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.

目前的SARS-COV-2大流行带来了毁灭性后果，有超过110万例全球2,400,000人死亡。超越SARS-COV-2感染的直接影响，大部分发病率和死亡率源于免疫系统的失调激活，最终导致全身表现从细胞因子风暴到自身免疫性。最近的工作表明，观察到的自身免疫性的基础 SARS-COV-2感染的并发症属于病毒蛋白之间的高度序列重叠和天然组织抗原。鉴于此序列重叠，并且具有分子模仿/诱导的潜力在SARS-COV-2感染的环境中，自身免疫性担心疫苗针对对SARS-COV-2峰值蛋白的受保护免疫反应产生可能会增加自动反应性 - 尤其是患有自身免疫性疾病和相关免疫的患者失调。因为基础自身免疫性疾病（例如特发性炎症）患者肌病，系统性硬化症，类风湿关节炎和原发性Sjogren综合征不包括在针对SARS-COV-2尖峰蛋白的疫苗的原始试验，明确的未满足需要更好了解这些患者种群中SARS-COV-2疫苗的后果 - 在疫苗方面反应以及疾病加剧/从头自身免疫性表现的潜力。再加上我们公认的，纵向风湿病数据库/生物措施，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并评估患者报告的结果（PRO）使我们唯一地定位进行疫苗诱导的临床/免疫反应的成功观察性研究。到评估临床疾病活动变化与疫苗诱导的自动反应性之间的关系，我们具有3个具体目标。在特定目标1中，我们将在定义的时间使用一般和特定疾病的专业人士疫苗发生前后的点，以评估12个月内疾病活动的变化，并比较在平行时间范围内，疾病活动前疫苗发生前的波动的这些变化。在特定的目标2中，我们将采用新型的，无辐射标记的免疫沉淀和凝胶电泳差异的方法评估在疫苗发生前和疫苗后时间收集的相应血清样品，并定义疫苗诱导的自身抗体谱的变化以及抗尖峰蛋白抗体的发展。具体 AIM 3，我们将使用不同的统计模型来评估这些抗体曲线和临床疾病活性的变化/自身免疫性表现。这些目标成功完成将直接解决围绕疫苗反应的现有知识差距疾病患者人群并建立临床队列/生物座席，该临床人群将无与伦比生物标志物发展的资源以及与疫苗相关免疫反应的未来研究。