in the complete cohort of 4500 patients, enrolling 100 ESRD and 76 renal transplant recipients with evidence of SARS-CoV-2-specific antibodies, based on a recent population seroprevalence estimate of 4% in Los Angeles. We will additionally recruit matched patients without evidence of SARS-CoV-2-specific antibodies. Antibody titer, isotype, subclass, avidity, infection neutralization and ability to interface with cell-mediated immunity will be determined at baseline with longitudinal follow-up 3-6 month and 9- 12 months later to assess longevity of humoral immune responses to SARS-CoV-2. Similarly, we will delineate the frequency, phenotype and longevity of SARS-CoV-2-specific cellular immune responses. This study will generate an extensive repository of clinical phenotypes, outcomes, and high-dimensional blood and urine profiling data on longitudinal samples of patients with and without exposure to SARS-CoV-2 in the California transplant population, providing an invaluable resource for the research community in understanding immunity to SARS-CoV-2. Utilizing state-of-the-art biostatistics and computational approaches, we will integrate high-dimensional data of humoral and cellular immune responses to develop models of combined adaptive immune profiles following SARS-CoV-2 exposure and assess their longevity and likelihood of protecting upon re-exposure.