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: 10371080
• 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 2024-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10371080
• 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; Persons; 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.

新的新冠肺炎病毒对0.2%到4%的感染者是致命的，老年男性受到的影响最严重 随着这一祸害的出现，80年来约15%的感染者死亡，使美国退伍军人人口 特别脆弱。了解这种致命的病理生理学机制是至关重要的。 以设计能够拯救生命的干预措施。MERS，SARS冠状病毒，现在新的人类新冠肺炎意味着 三种冠状病毒有可能成为全世界可怕的公共卫生问题，这 上一家，也是最近一家，新冠肺炎取得了成功。 一些针对这种病毒形成的抗体似乎加重了疾病的临床严重性，可能 免疫反应的具体细节导致了许多感染患者的死亡。我们 已经有20多年的经验，因为VA Merit支持研究人员探索抗原 狼疮自身抗原的结构，使我们得出了爱泼斯坦-巴尔病毒引起狼疮的理论，这是一种 现在有令人信服的间接证据支持这一假设。我们建议将我们的经验应用于 探索抗新冠肺炎抗体反应良好的抗原性的细节，以便 了解哪些特定抗体是危险的。我们建议探索两个假设： 假设1.对新冠肺炎的抗体免疫反应的具体和详细了解将是 有助于阐明致病机制，预测疾病严重程度，设计疫苗， 选择治疗性血浆，做出病人护理决定，告知人群流行病学， 确定感染动态，面对新冠肺炎选择个人行为 大流行。 假设2.抗新冠肺炎抗体良好的抗原特异性将与临床相关 临床表现和感染严重程度。 我们提出两个目标： 目的1.建立和应用分析形成抗Shared抗体的抗原性精细特异性的方法 并在自然感染新冠肺炎的人中亚株特异性新冠肺炎抗原。 目的2.分离和纯化抗新冠肺炎主要表位的抗体和 与严重的肺部疾病有关。 我们将使用Western blotting、固相分析(ELISA)、表达30聚体氨基酸的噬菌体展示文库 酸性多肽，并合成重叠的Fmoc多肽，以充分表征良好的特异性抗体 对新冠肺炎病毒的回应。我们将从退伍军人和其他人那里获得血浆和血清 评估与临床结果的相关性。我们将分离出个体的特殊性并描述它们的特征 与类型、同种类型、糖基化和活性有关的性质。我们将进行假型检测 BSL2的全部谱系和单个抗体的特异性，并与中和试验确认 拥有BSL3设施的协作者。从这些研究中，我们希望了解如何识别可能是 患有更严重的疾病，并为开发能够成功改善的方法提供线索 严重感染，预防严重疾病。