COVID19: Anti-SARS-CoV-2 Antibodies and Infection Severity

COVID19：抗 SARS-CoV-2 抗体和感染严重程度

• 批准号: 10152299
• 负责人: KENNETH M KAUFMAN
• 金额: --
• 依托单位: CINCINNATI VA MEDICAL CENTER RESEARCH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10152299
• 关键词: 2019-nCoV; Amino Acids; Antibodies; Antibody Response; Antibody Specificity; Antigenic Specificity; Antigens; Asphyxia; B-Lymphocyte Epitopes; Behavior; Biological Assay; Breathing; COVID-19; COVID-19 mortality; COVID-19 pandemic; Cessation of life; Characteristics; Clinical; Contracts; Coronavirus; Dangerousness; Development; Diagnostic tests; Disease; Disease Outcome; Disease model; Donor Selection; Enzyme-Linked Immunosorbent Assay; Epidemiology; Epitope spreading; Epitopes; Formulation; Functional disorder; Healthcare Systems; Human; Human Herpesvirus 4; Immune response; Individual; Infection; Infectious Agent; Inflammatory Response; Knowledge; Ku70 protein; Learning; Libraries; Lung diseases; Lupus; Maps; Mediating; Middle East Respiratory Syndrome; Minor; Morbidity - disease rate; Occupations; Outcome; Passive Immunotherapy; Pathogenicity; Patient Care; Patients; Peptides; Phage Display; Phase; Plasma; Polyethylenes; Population; Property; Proteins; Public Health; Reagent; Recombinant Proteins; Research Personnel; Resolution; Risk; SARS coronavirus; SARS-CoV-2 antibody; SARS-CoV-2 antigen; SARS-CoV-2 infection; Scourge; Severe Acute Respiratory Syndrome; Severities; Severity of illness; Solid; Source; Specificity; Structure; Techniques; Testing; Therapeutic; Time; Vaccination; Vaccine Design; Veterans; Virus; Western Blotting; Work; base; biosafety level 3 facility; comorbidity; experience; experimental study; glycosylation; lung injury; military veteran; older men; pandemic disease; prevent; theories; therapy design; vaccine response; 2019-nCoV; Amino Acids; Antibodies; Antibody Response; Antibody Specificity; Antigenic Specificity; Antigens; Asphyxia; B-Lymphocyte Epitopes; Behavior; Biological Assay; Breathing; COVID-19; COVID-19 mortality; COVID-19 pandemic; Cessation of life; Characteristics; Clinical; Contracts; Coronavirus; Dangerousness; Development; Diagnostic tests; Disease; Disease Outcome; Disease model; Donor Selection; Enzyme-Linked Immunosorbent Assay; Epidemiology; Epitope spreading; Epitopes; Formulation; Functional disorder; Healthcare Systems; Human; Human Herpesvirus 4; Immune response; Individual; Infection; Infectious Agent; Inflammatory Response; Knowledge; Ku70 protein; Learning; Libraries; Lung diseases; Lupus; Maps; Mediating; Middle East Respiratory Syndrome; Minor; Morbidity - disease rate; Occupations; Outcome; Passive Immunotherapy; Pathogenicity; Patient Care; Patients; Peptides; Phage Display; Phase; Plasma; Polyethylenes; Population; Property; Proteins; Public Health; Reagent; Recombinant Proteins; Research Personnel; Resolution; Risk; SARS coronavirus; SARS-CoV-2 antibody; SARS-CoV-2 antigen; SARS-CoV-2 infection; Scourge; Severe Acute Respiratory Syndrome; Severities; Severity of illness; Solid; Source; Specificity; Structure; Techniques; Testing; Therapeutic; Time; Vaccination; Vaccine Design; Veterans; Virus; Western Blotting; Work; base; biosafety level 3 facility; comorbidity; experience; experimental study; glycosylation; lung injury; military veteran; older men; pandemic disease; prevent; theories; therapy design; vaccine response

The new Covid-19 virus is deadly for 0.2% to 4% of people infected, with older men the most severely afflicted with this scourge, being mortal to ~15% of those infected over 80 years, making the US Veteran population especially vulnerable. It is critically important to understand the mechanisms of this lethal pathophysiology in order to design interventions that will save lives. MERS, SARS-CoV, and now the new human Covid-19 mean that three coronaviruses have threatened to become horrific public health problems for the entire world; this last and most recent one, Covid-19, has succeeded. Some of the antibodies formed against this virus appear to accentuate the clinical severity of disease, possibly making the specific details of the immune response responsible for the demise of many infected patients. We have had more than two decades of experience as VA Merit supported investigators exploring the antigenic structure of the lupus autoantigens, leading us to the theory that Epstein-Barr virus causes lupus, which is a hypothesis now supported by convincing circumstantial evidence. We propose to apply our experience to exploring the details of the fine antigenic specificity of the anti-Covid-19 antibody response in order to understand what specific antibodies are dangerous. We propose to explore two hypotheses: Hypothesis 1. Specific and detailed knowledge of antibody immune responses to Covid-19 will be useful for elucidating pathogenic mechanisms, predicting disease severity, designing vaccines, selecting therapeutic plasmas, making patient care decisions, informing population epidemiology, determining infection dynamics, and choosing individual behaviors in the face of the Covid-19 pandemic. Hypothesis 2. Anti-Covid-19 antibody fine antigenic specificity will correlate with clinical manifestations and infection severity. We propose two aims: Aim 1. Develop and apply assays to dissect the antigenic fine specificity of antibodies forming against shared and sub-strain specific Covid-19 antigens in the natural human Covid-19 infection. Aim 2. Isolate and purify anti-Covid-19 antibodies against the major epitopes and any specific antibodies that are associated with severe pulmonary disease. We will use Western blotting, solid phase assays (ELISAs), phage display libraries expressing 30-mer amino acid peptides, and synthesized overlapping fmoc peptides to fully characterize the fine specificity antibody response to the Covid-19 virus. We will obtain plasma and serum from Veterans and others which we will evaluate for correlates with clinical outcome. We will isolate individual specificities and characterize their properties with respect to type, isotype, glycosylation, and activity. We will perform pseudotype assays on whole repertoires and individual antibody specificities in BSL2 and test for confirmation with neutralization with collaborators with BSL3 facilities. From these studies we hope to learn how to identify Veterans who are likely to have a more severe illness and provide clues for developing approaches that could succeed in ameliorating infection severity and prevent severe disease.

新的Covid-19病毒是致命的，其中0.2％至4％被感染的人，年龄较大的男人受到最严重折磨 有了这次祸害，造成了80年来感染的人中约有15％，使美国退伍军人人口成为 特别脆弱。了解这种致命病理生理学的机制至关重要 为了设计可以挽救生命的干预措施。 MERS，SARS-COV，以及现在的新人类Covid-19 三个冠状病毒威胁要成为全世界的可怕公共健康问题。这 最后一个也是最近一个，即Covid-19，已经成功了。 针对该病毒形成的一些抗体似乎突显了疾病的临床严重程度，可能 使免疫反应的具体细节负责许多受感染患者的灭亡。我们 由于VA功绩支持探索抗原的研究人员，经验有二十年多的经验 狼疮自动抗原的结构，导致我们得出这样的理论，即爱泼斯坦 - 巴尔病毒会导致狼疮，这是一种 现在，有令人信服的间接证据支持假设。我们建议将我们的经验应用于 探索抗COVID-19抗体反应的细细节，以便 了解哪些特定抗体是危险的。我们建议探讨两个假设： 假设1。对抗体免疫反应的特定和详细知识将是COVID-19将是 用于阐明致病机制，预测疾病严重程度，设计疫苗， 选择治疗性等离子体，做出患者护理决定，告知人口流行病学， 确定感染动态，并在Covid-19中选择个体行为 大流行。 假设2。抗covid-19抗体细胞特异性将与临床相关 表现和感染严重程度。 我们提出了两个目标： 目标1。开发和应用测定法，以剖析形成共同形成的抗体的抗原精细特异性 自然人类共卷19感染中的特定于19抗原的特异性covid-19抗原。 AIM 2。分离并纯化抗COVID-19的抗体，针对主要表位和任何特定抗体 与严重的肺部疾病有关。 我们将使用蛋白质印迹，固相测定（ELISA），表达30-mer氨基的噬菌体展示库 酸性肽，并合成重叠的FMOC肽，以完全表征精细的特异性抗体 对COVID-19病毒的反应。我们将从退伍军人和其他人那里获得血浆和血清 评估与临床结果相关。我们将隔离个人特异性并描述他们的特殊性 关于类型，同种型，糖基化和活性的特性。我们将在 BSL2中的全部库和个体抗体特异性，并测试确认并用中和 与BSL3设施的合作者。从这些研究中，我们希望学习如何识别可能有可能的退伍军人 患有更严重的疾病，并为开发可以成功改善的方法提供线索 感染严重程度并预防严重疾病。