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.

总结 随着COVID-19大流行的持续，迫切需要更好地了解疾病和宿主 应答在2020年春天，我们建立了两个美国医疗保健工作者（HCW）群体，这是一个特别困难的群体， 打击前线社区，了解疾病的特点，并确定预测贫困 结果，以及长期后遗症。随着当前研究阶段的结束，后续活动的扩展 在这些特征良好的队列中， 快速发展的情况，现在包括疫苗接种和病毒变种的出现。在这个时候- 敏感的建议，我们延长随访期额外3年，使我们能够回答重要的 关于感染、症状、长期结果和保护性的流行病学和机制问题 免疫力在目标1中，我们将定义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从队列受试者中采集的系列生物样本。我们将测试 假设症状发作和严重程度对应于预先存在因素的基线差异， 包括口腔病毒组特征和外周血转录组。我们还将测试， SARS-CoV-2+个体，疾病严重程度的进展可以通过分析早期生物标志物来预测， 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，如心肌酶和凝血因子。在第二章中，我们将讨论长期的... 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 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），关注纵向生物标志物和肺功能。我们将研究一些 受感染的个体在免疫学、病毒学和终末器官生物标志物方面具有持续的异常， 肺功能，与感染前生物标志物和未感染的对照受试者相比。我们也将 评估生物标志物的持续异常是否与恢复期延长相关， 肺功能下降。在目标3中，我们将确定急性感染后持续存在的血清标志物， 赋予保护性豁免权使用来自SARS-CoV-2+个体的血清，我们将表征谱， 抗SARS-CoV-2抗体的功能及其与免疫保护的关系， 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应答谱。我们将检验这个假设， 抗SARS-CoV-2抗体浓度和保护功能与较低的 受疫苗接种状态影响，队列参与者随后再次感染。生物标本（目前 > 40，000）将可用于合作研究。