Evaluating Clinical and Immunological Consequences of SARS-CoV-2 Vaccination in Rheumatic Disease

评估风湿性疾病中 SARS-CoV-2 疫苗接种的临床和免疫学后果

基本信息

批准号：
10532784
负责人：
DANA P ASCHERMAN
金额：
$ 20.99万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-12-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10532784
关键词：
2019-nCoV Address Antibodies Antigens Antiviral Response Autoantibodies Autoimmune Autoimmune Diseases Autoimmune Responses Autoimmunity COVID-19 pandemic COVID-19 vaccination COVID-19 vaccine Cessation of life Clinical Coupled Data Data Management Resources Database Management Systems Databases Detection Development Disease Disease susceptibility Feedback Generations Idiopathic Inflammatory Myopathies Immune Immune response Immune system Immunization Programs Immunologics Immunoprecipitation Infection Infrastructure Innate Immune Response Knowledge Link Literature Longitudinal cohort Measures Methods Modeling Molecular Mimicry Morbidity - disease rate Observational Study Online Systems Organ Outcome Measure Patient Outcomes Assessments Patients Peptides Pharmaceutical Preparations Physicians Population Control Positioning Attribute Price Prospective cohort Proteins Questionnaires Resources Rheumatism Rheumatoid Arthritis Risk SARS-CoV-2 infection SARS-CoV-2 spike protein Sampling Sequence Homology Serology Serum Sjogren&apos s Syndrome Specimen Statistical Models System Systemic Scleroderma Techniques Technology Testing Therapeutic immunosuppression Time Tissues Universities Vaccinated Vaccination Vaccine Design Vaccines Viral Viral Proteins Viral Vaccines Work adaptive immune response anti-tumor immune response autoinflammatory autoreactivity biobank biomarker development cohort cross reactivity cytokine release syndrome data integration design digital assessment digital platform disorder risk experience gel electrophoresis immune activation insight mortality novel patient population radiotracer response side effect stem vaccine delivery vaccine development vaccine efficacy vaccine response vaccine trial

项目摘要

The current SARS-CoV-2 pandemic has had devastating consequences, with more than 110,000,000 cases and 2,400,000 deaths worldwide. Beyond the direct effects of SARS-CoV-2 infection, much of the morbidity and mortality stems from dysregulated activation of the immune system that culminates in systemic manifestations ranging from cytokine storm to autoimmunity. Recent work suggests that the basis for observed autoimmune complications of SARS-CoV-2 infection resides in the high degree of sequence overlap between viral proteins and native tissue antigens. Given this sequence overlap and the potential for molecular mimicry/induction of autoimmunity in the setting of SARS-CoV-2 infection, there is concern that vaccines geared towards the generation of protective immune responses against the SARS-CoV-2 spike protein may increase the risk of autoreactivity—particularly in patients with pre-existing autoimmune disease and associated immune dysregulation. Because patients with underlying autoimmune diseases such as idiopathic inflammatory myopathy, systemic sclerosis, rheumatoid arthritis, and primary Sjogren’s syndrome were not included in the original trials of vaccines targeting the SARS-CoV-2 spike protein, there is a clear unmet need to better understand the consequences of SARS-CoV-2 vaccination in these patient populations—both in terms of vaccine response as well as the potential for disease exacerbation/development of de novo autoimmune manifestations. Coupled with our well-established, longitudinal rheumatic disease database/biorepository that includes an integrated data management system (RDMS=Rheumatic Disease Data Management System), our experience with the use of remote digital platforms and assessment of patient reported outcomes (PROs) makes us uniquely positioned to conduct successful observational studies of vaccine-induced clinical/immunological responses. To evaluate the relationship between changes in clinical disease activity and vaccine-induced autoreactivity, we have 3 specific aims. In Specific Aim 1, we will use general as well as disease-specific PROs at defined time points pre- and post-vaccination to assess changes in disease activity over a 12 month period—and compare these changes to pre-vaccination fluctuations in disease activity over a parallel time frame. In Specific Aim 2, we will apply novel, radiolabel-free methods of immunoprecipitation and Difference in Gel Electrophoresis to assess corresponding serum samples collected at pre- and post-vaccination time points and define vaccine- induced shifts in autoantibody profile as well as the development of anti-spike protein antibodies. In Specific Aim 3, we will use different statistical models to evaluate the relationship between these antibody profiles and changes in clinical disease activity/de novo autoimmune manifestations. Successful completion of these aims will directly address the existing knowledge gap surrounding vaccine responses in understudied rheumatic disease patient populations and establish a clinical cohort/biorepository that will serve as an unparalleled resource for biomarker development as well as future research in vaccine-associated immune alterations.

当前的 SARS-CoV-2 大流行造成了毁灭性后果，病例数超过 1.1 亿，除了 SARS-CoV-2 感染的直接影响之外，全球还有 2,400,000 人死亡。死亡源于免疫系统激活失调，最终导致全身表现从细胞因子风暴到自身免疫，最近的工作表明观察到的自身免疫的基础。 SARS-CoV-2 感染的并发症在于病毒蛋白之间的高度序列重叠考虑到这种序列重叠和分子模拟/诱导的潜力。 SARS-CoV-2 感染情况下的自身免疫，人们担心疫苗针对的是针对 SARS-CoV-2 刺突蛋白的保护性免疫反应的产生可能会增加感染的风险自身反应性——特别是在患有自身免疫性疾病和相关免疫的患者中因为患有潜在自身免疫性疾病（例如特发性炎症）的患者。肌病、系统性硬化症、类风湿性关节炎和原发性干燥综合征不包括在其中针对 SARS-CoV-2 刺突蛋白的疫苗的最初试验，显然存在一个未满足的需求：了解 SARS-CoV-2 疫苗接种对这些患者群体的影响——无论是在疫苗方面反应以及疾病恶化/新发自身免疫表现的可能性。再加上我们完善的纵向风湿病数据库/生物存储库，其中包括综合数据管理系统（RDMS=风湿病数据管理系统），我们的经验通过使用远程数字平台和对患者报告结果 (PRO) 的评估，使我们独一无二定位于对疫苗诱导的临床/免疫学反应进行成功的观察研究。评估临床疾病活动性变化与疫苗诱导的自身反应性之间的关系，我们有 3 个具体目标在具体目标 1 中，我们将在规定的时间使用一般和特定疾病的 PRO。接种疫苗前和接种后的点，以评估 12 个月内疾病活动的变化，并进行比较在特定目标 2 中，疫苗接种前疾病活动波动的这些变化。我们将应用新型、无放射性标记的免疫沉淀方法和凝胶电泳差异法来评估在疫苗接种前和疫苗接种后时间点收集的相应血清样本并定义疫苗- 诱导自身抗体谱的变化以及特定的抗刺突蛋白抗体的发展。目标3，我们将使用不同的统计模型来评估这些抗体谱与临床疾病活动/新的自身免疫表现的变化成功完成这些目标。将直接解决围绕风湿病疫苗反应的现有知识差距疾病患者群体并建立一个临床队列/生物样本库，作为无与伦比的生物标志物开发以及疫苗相关免疫改变的未来研究的资源。