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

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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.