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

摘要 随着新冠肺炎大流行的持续，迫切需要更好地了解疾病和宿主 回应。2020年春，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- 打击一线社区，了解疾病特征并确定贫困的预测因素 结果，以及长期后遗症。随着当前研究阶段的结束，延长后续活动 在这些特征良好的队列中是监测感染及其后遗症演变的关键 局势迅速演变，现在包括接种疫苗和出现病毒变种。在这段时间里- 敏感的建议，我们将追踪期再延长3年，使我们能够回答重要的 关于感染、症状、长期结果和保护的流行病学和机械性问题 豁免权。在目标1中，我们将定义SARS-CoV-2症状发生和严重程度的生物标记物，利用 在感染前和感染早期阶段从队列受试者收集的连续生物检疫标本。我们将测试 假设症状的出现和严重程度与预先存在的因素的基线差异相对应， 包括口腔病毒体特征和外周血转录组。我们还将测试是否，在 在SARS-CoV-2+个体中，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，如心肌酶和凝血因子。在目标2中，我们将研究Long- 无症状和有症状的新冠肺炎感染的长期后遗症。我们将评估证据是否持续 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 感染者在免疫学、病毒学和终末器官生物标志物和 肺功能，与感染前的生物标志物和未感染的对照对象进行比较。我们也会 评估生物标志物的持续异常是否与康复时间延长和 肺功能减退。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 授予保护豁免权。使用SARS-CoV-2+个体的血清，我们将表征光谱和 抗SARS-CoV-2抗体在队列和人群中的功能及其与免疫保护的关系 创新的体外肺切片模型。我们将具体检查震级、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。我们将检验这一假设 抗SARS-CoV-2抗体浓度和保护功能与较低的 受疫苗接种状况的影响，队列参与者随后再次感染。生物制品(目前 这些队列中的40,000个)将可用于协作研究。

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.