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

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.

新型冠状病毒对0.2%至4%的感染者是致命的，老年男性受影响最严重