Project 2: Serologic and molecular determinants of COVID-19 severity and immune protection

项目 2：COVID-19 严重程度和免疫保护的血清学和分子决定因素

• 批准号: 10688394
• 负责人: Linda J. Saif
• 金额: $ 59.98万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-18 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10688394
• 关键词: 2019-nCoV; ACE2; Age; Animals; Antibodies; Antibody Response; Antibody-Dependent Enhancement; Binding; Biological Assay; Blood; COVID-19; COVID-19 monitoring; COVID-19 pandemic; COVID-19 severity; Child; Clinical; Common Cold; Data; Data Set; Development; Diagnostic; Disease; Disease Outcome; Elderly; Enzyme-Linked Immunosorbent Assay; Epitopes; Exposure to; Family; Frequencies; Future; General Population; Genes; Genetic; Genetic Polymorphism; Genetic Transcription; Goals; Household; Human; Immune; Immune response; Immunity; Immunoglobulin A; Immunoglobulin G; Immunoglobulin Isotypes; Immunoglobulin M; Immunologic Factors; Immunologist; Immunoprecipitation; Individual; Infection; Infection prevention; Integration Host Factors; Kinetics; Knowledge; Lead; Link; Luciferases; Measures; Mediating; Middle East Respiratory Syndrome Coronavirus; Molecular; Mucosal Immune Responses; Mucous Membrane; Mutation; Open Reading Frames; Outcome; Patients; Pattern; Peptides; Population; Prevalence; Prevention strategy; Proteins; Protocols documentation; Public Health; Reverse Transcriptase Polymerase Chain Reaction; Risk; SARS coronavirus; SARS-CoV-2 antibody; SARS-CoV-2 infection; SARS-CoV-2 pathogenesis; SARS-CoV-2 transmission; Sampling; Serology; Serology test; Serum; Severities; Severity of illness; Source; Specificity; Symptoms; Testing; Vaccinated; Vaccinee; Vaccines; Viral; Viral Proteins; Virus; betacoronavirus; career; co-infection; cohort; comorbidity; coronavirus disease; first responder; gene induction; high risk; human coronavirus; improved outcome; infection risk; innovation; insight; member; mucosal site; neutralizing antibody; novel; response; screening; seropositive; severe COVID-19; transcriptome; transcriptome sequencing; tumor-immune system interactions; vaccine-induced immunity

Project 2 Summary PROJECT 2. Serologic and molecular determinants of COVID-19 severity and immune protection. Unresolved scientific questions remain about how the type, kinetics and duration of SARS-CoV-2 serologic responses correlate with patient age, disease severity, protective immunity, and risk of spread to close contacts. Our overall goal is to utilize the well-annotated STOP-COVID data sets and longitudinal samples collected from the first-responder cohort (at high-risk for re-exposure) and family contacts (Project 1, Core B) to advance understanding of the specific host and viral factors that underlie long-lasting and protective serologic responses. Our three highly interactive aims include: to identify differences in virus neutralizing (VN) antibody isotypes and their target viral proteins/peptides/epitopes; to assess cross-protective immunity versus disease exacerbation by antibodies to common cold CoVs; and to probe, by virus-host transcriptome analysis, how SARS-CoV titer or sequence and initial immune response at mucosal sites or blood interrelate with disease outcomes and the above serologic responses. Aim 1: Define immunoglobulin isotypes, titer, target proteins and viral neutralization activity of SARS-CoV-2 specific Abs and their correlations with disease severity and protection: We will utilize VN assays (VNA) and a luciferase immunoprecipitation assay to identify VN antibody isotype specificities and their immunodominant and unique target viral proteins/peptides/epitopes relevant to disease severity and protection. Expected outcomes include data that delineate the temporal antibody isotypes and viral targets to refine protocols for serologic testing that align with protective immunity. Aim 2: Determine the impact of common cold CoVs (CCCoV) and SARS-CoV-2 specific antibodies on COVID-19 protection and disease severity in a high-exposure risk cohort of first responders and their household contacts. Diagnostic serum samples will be used in innovative ELISA platforms directed against unique and conserved CCCoV peptides, and Spike pseudotyped CCCoV to assess CCCoV antibody responses. Expected outcomes include original data on whether pre-existing CCCoV antibodies relate to COVID-19 clinical symptoms, severity or strain specificity of SARS-CoV-2 infection (Aim 3), or re-infection risk. Aim 3. Correlate patterns of mucosal and serologic immune responses with virus and host genetics. We will utilize a novel targeted host-SARS-CoV-2 RNA sequencing assay (CoV-DXVX) to assess whether virus titer or functional alterations in SARS-CoV-2 S1, S2, N proteins or other ORFs impact disease presentation, progression and outcome. Host response measured by the profile and strength of mucosal or blood immune gene induction will be correlated with the duration, type and protective ability of these serologic responses and with the ones above. Once vaccines are deployed to our first-responder cohort, all 3 aims will pivot to analyze how the above serologic response profiles and host immune gene induction differ in vaccinated SARS-CoV-2 seronegative and seropositive individuals compared with the naturally-infected individuals.

项目2总结 项目 2。COVID-19 严重程度和免疫保护的血清学和分子决定因素。 尚未解决的科学问题仍然是 SARS-CoV-2 血清学的类型、动力学和持续时间如何 反应与患者年龄、疾病严重程度、保护性免疫力和传播风险相关 联系人。我们的总体目标是利用注释良好的 STOP-COVID 数据集和纵向样本 从急救人员队列（再次暴露的高风险）和家庭接触者中收集（项目 1，核心 B） 加深对构成持久和保护性血清学基础的特定宿主和病毒因素的了解 回应。我们的三个高度互动的目标包括： 识别病毒中和 (VN) 抗体的差异 同种型及其目标病毒蛋白/肽/表位；评估针对疾病的交叉保护性免疫力 普通感冒冠状病毒抗体导致病情恶化；并通过病毒宿主转录组分析来探究如何 SARS-CoV 滴度或序列以及粘膜部位或血液的初始免疫反应与疾病相关 结果和上述血清学反应。目标 1：定义免疫球蛋白同种型、滴度、靶蛋白和 SARS-CoV-2 特异性抗体的病毒中和活​​性及其与疾病严重程度和感染的相关性 保护：我们将利用 VN 测定 (VNA) 和荧光素酶免疫沉淀测定来鉴定 VN 抗体 同种型特异性及其免疫显性和独特的目标病毒蛋白/肽/表位相关 疾病的严重程度和保护。预期结果包括描述时间抗体同种型的数据 和病毒目标，以完善与保护性免疫相一致的血清学检测方案。目标 2：确定 普通感冒 CoV (CCCoV) 和 SARS-CoV-2 特异性抗体对 COVID-19 保护的影响和 由急救人员及其家庭接触者组成的高暴露风险人群中疾病的严重程度。诊断 血清样本将用于针对独特且保守的 CCCoV 的创新 ELISA 平台 肽，以及 Spike 假型 CCCoV 来评估 CCCoV 抗体反应。预期成果包括 关于先前存在的 CCCoV 抗体是否与 COVID-19 临床症状、严重程度或相关性相关的原始数据 SARS-CoV-2 感染的毒株特异性（目标 3）或再次感染风险。目标 3. 关联粘膜和 病毒和宿主遗传学的血清免疫反应。我们将利用一种新型靶向宿主——SARS-CoV-2 RNA 测序测定 (CoV-DXVX) 用于评估 SARS-CoV-2 S1 中的病毒滴度或功能是否发生变化， S2、N 蛋白或其他 ORF 影响疾病的表现、进展和结果。主持人回应 通过粘膜或血液免疫基因诱导的概况和强度测量将与 这些血清学反应以及上述血清学反应的持续时间、类型和保护能力。一旦疫苗被 部署到我们的急救人员队列中，所有 3 个目标都将重点分析上述血清学反应如何 已接种疫苗的 SARS-CoV-2 血清阴性和血清阳性的概况和宿主免疫基因诱导有所不同 个体与自然感染个体的比较。