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

SARS-CoV-2病毒感染和相关的COVID-19疾病已造成前所未有的全球发病率， 在以前健康的患者中，仅在美国就有超过400万例病例和150，000例死亡。老年 经历与衰老相关的免疫功能障碍的患者，以及具有潜在健康问题的患者， 如慢性肾脏疾病，受到COVID-19的不公平负担。了解相关的 保护免受SARS-CoV-2感染，以及为什么这些免疫功能低下的患者显然具有 在产生这些保护性免疫应答方面的缺陷对于开发这些免疫应答的临床实践至关重要。 高危人群。为了解决这个基本的知识差距，这项研究将描述自然免疫 免疫功能低下患者对SARS-CoV-2病毒感染的反应，并确定免疫力是否 持久的具体来说，我们将评估SARS-CoV-2抗体的数量和质量，以及它们的免疫原性。 与SARS-CoV-2特异性T细胞的频率和功能的关系，因此产生了一个完整的 免疫功能低下患者对SARS-CoV-2的适应性免疫反应图片。 为了实现我们的目标，我们利用加州大学的四个肾移植中心， 2500例等待移植的终末期肾病（ESRD）患者和2000例肾移植患者 在高度种族和民族多样性的国家， 人口，其中40%来自少数民族人口，他们受到COVID-19的不公平负担。我们 将在4500名患者的完整队列中筛选SARS-CoV-2暴露，招募100名ESRD和76名 基于近期人群，有SARS-CoV-2特异性抗体证据的肾移植受者 洛杉矶的血清阳性率估计为4%。我们将额外招募匹配的患者， SARS-CoV-2特异性抗体。抗体滴度、同种型、亚类、亲合力、感染中和和 与细胞介导免疫的界面将在基线时确定，纵向随访3-6个月和9- 10个月。 12个月后，以评估SARS-CoV-2体液免疫应答的寿命。同样，我们将描绘 SARS-CoV-2特异性细胞免疫应答的频率、表型和寿命。 这项研究将产生一个广泛的临床表型，结果和高维血液储存库， 和尿液分析数据的纵向样本的患者有和没有暴露于SARS-CoV-2在 加州移植人口，为研究界提供了宝贵的资源， 对SARS-CoV-2免疫。利用最先进的生物统计学和计算方法，我们将整合 体液和细胞免疫应答的高维数据，以开发组合自适应模型 SARS-CoV-2暴露后的免疫特征，并评估它们的寿命和保护 再曝光

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.