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SARS-CoV-2感染的临床范围从无症状到危重疾病， 怀孕本身会增加患严重和危重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，通过经胎盘转移免疫球蛋白G（IgG）对新生儿的被动免疫是至关重要的。 在生命的前六个月很重要，特别是因为COVID-19疫苗仅被批准用于儿童 >六个月的年龄。混合免疫，定义为在自然感染之前或之后疫苗诱导的免疫， SARS-CoV-2在非妊娠人群中产生的反应比孤立的任何一种类型都要强烈。的 妊娠期对SARS-CoV-2混合免疫的长期炎症和免疫反应， 以严格调节的T细胞控制和免疫调节为标志，与自然感染相比是未知的。 随着SARS-CoV-2成为地方病，这项建议将解决文献中的一个空白， 与疫苗诱导的免疫相比，对妊娠期自然感染SARS-CoV-2的影响。利用现有的 COVID-19母婴配对结局（COMP）研究，一项跟踪225名母婴的纵向队列研究 在怀孕期间被诊断为SARS-CoV-2感染的夫妇中，该提案旨在更好地了解长期 妊娠期SARS-CoV-2混合免疫的长期后果。我们假设SARS-CoV-2杂交体 与妊娠期自然感染相比， 减少母体全身性炎症，并在母婴对中产生更强的免疫反应。 本研究的目的是：1）估计围产期和产后延迟的患病率和危险因素 SARS-CoV-2混合免疫者与SARS-CoV-2混合免疫者之间的COVID-19妊娠并发症 自然感染; 2）比较全身炎症景观，如通过细胞因子谱测量， 分娩时和产后一年内有SARS-CoV-2混合免疫和自然感染的孕妇; 和3）评估对祖先和Omicron（BA.5）菌株的细胞和体液免疫应答， SARS-CoV-2混合病毒母婴配对中妊娠分娩和产后6个月的COVID-19 与自然感染相比。K23将支持Cambou博士发展高级应用技能 免疫学，2）围产期感染，和3）细胞因子分析，以成为一个有效的翻译 物理学家兼科学家Karin Nielsen博士，世界著名的儿科感染性疾病（ID）专家，在围产期 感染，将作为主要的导师。Otto O. Yang和Grace Aldrovandi， 病毒免疫学，拥有超过20年的持续NIH资助和成功的成功记录， 导师制Debika Bhattacharya博士将作为围产期成人ID临床研究人员提供指导 病毒感染K23将使Cambou博士能够开拓出一个独特的多学科研究融合的利基市场 怀孕期间病毒感染的免疫学，以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.