Project 2: Characterizing humoral responses to SARS-CoV-2, and the immunological and biological effects of plasma therapy for severe Covid-19

项目 2：表征对 SARS-CoV-2 的体液反应，以及血浆疗法对严重 Covid-19 的免疫学和生物学效应

• 批准号: 10222245
• 负责人: Luther A Bartelt
• 金额: $ 72.71万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10222245
• 关键词: 2019-nCoV; Acute; Address; Adult Respiratory Distress Syndrome; Animal Model; Antibodies; Antigen-Antibody Complex; Antigens; Antiviral Agents; Applied Research; Automobile Driving; B-Lymphocyte Subsets; Basic Science; Binding; Biological; Biological Assay; Blood; Blood Coagulation Disorders; COVID-19; Cessation of life; Clinical; Collaborations; Collection; Data; Databases; Development; Disease; Disease Outbreaks; Drug or chemical Tissue Distribution; Enrollment; Epidemic; Ferritin; Fibrin fragment D; Frequencies; Funding; Human; Illness Days; Immune; Immune response; Immunoglobulin A; Immunoglobulin G; Immunoglobulin M; Immunologic Markers; Immunologics; Individual; Infection; Inflammation; Inflammatory; Infrastructure; Infusion procedures; Institution; Interruption; Kinetics; Libraries; Light; Link; Measures; Memory B-Lymphocyte; Molecular; Mucous Membrane; Mus; North Carolina; Outcome; Participant; Passive Immunotherapy; Pathogenesis; Patients; Phase; Plasma; Plasma Cells; Pneumonia; Property; Proteins; Randomized; Recombinants; Recovery; Research; Research Personnel; Resolution; SARS coronavirus; Sampling; Serologic tests; Serological; Serum; Severity of illness; Site; Specificity; Specimen; Speed; Syndrome; System; Testing; Therapeutic; Therapeutic Studies; Tissues; Unit of Measure; Viral; Viral Respiratory Tract Infection; Virus; Virus Replication; attenuation; base; biobank; cohort; cytokine; demographics; immune activation; immunoregulation; inflammatory marker; innovation; investigator-initiated trial; metabolomics; mortality; mouse model; mucosal site; neutralizing antibody; novel; pandemic disease; pathogen; plasma cell development; polyclonal antibody; prevent; receptor binding; repository; response; technology development; trafficking; translational model; treatment program; virology

Abstract This SeroNet Center of Excellence in SARS-CoV2 basic and applied research will use human clinical samples and small animal models to illuminate the molecular mechanisms driving serological and humoral immune responses to this pandemic pathogen. Here we outline Project 2, which will investigate the influence of polyclonal antibodies present in convalescent plasma on the virologic and immunobiological outcomes, and immune responses in patients treated with convalescent plasma for severe SARS-CoV-2 infection, the agent of Covid-19. This project leverages the robust infrastructure for collection and infusion of CCP as therapy at our institution. Serum and mucosal samples collected from CCP donors and CCP recipients provide a comprehensive and longitudinal biorepository to examine the fundamental immunobiological properties of antibodies in CCP. Samples are provided by participants enrolled in an integrated but separately funded, investigator-initiated trial of convalescent plasma therapy at our institution. Project 2, Aim 1 will provide an in-depth analysis that addresses whether neutralizing and/or non-neutralizing antibodies in CCP accelerate viral clearance and resolve inflammation in blood and mucosal compartments. CCP containing different concentrations of neutralizing antibodies will also be tested in a novel translational model of SARS-CoV-2 mouse challenge with Project 1. In Project 2 Aim 2, we will employ novel recombinant antigen development technologies and systems serology (Core B) and Ig seq (Core C) to define the isotype-specific properties of antibodies in donor CCP units, and measure the trafficking of these antibodies in CCP recipients. Project 2 Aim 3 will longitudinally follow CCP recipients to evaluate the influence of CCP therapy on de novo development of long lived plasma blasts and memory B cells. This project contributes critically to Project 1 in the serocenter by the provision of a robust clinical-immunobiological repository of CCP donors and recipients. Interactions with Project 3 allow for comparisons between these cohorts and other observational cohorts of patients with SARS-CoV-2 infection who did not receive CCP. Facilitated by Core A, Cores B and C provide innovative assays necessary to address long-standing questions regarding differential antiviral and immunomodulatory properties of specific antibodies in convalescent plasma. The virological and immunobiological data generated in this proposal can be linked to a granular database of individual demographics and clinical variables in patients with SARS-CoV-2 infection. The integration of this Project within the serocenter, and the potential to link biological observations to clinical outcomes in our parallel, randomized therapeutic study in which hospitalized COVID- 19 patients receive either standard or high-neutralizing titer CCP, will allow this Project to contribute substantially to the understanding of the immune response to SARS-CoV2.

摘要 这个SARS-CoV 2基础和应用研究的SeroNet卓越中心将使用人类临床样本和小 动物模型来阐明驱动血清学和体液免疫应答的分子机制 流行病病原体。在这里，我们概述了项目2，这将调查的影响，多克隆抗体存在于 恢复期血浆对病毒学和免疫生物学结果以及用 严重SARS-CoV-2感染的恢复期血浆，Covid-19的病原体。该项目利用了强大的 收集和输注CCP作为我们机构治疗的基础设施。血清和粘膜样本采集自 CCP捐赠者和CCP接受者提供了一个全面的纵向生物储存库，以检查基本的 CCP中抗体的免疫生物学特性。样本由参加综合但 在我们机构进行的单独资助的、由麻醉师发起的恢复期血浆治疗试验。项目2，目标1将 提供深入分析，解决CCP中的中和和/或非中和抗体是否加速了 病毒清除和解决血液和粘膜区室中的炎症。不同浓度CCP 中和抗体也将在SARS-CoV-2小鼠攻击的新翻译模型中进行测试， 1.在项目2目标2中，我们将采用新的重组抗原开发技术和系统血清学（核心 B）和IG seq（核心C）来定义供体CCP单位中抗体的同种型特异性性质，并测量供体CCP单位中抗体的同种型特异性。 这些抗体在CCP接受者中的运输。项目2目标3将纵向跟踪CCP接受者， CCP治疗对长寿命血浆母细胞和记忆B细胞从头发育影响这个项目 通过提供一个强大的临床免疫生物学储存库， CCP捐助者和受援者。通过与项目3的互动，可以将这些群组与其他群组进行比较。 未接受CCP的SARS-CoV-2感染患者的观察队列。由核心A、核心B 和C提供了必要的创新检测方法，以解决长期存在的问题， 恢复期血浆中特异性抗体的免疫调节特性。病毒学和免疫生物学数据 该提案中生成的数据可以链接到个人人口统计和临床变量的粒度数据库， SARS-CoV-2感染者。该项目在血清中心的整合，以及与 在我们的平行、随机治疗研究中， 19名患者接受标准或高中和滴度CCP，将使该项目能够为 了解对SARS-CoV 2的免疫反应。