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

• 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
• 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' 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

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大流行已经造成了毁灭性的后果，有超过1.1亿病例和 全球有240万人死亡。除了SARS-CoV-2感染的直接影响外，许多发病率和 死亡源于免疫系统的异常激活，最终导致全身症状。 从细胞因子风暴到自身免疫。最近的研究表明，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高度重叠的序列 和天然组织抗原。鉴于这种序列重叠和分子模拟/诱导的可能性 自身免疫在SARS-CoV-2感染的背景下，人们担心针对 产生针对SARS-CoV-2刺突蛋白的保护性免疫反应可能会增加 自身反应性--特别是在既有自身免疫性疾病和相关免疫的患者中 监管失调。因为患有自身免疫性疾病的患者，如特发性炎症性疾病 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 针对SARS-CoV-2刺突蛋白的疫苗的原始试验，显然存在着更好的未得到满足的需求 了解在这些患者群体中接种SARS-CoV-2疫苗的后果--在疫苗方面 反应以及疾病恶化/新出现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评估患者报告结果(PRO)，使我们独一无二 定位于对疫苗引起的临床/免疫反应进行成功的观察性研究。至 评价临床疾病活动性的变化与疫苗诱导的自身反应性之间的关系 有三个明确的目标。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专业技能 在接种疫苗前和接种后评估12个月内疾病活跃度的变化，并比较 这些变化与疫苗接种前疾病活动在平行时间范围内的波动有关。在具体目标2中， 我们将应用新的、无放射性标记的免疫沉淀和凝胶差异电泳方法来 评估在接种疫苗前和接种后的时间点收集的相应血清样本，并确定疫苗- 引起自身抗体谱的改变以及抗刺蛋白抗体的发展。具体而言 目的3，我们将使用不同的统计模型来评估这些抗体谱与 临床疾病活动性/从头开始自身免疫表现的变化。圆满完成这些目标 将直接解决围绕未被研究的风湿性疾病疫苗反应的现有知识差距 疾病患者群体并建立临床队列/生物信息库，这将成为无与伦比的 生物标记物开发以及疫苗相关免疫改变未来研究的资源。