Cohort and biomarkers for COVID-19 severity, natural history, and reinfection

COVID-19 严重程度、自然病程和再感染的队列和生物标志物

• 批准号: 10375868
• 负责人: MARTIN J BLASER
• 金额: $ 78.5万
• 依托单位: RBHS-ROBERT WOOD JOHNSON MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-17 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10375868
• 关键词: 2019-nCoV; Address; Affect; Antibodies; Antibody Response; Autoimmunity; Biological; Biological Markers; Biological Specimen Banks; Blood Coagulation Factor; COVID-19; COVID-19 pandemic; COVID-19 patient; COVID-19 severity; Cardiac; Cells; Characteristics; Clinical; Clinical Data; Communities; Convalescence; Data; Data Collection; Diagnosis; Diagnostic Trial; Disease; Employee; Enzymes; Epidemiology; Evolution; Functional disorder; Future; Health; Health Personnel; Hospitals; Human; Immune; Immune response; Immunity; Immunologic Markers; Immunologics; Individual; Infection; Inflammatory; Light; Lung; Maintenance; Modeling; Monitor; Natural History; Oral; Organ; Outcome; Participant; Phase; Phenotype; Physiological; Population; Positioning Attribute; Prospective cohort; Research; Research Design; SARS coronavirus; SARS-CoV-2 antibody; SARS-CoV-2 infection; SARS-CoV-2 transmission; Sampling; Serum Markers; Severe Acute Respiratory Syndrome; Severities; Severity of illness; Slice; Surveys; Symptoms; Testing; Time; Vaccinated; Vaccination; Vaccines; Variant; Viral; Virus; Wood material; acute infection; asymptomatic COVID-19; biological heterogeneity; cohort; cytokine; data repository; early detection biomarkers; experience; follow-up; high risk; immunological status; infection rate; innovation; insight; multidisciplinary; pandemic disease; peripheral blood; pulmonary function; screening; screening program; specific biomarkers; symptomatic COVID-19; transcriptome; treatment trial; vaccine response; vaccine trial; virology; virome

Summary As the COVID-19 pandemic continues, there is an urgent need to better understand the illness and host responses. In spring 2020, we established two cohorts of U.S. healthcare workers (HCW), a particularly hard- hit frontline community, to understand the characteristics of the illness and to identify predictors of poor outcomes, as well as of long-term sequelae. With the current study phase ending, extending follow-up activities in these well-characterized cohorts is critical to monitor the evolution of the infection and its sequelae in a rapidly evolving situation, which now includes vaccination and emergence of virus variants. In this time- sensitive proposal, we extend the follow-up period for an additional 3 years, allowing us to answer important epidemiological and mechanistic questions about infection, symptoms, long-term outcomes, and protective immunity. In Aim 1, we will define biomarkers of SARS- CoV-2 symptom onset and severity, capitalizing on serial biospecimens collected from cohort subjects prior to and during early stages of infection. We will test the hypothesis that symptom onset and severity correspond to baseline differences in pre-existing factors, including oral virome characteristics and peripheral blood transcriptome. We also will test whether, among SARS-CoV-2+ individuals, progression of illness severity can be predicted by analysis of early biomarkers at the time of diagnosis, including inflammatory biomarkers, immune cell populations, and organ-specific biomarkers of dysfunction, such as cardiac enzymes and coagulation factors. In Aim 2, we will examine long- term sequelae of asymptomatic and symptomatic COVID-19 infections. We will assess evidence of sustained physiological dysregulation up to 3 years following SARS-CoV-2 infections of varying severity (including asymptomatic), focusing on longitudinal biomarkers and pulmonary function. We will examine whether some infected individuals have persistent abnormalities in immunologic, virologic, and end-organ biomarkers and pulmonary function, compared to pre-infection biomarker and uninfected comparison subjects. We also will assess whether persistent abnormalities in biomarkers are associated with prolonged convalescence and reduced pulmonary function. In Aim 3, we will identify serum markers persisting after acute infection that may confer protective immunity. Using sera from SARS-CoV-2+ individuals, we will characterize the spectrum and functions of anti-SARS-CoV-2 antibodies and their relation to immune protection in the cohort as well as in an innovative ex vivo lung slice model. We will specifically examine variation in magnitude, duration, function, and spectrum of antibody responses in relation to severity of initial clinical infection. We will test the hypothesis that anti-SARS-CoV-2 antibody concentrations and protective functions are associated with lower rates of subsequent re-infection in cohort participants, as affected by vaccination status. The biospecimens (currently >40,000) from these cohorts will be available for collaborative studies.

概括 随着Covid-19的大流行的继续，迫切需要更好地了解疾病和宿主 回答。在2020年春季，我们建立了两名美国医疗保健工人（HCW），这是一个特别艰苦的 击中前线社区，了解疾病的特征并确定穷人的预测指标 结局以及长期后遗症。随着当前的研究阶段结束，扩展了后续活动 在这些特征良好的队列中，对于监测感染的演变及其后遗症至关重要 快速发展的情况，现在包括病毒变体的疫苗接种和出现。在这个时候 - 敏感的建议，我们将后续时间延长了3年，使我们能够回答重要 关于感染，症状，长期结局和保护性的流行病学和机械问题 免疫。在AIM 1中，我们将定义SARS-COV-2症状发作和严重性的生物标志物，并利用 在感染的早期和早期阶段，从队列受试者中收集的系列生物测量。我们将测试 症状发作和严重程度对应于先前存在的因素的基线差异的假设， 包括口服病毒蛋白特征和外周血转录组。我们还将测试是否 SARS-COV-2+个体，可以通过分析早期生物标志物来预测疾病严重程度的进展 诊断时间，包括炎症生物标志物，免疫细胞群和器官特异性的时间 功能障碍的生物标志物，例如心脏酶和凝血因子。在AIM 2中，我们将检查长期 无症状和有症状的Covid-19感染的术语后遗症。我们将评估持续的证据 SARS-COV-2感染不同严重程度后最多3年的生理失调（包括 无症状），专注于纵向生物标志物和肺功能。我们将检查是否有些 受感染的个体在免疫，病毒学和末端生物标志物中具有持续的异常 与感染前生物标志物和未感染的比较受试者相比，肺功能。我们也会 评估生物标志物的持续异常是否与康复长期相关 肺功能降低。在AIM 3中，我们将确定急性感染后持续存在的血清标志物可能 赋予保护性免疫。使用来自SARS-COV-2+个体的血清，我们将表征频谱和 抗SARS-COV-2抗体的功能及其与队列中的免疫保护的关系 创新的离体肺切片模型。我们将专门检查大小，持续时间，功能和 与初始临床感染的严重程度有关的抗体反应光谱。我们将检验以下假设 抗SARS-COV-2抗体浓度和保护功能与较低的速率有关 随后在队列参与者中重新感染，受疫苗接种状态的影响。生物测量（目前 > 40,000）从这些队列中可以进行协作研究。