Progesterone induced immune modulation during pregnancy – supplemental research in COVID-19

项目摘要：尽管新型冠状病毒COVID-19大流行，但知识差距仍然很大 特别是对于疾病控制中心指定的高危人群，如孕妇。的 具有高度临床重要性的是孕妇对感染的易感性、对母亲的直接风险以及 疾病严重程度（包括早产和胎儿死亡）对妊娠的间接影响。虽然大部分 从转化研究到COVID-19的干预试验，正在进行研究，孕妇 几乎普遍被排除在干预和观察性试验之外。对孕妇的研究 最高优先级了解哪些孕妇有严重COVID-19疾病风险的能力，周 即使不是在临床诊断前几个月，也可以为预防性治疗提供新的重要窗口。 采取干预措施，限制孕产妇发病率和死亡率。此外，如果临床数据显示，大多数 与其他呼吸道病毒相比，孕妇实际上可能对SARS-CoV-2更耐受， 了解妊娠期的免疫学变化可能有助于了解调节疾病的方法。 未怀孕人群的风险。为了解决所有这些知识差距， 需要COVID-19高流行地区的生物标本和详细的表型分析。既定 为前瞻性分析设计的两个活跃产妇队列的调查小组和研究基础设施 现在可以利用妊娠期间母体免疫力（R 01-A1145840）研究深部免疫 在获得COVID-19之前对孕妇进行表型分析。我们将能够研究 免疫表型预测孕妇COVID-19感染补充现有的专门知识， 本研究增加了母体RO 1的免疫学和病毒学专业知识， 宾夕法尼亚大学。我们建议调查以下三个科学上重要的目标：1）是否 母体免疫特征与孕妇COVID 19的获得和严重程度相关; 2） 活动性COVID 19孕妇的免疫特征是否与非孕妇相似 疾病严重程度和3）妊娠第二个三个月的免疫状况是否与不良反应相关 生殖结果。所有入组的女性都将收集大量元数据，并对COIVD进行裁定- 19产科结局的状态和严重程度以及详细的临床表型。深度免疫 表型分析将提供创新和严格的调查先天和适应性免疫状态， 妊娠，并将询问其与COVID 19表型的相关性。我们还将 调查在同一时间点是否存在母体抗体（抗SARS-CoV-2的IgG和IgM）， 免疫分析我们拥有必要的专业知识、研究基础设施和患者群体， 在2年时间内完成400人队列的拟议研究。这项研究涉及许多重要的 知识上的差距，包括有关怀孕期间免疫生物学的基本问题。

Project Summary: Despite pandemic spread of the novel coronavirus, COVID-19, significant knowledge gaps remain especially for Center for Disease Control designated high risk populations such as pregnant women. Of high clinical importance is the susceptibility of pregnant women to infection, the direct risk to the mother and the indirect impact of disease severity (including preterm delivery and fetal death) on the pregnancy. While much research is being pursued from translational research to intervention trials for COVID-19, pregnant women are almost universally excluded from intervention and observational trials. Research in pregnant women is of the highest priority. The ability to understand which pregnant women are at risk for severe COVID-19 disease, weeks if not months prior to clinical symptomatology, could provide novel and important windows for preventative interventions to limit maternal morbidity and mortality. Additionally, if clinical data emerges that the majority of pregnant women may actually be more tolerant of SARS-CoV-2 compared to other respiratory viruses, understanding the immunological changes of pregnancy may provide insights as to ways to modulate disease risk in non-pregnant populations. To address all of these gaps in knowledge, large maternal cohorts with biospecimens and detailed phenotyping in areas of high prevalence of COVID-19 are required. The established investigative team and research infrastructure for two active maternal cohorts designed for prospective analysis of maternal immunity during pregnancy (R01-A1145840) can now be leveraged to investigate deep immune phenotyping of pregnant women prior to acquisition of COVID-19. We will be able to investigate how different immune phenotypes predict COVID-19 infection in pregnant women. Complementing the existing expertise in perinatology and immunology for the parent RO1, this study add the immunology and virology expertise at the University of Pennsylvania. We propose to investigate the following three scientifically important aims: 1) whether maternal immune profiles are associated with acquisition and severity of COVID19 in pregnant women; 2) whether immune profiles in pregnant women with active COVID19 are similar to non-pregnant women with similar disease severity and 3) whether immune profiles in the 2nd trimester of pregnancy are associated with adverse reproductive outcomes. All women enrolled will have extensive metadata collected with adjudication of COIVD- 19 status and severity as well as detailed clinical phenotyping of obstetrical outcomes. Deep immune phenotyping will provide innovative and rigorous investigation of innate and adaptive immune states during pregnancy and will be interrogated regarding their association with COVID19 phenotypes. We will also investigate the presence of maternal antibodies (IgG and IgM against SARS-CoV-2) at the same time point as immune profiling. We have the necessary expertise, the research infrastructure and the patient population to complete the proposed study in the 2 year time line with a 400 person cohort. This study address many significant gaps in knowledge including essential questions regarding the immune biology in pregnancy.