COVID19: Respiratory SARS-CoV-2 seroprevalence and the association of humoral immune responses with clinical outcomes in veterans and employees in the Cleveland VA Medical Center

COVID19：克利夫兰退伍军人医疗中心退伍军人和员工的呼吸道 SARS-CoV-2 血清流行率以及体液免疫反应与临床结果的关联

• 批准号: 10160554
• 负责人: Carey Lynn Shive
• 金额: --
• 依托单位: LOUIS STOKES CLEVELAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10160554
• 关键词: 2019-nCoV; ACE2; Accident and Emergency department; Address; Affect; Affinity; Age; Antibodies; Antibody Affinity; Antibody Response; Antibody titer measurement; Antigens; Avidity; B-Lymphocyte Subsets; B-Lymphocytes; Binding; Biological Assay; Blood specimen; COVID-19; COVID-19 morbidity; COVID-19 mortality; COVID-19 pandemic; Cells; Characteristics; Clinic; Clinical; Common Cold; Coronavirus; Development; Disease Progression; Elderly; Employee; Enrollment; Enzyme-Linked Immunosorbent Assay; Epithelial Cells; Epitopes; Exposure to; Flow Cytometry; Foundations; Frequencies; Functional disorder; Future; Generations; Health Personnel; Healthcare; Helper-Inducer T-Lymphocyte; Hospitals; Humoral Immunities; Immune response; Immunoglobulin Class Switching; Immunoglobulin Somatic Hypermutation; Immunologics; Individual; Infection; Inpatients; Intensive Care Units; KAI1 gene; Knowledge; Length; Leukocytes; Lung; Lymphopenia; Measures; Mediating; Medical center; Memory B-Lymphocyte; Ohio; Outcome; Outpatients; Patients; Play; Proteins; Recombinants; Research Personnel; Risk; Role; SARS coronavirus; SARS-CoV-2 antibody; SARS-CoV-2 exposure; SARS-CoV-2 immunity; SARS-CoV-2 infection; SARS-CoV-2 positive; SARS-CoV-2 spike protein; Sampling; Seroprevalences; Serum; Severity of illness; T-Lymphocyte; Testing; Vaccines; Veterans; Viral; Virus; antibody detection; antibody test; antigen detection; base; falls; first responder; high risk; high throughput screening; infection risk; lymph nodes; neutralizing antibody; novel therapeutics; pandemic disease; prevent; receptor; receptor binding; respiratory; response; symptomatic COVID-19; therapeutic development; therapy development; vaccine development; ward

The global pandemic of SARS-CoV-2 is placing urgent demands on health care workers and researchers. Between April 3rd and May 1st global cases of COVID19 nearly tripled from approximately 1 million to over 3 million. With the possibility of a reemergence of SARS-CoV-2 in the fall, rapid specific antibody assays are essential. This application proposes to investigate the humoral immune responses to SARS-CoV-2 in veterans and employees at the Cleveland VA Medical Center. The proposal has three aims. Aim 1) To develop rapid, high throughput assays to measure total and functional antibodies to SARS-CoV-2 proteins in COVID19 infected individuals. In aim 1, we will establish a magnet bead-based assay that can detect antibody (Ab) responses to up to 50 different epitopes of SARS-CoV-2 in one serum sample. This assay will also be able to detect Abs that interfere with the binding of the receptor binding domain (RBD) of the spike protein of SARS- CoV-2 to its receptor, ACE2. Antibodies that can block binding between the RBD and ACE2 on lung epithelial cells will prevent viral entry and will likely be neutralizing. Aim 2) To determine if robust humoral immunity and higher neutralizing Ab titers protect VA health care employees from clinical COVID19 compared to their colleagues with low or no SAR2-CoV-2 specific antibodies. In aim 2 we will use a rapid antibody test to screen Cleveland VA health care employees at high-risk for infection with COVID19 (first responders, emergency department staff, intensive care unit staff, COVID19 ward staff). We will ask for a serum sample from those that are Ab positive for COVID19 to examine the SARS-CoV-2 Ab response in more depth. We will examine general Ab titers, neutralizing Ab titers, and antibody isotypes. If there is a resurgence of COVID19 in the fall, we will determine if those health care employees with a robust humoral response are better protected from re- infection than those employees who had a weak or no Ab response. Aim 3) To examine the association of COVID19-induced lymphopenia with the ability to generate a humoral immune response. Older age, SARS- CoV-1 and SARS-COV-2 infection are all associated with a decrease of white blood cells or lymphopenia. In aim 3 we will examine the effect of lymphopenia on the development of the humoral Ab response to COVID19. We expect that those individuals with severe lymphopenia will have few T follicular helper cells in their lymph nodes and this will lead to poor Ab affinity maturation, isotype switching, and B cell memory development. In summary, results from this project will provide a rapid SARS-CoV-2 specific serum assay able to detect neutralizing Ab that can be used to screen VA healthcare workers for exposure to SARS-CoV-2. We will investigate the humoral antibody responses of high-risk health care employees that were infected with COVID19 and try to determine what constitutes protection from re-infection if there is a resurgence of COVID19 in the fall. Lastly, we will gain an understanding of the B cell affinity maturation, isotype switching and generation of B cell memory and neutralizing Ab titers and determine how lymphopenia may play a role in the dysfunction of humoral immunity to COVID19. This knowledge will aid in development of better treatment and future vaccines.

SARS-COV-2的全球大流行正对医护人员和研究人员提出紧急需求。 在4月3日至5月1日，2019年的全球案件在大约100万到3个 百万。随着秋季中SARS-COV-2重新出现的可能性，快速的特异性抗体测定是 基本的。该申请建议研究退伍军人对SARS-COV-2的体液免疫反应 以及克利夫兰弗吉尼亚州医疗中心的员工。该提案有三个目标。目标1）迅速发展， 高吞吐量测定以测量covid19中与SARS-COV-2蛋白的总和功能抗体 受感染的人。在AIM 1中，我们将建立一个基于磁珠的测定法，该测定法可以检测抗体（AB） 在一个血清样品中，对多达50个不同表位的SARS-COV-2的响应。该测定也将能够 检测ABS干扰SARS-尖峰蛋白的受体结合结构域（RBD）的结合 COV-2对其受体ACE2。可以阻止肺上皮上RBD和ACE2之间结合的抗体 细胞将防止病毒进入，并可能中和。目标2）确定强大的体液免疫力和 更高的中和AB滴度可保护VA医疗保健员工免受临床Covid19的影响 低或没有SAR2-COV-2特异性抗体的同事。在AIM 2中，我们将使用快速抗体测试进行筛选 Cleveland VA Health Care雇员在Covid19感染高风险（第一响应者，紧急情况） 部门工作人员，重症监护室工作人员，Covid19病房工作人员）。我们将从其中要求一个血清样品 Covid19呈阳性的AB呈阳性，以更深入地检查SARS-COV-2 AB响应。我们将检查 一般的AB滴度，中和AB滴度和抗体同种型。如果秋天有covid19的复兴， 我们将确定那些具有强大体液反应的卫生保健员工是否受到更好的保护 感染比那些反应较弱或没有AB的员工。目标3）检查 COVID19诱导的淋巴细胞减少症具有产生体液免疫反应的能力。年龄较大，sars- COV-1和SARS-COV-2感染都与白细胞或淋巴细胞减少的降低有关。在 AIM 3我们将研究淋巴细胞减少症对COVID19的体液AB反应的发展。 我们预计那些患有严重淋巴细胞减少症的人的淋巴中会有很少的T卵泡细胞 节点和这将导致AB亲和力成熟，同型切换和B细胞记忆发展。在 摘要，该项目的结果将提供能够检测到的快速SARS-COV-2特定血清测定法 中和可用于筛查VA医疗保健工人的AB，以暴露于SARS-COV-2。我们将 调查感染的高风险医疗保健员工的体液抗体反应 COVID19，并尝试确定哪种构成免受重新感染的保护 Covid19在秋天。最后，我们将了解B细胞亲和力成熟，同型切换 以及B细胞记忆的产生和中和AB滴度，并确定淋巴细胞减少症如何在 对COVID19的体液免疫功能障碍。这些知识将有助于发展更好的治疗 和未来的疫苗。