Adaptive Immunity and Persistent SARS-CoV-2 Replication

适应性免疫和持续 SARS-CoV-2 复制

基本信息

批准号：
10854996
负责人：
Suresh B Boppana
金额：
$ 151.21万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-22 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10854996
关键词：
2019-nCoV Animal Model Antibody Response CD8-Positive T-Lymphocytes COVID-19 patient COVID-19 severity Cessation of life Chemotherapy-Oncologic Procedure Child China Chronic Clinical Consensus Coronavirus Coupled Data Development Disease Generations Genetic Variation Goals Hematological Disease Herd Immunity Immune Immune response Immunity Immunocompetence Individual Infection Maintenance Malignant Neoplasms Middle East Respiratory Syndrome Natural History Nature Outcome Patient-Focused Outcomes Patients Pattern Play Population Predisposition Preventive vaccine Recovery Research Personnel Resistance Resolution Role SARS coronavirus SARS-CoV-2 antibody SARS-CoV-2 immunity SARS-CoV-2 infection SARS-CoV-2 infection history SARS-CoV-2 variant Secondary to Serology test Severe Acute Respiratory Syndrome Severity of illness Sickle Cell Anemia Stratification Suggestion Symptoms System T cell response Testing Therapeutic Monoclonal Antibodies Time Translating Upper respiratory tract Vaccines Variant Viral Viral Antibodies Virus Virus Replication Virus Shedding acute infection adaptive immune response adaptive immunity chemotherapy clinical phenotype cohort convalescent plasma defined contribution human monoclonal antibodies improved in vivo insight microbial novel novel coronavirus optimism pandemic disease passive immunoprophylaxis patient population patient subsets prevent response study population unvaccinated vaccine candidate vaccine development

项目摘要

Project Summary/Abstract The pandemic caused by the novel coronavirus, SARS-CoV-2 (SARS2) has so far infected greater than 3.5 million individuals and resulted in >138,000 deaths in the US. Although it has been suggested that adaptive immunity plays an important role in improving clinical outcomes of patients infected with SARS2, protective immune responses have not been specifically defined. Also, the variability in clinical disease and outcome in patients with SARS2 infection has not been explained based on qualitative and quantitative antiviral immune responses. Interestingly, a significant proportion of children with presumed deficits in immune competence secondary to cancer chemotherapy and hematologic disorders have been observed to shed virus from the upper respiratory tract for prolonged periods of time (>4 weeks), even after complete resolution of clinical symptoms. This finding raises the possibility that specific qualitative or quantitative deficits in adaptive immune responses in some individuals can result in incomplete control of virus replication and prolonged virus shedding. Therefore, an understanding of the immune responses that lead to control of virus shedding could help define correlates of protective immunity and perhaps more importantly, determine the potential value of vaccines to limit spread of SARS2 to unvaccinated populations. The major goal of our studies is to quantify adaptive immune responses to SARS2 in a cohort of children with varying levels immune responsiveness and to relate these responses to the control of virus shedding in the upper respiratory tract, thus allowing stratification immune reactivity and control of virus replication. Defining relationships between variations in immune competence and virus shedding could provide novel insight into the level and nature of adaptive immunity, more specifically antiviral antibodies, that can restrict or eliminate viral shedding in SARS2 infected patients. Our studies will also identify SARS2 variants that arise during poorly controlled virus replication in these patients as prolonged virus replication coupled with ineffective immunity offers an ideal opportunity for the generation of viral variants. Analysis of these variants in terms of the quality and quantity of SARS2 antibody responses will help elucidate the role of SARS2 sequence variation and persistent virus replication as a mechanism for prolonged virus replication. Together, these studies will test our hypothesis that variations in immune responsiveness contribute to prolonged viral replication and shedding.

项目摘要/摘要由新型冠状病毒引起的大流行，SARS-COV-2（SARS2）到目前为止感染了大于 350万个人，在美国导致> 138,000人死亡。虽然有人建议自适应免疫在改善感染患者的临床结局中起着重要作用 SARS2，尚未明确定义保护性免疫反应。另外，临床变异性 SARS2感染患者的疾病和结局尚未根据定性和定量抗病毒免疫反应。有趣的是，有相当一部分的孩子继发于癌症化学疗法和血液学疾病的免疫能力缺陷具有被观察到从上呼吸道散发病毒长时间（> 4周），即使完全解决临床症状。这一发现提高了特定的可能性某些个体的自适应免疫反应中的定性或定量缺陷可能会导致对病毒复制和长期病毒脱落的不完全控制。因此，了解导致控制病毒脱落的免疫反应可以帮助定义保护性的相关性免疫，也许更重要的是，确定疫苗限制传播的潜在价值 SARS2到未接种的人群。我们研究的主要目标是量化适应性免疫对具有不同水平的免疫反应性的儿童队列中对SARS2的反应这些对上呼吸道中病毒脱落的控制的反应，从而允许分层免疫反应性和病毒复制的控制。定义免疫变化之间的关系能力和病毒脱落可以为适应性的水平和性质提供新颖的见解免疫力，更具体地说是抗病毒抗体，可以限制或消除SARS2的病毒脱落感染的患者。我们的研究还将确定在控制不良的病毒期间出现的SARS2变体这些患者的复制是长时间的病毒复制，加上无效的免疫力提供了生成病毒变体的理想机会。根据质量和 SARS2抗体反应的数量将有助于阐明SARS2序列变化的作用和持续的病毒复制是长期病毒复制的机制。这些研究将在一起测试我们的假设，即免疫反应性的变化有助于长期的病毒复制和脱落。