SARS-CoV-2 in Pregnancy: Comparison of Natural Infection and Hybrid Immunity in Mother-Infant Pairs

项目概要/摘要 虽然妊娠期间 SARS-CoV-2 感染的临床谱范围从无症状到危重疾病， 怀孕本身会增加患严重和危重症 COVID-19 的风险。美国领先的产科协会 建议在怀孕期间接种 COVID-19 信使 RNA (mRNA) 疫苗，以预防严重疾病。 此外，通过免疫球蛋白 G (IgG) 经胎盘转移对新生儿产生被动免疫至关重要 在生命的前六个月很重要，特别是因为 COVID-19 疫苗仅批准用于儿童 >六个月大。混合免疫，定义为自然感染之前或之后疫苗诱导的免疫 SARS-CoV-2 在非怀孕人群中产生的反应比任何一种单独的病毒都更强烈。的 妊娠期对 SARS-CoV-2 混合免疫的长期炎症和免疫反应，一种状态 与自然感染相比，其特点是严格调节的 T 细胞控制和免疫调节。 随着 SARS-CoV-2 流行，该提案将解决文献中的一个空白，该空白主要集中于 与疫苗诱导的免疫相比，妊娠期自然 SARS-CoV-2 感染的影响。利用现有 COVID-19 母婴配对 (COMP) 研究是一项跟踪 225 名母婴的纵向队列研究 对于在怀孕期间诊断出 SARS-CoV-2 感染的二人组，该提案旨在更好地了解长期 妊娠期间 SARS-CoV-2 混合免疫的长期后果。我们假设 SARS-CoV-2 杂合体 与怀孕期间的自然感染相比，免疫力可以预防产后并发症，导致 减少母体全身炎症，并导致母婴对产生更强大的免疫反应。 研究目的是：1）估计围产期和产后延迟的患病率和危险因素 具有 SARS-CoV-2 混合免疫能力的人和患有 自然感染； 2) 比较通过细胞因子谱测量的全身炎症状况 患有 SARS-CoV-2 混合免疫且在分娩时和产后一年自然感染的孕妇； 3) 评估对祖先和 Omicron (BA.5) 菌株的细胞和体液免疫反应 患有 SARS-CoV-2 杂合体的母婴二人中妊娠期分娩时和产后 6 个月内的 COVID-19 与自然感染相比的免疫力。 K23 将支持 Cambou 博士发展以下方面的高级技能：1) 应用 免疫学，2）围产期感染，3）细胞因子分析，以成为有效的转化 医生科学家。 Karin Nielsen博士，世界著名围产期儿科传染病（ID）专家 感染，将作为主要导师。共同导师博士。 Otto O. Yang 和 Grace Aldrovandi，专家 病毒免疫学，拥有 20 多年的 NIH 持续资助和成功的记录 指导。联合导师 Debika Bhattacharya 博士将作为成人 ID 临床研究员在围产期提供指导 病毒感染。 K23 将使 Cambou 博士能够在多学科研究融合中开辟出独特的利基市场 怀孕期间病毒感染的免疫学，以便开始她作为独立研究者的职业生涯。

PROJECT SUMMARY/ABSTRACT While the clinical spectrum of SARS-CoV-2 infection in pregnancy ranges from asymptomatic to critical disease, pregnancy itself augments the risk of severe and critical COVID-19. The leading obstetrical societies in the U.S. recommend COVID-19 messenger RNA (mRNA) vaccination in pregnancy to prevent severe disease. Furthermore, passive immunity to the neonate via transplacental transfer of immunoglobulin G (IgG) is critically important during the first six months of life, particularly as the COVID-19 vaccines are approved only for children >six months of age. Hybrid immunity, defined as vaccine-induced immunity before or after natural infection with SARS-CoV-2, produces a more robust response in non-pregnant populations than either type in isolation. The long-term inflammatory and immunologic responses to SARS-CoV-2 hybrid immunity in pregnancy, a state marked by tightly regulated T cell control and immune modulation, compared to natural infection are unknown. As SARS-CoV-2 becomes endemic, this proposal will address a gap in the literature that has focused primarily on natural SARS-CoV-2 infection in pregnancy compared to vaccine-induced immunity. Leveraging the existing COVID-19 Outcomes in Mother-Infant Pairs (COMP) study, a longitudinal cohort that follows 225 mother-infant dyads diagnosed with SARS-CoV-2 infection in pregnancy, the proposal seeks to better understand the long- term consequences of SARS-CoV-2 hybrid immunity in pregnancy. We hypothesize that SARS-CoV-2 hybrid immunity compared to natural infection in pregnancy confers protection against postpartum complications, leads to less maternal systemic inflammation, and results in more robust immune responses in mother-infant pairs. The study aims are: 1) to estimate the prevalence and risk factors of peripartum and delayed postpartum complications of COVID-19 in pregnancy between those with SARS-CoV-2 hybrid immunity, and those with natural infection; 2) to compare the systemic inflammatory landscapes, as measured by cytokine profiles, of pregnant women with SARS-CoV-2 hybrid immunity and natural infection at delivery and one year postpartum; and 3) to evaluate cellular and humoral immune responses to the ancestral and Omicron (BA.5) strains following COVID-19 in pregnancy at delivery and six months postpartum in mother-infant dyads with SARS-CoV-2 hybrid immunity compared to natural infection. The K23 will support Dr. Cambou to develop advanced skills in 1) applied immunology, 2) perinatal infections, and 3) cytokine analysis, in order to become an effective translational physician-scientist. Dr. Karin Nielsen, a world-renowned pediatric infectious diseases (ID) expert in perinatal infections, will serve as the primary mentor. Co-mentors Drs. Otto O. Yang and Grace Aldrovandi, experts in viral immunology, have over 20 years of continuous NIH funding and proven track records of successful mentorship. Co-mentor Dr. Debika Bhattacharya will offer guidance as an adult ID clinical researcher in perinatal viral infections. The K23 will allow Dr. Cambou to carve out a unique niche of multidisciplinary research blending immunology with viral infections in pregnancy, in order to launch her career as an independent investigator.