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 大流行的持续，迫切需要更好地了解疾病和宿主 回应。 2020 年春季，我们建立了两个美国医护人员 (HCW) 队列，这是一个特别困难的群体 深入一线社区，了解疾病的特征并确定贫困的预测因素 的结果，以及长期的后遗症。随着当前研究阶段的结束，扩大后续活动 在这些特征明确的队列中监测感染及其后遗症的演变至关重要 形势迅速发展，现在包括疫苗接种和病毒变种的出现。在这个时候—— 敏感提案，我们将后续期限再延长 3 年，以便我们能够回答重要问题 有关感染、症状、长期结果和保护性的流行病学和机制问题 免疫。在目标 1 中，我们将利用以下因素定义 SARS-CoV-2 症状发作和严重程度的生物标志物： 在感染之前和感染早期阶段从队列受试者中收集的系列生物样本。我们将测试 假设症状的出现和严重程度与先前存在的因素的基线差异相对应， 包括口腔病毒组特征和外周血转录组。我们还将测试是否，其中 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 功能障碍的生物标志物，例如心肌酶和凝血因子。在目标 2 中，我们将研究长期 无症状和有症状的 COVID-19 感染的长期后遗症。我们将评估持续的证据 不同严重程度的 SARS-CoV-2 感染后长达 3 年的生理失调（包括 无症状），重点关注纵向生物标志物和肺功能。我们将检查是否有一些 感染者的免疫学、病毒学和终末器官生物标志物持续异常， 与感染前的生物标志物和未感染的对照受试者相比，肺功能。我们也会 评估生物标志物的持续异常是否与长期康复相关 肺功能下降。在目标 3 中，我们将鉴定急性感染后持续存在的血清标志物，这些标志物可能 赋予保护性免疫力。使用 SARS-CoV-2+ 个体的血清，我们将表征谱系并 抗 SARS-CoV-2 抗体的功能及其与队列和免疫保护的关系 创新的离体肺切片模型。我们将专门检查幅度、持续时间、功能和 与初始临床感染严重程度相关的抗体反应谱。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感染率相关 由于疫苗接种状态的影响，队列参与者随后再次感染。生物样本（目前 这些队列中的超过 40,000 名）将可用于合作研究。