Protection of at-risk low birth weight infants against influenza via maternal antibody

项目摘要/摘要 急性呼吸道感染是全球新生儿死亡的主要原因，特别是在低出生人口中。 妊娠合并早产或胎盘功能不全的出生体重婴儿。母体免疫- 免疫接种是为孕妇接种疫苗，以增强抗体通过胎盘输送到胎儿的过程，是 越来越多地被用作一种感染预防战略，以保护新生儿免受流感等病原体的侵袭， 随着针对SARS-CoV-2的新疫苗的开发，这可能是至关重要的。这项建议旨在更好地澄清- 低风险和高风险妊娠，特别是早产儿或早产儿的经胎盘抗体转移日期 胎盘功能不全，目前尚不清楚。它还描述了一个研究培训计划，它将使我能够 成为一名独立的内科科学家，参与专注于传染病的翻译研究计划 怀孕期间的疾病和疫苗。这项建议建立在我在高危产科和全球 健康，并提供了一个详细的计划，以提高我的病毒学，免疫学，疫苗学，队列 研究和统计分析。它融合了一支杰出的导师团队的专业知识，包括 致力于传染病、免疫学、病理学、统计学和计算生物学的专家 为这个项目的成功和我作为一名独立临床研究员的职业发展干杯。 这项建议的第一个目标是建立正常和高危妊娠队列，并量化 妊娠导致正常和低出生体重的胎盘抗体转移 婴儿，包括合并胎盘功能不全导致小于胎龄儿或 早产儿。我将比较总免疫球蛋白、流感和SARS冠状病毒经胎盘的抗体转移量。 2特异性抗体及胎盘组织中新生儿Fc受体的表达。我也会比较新生儿 在怀孕期间接种和未接种流感疫苗的妇女对流感的免疫力， 从而有机会开发多变量模型并针对多个临床协变量进行调整。为了我的 第二个目标是，我将使用一种新的方法来描述相同队列中的抗体谱和经胎盘转移。 用系统血清学方法确定母体和胎儿免疫的生物物理和效应功能。 通过实现这项建议中的目标，我将对我们对产妇的了解做出重大贡献 针对流感和新生儿的免疫接种、孕产妇和新生儿免疫互动和新生儿免疫 SARS-CoV-2。改进了对经胎盘抗体转移的理解和特征 母体免疫接种可为疫苗交付的优化和个性化提供洞察力 在高危妊娠中选择时机，并最终有可能提高全球新生儿存活率。这 建议书将使我能够发展一套独特的跨学科技能和专业知识，以便过渡到 独立作为一名内科科学家，有一个更大的研究项目，专门研究呼吸道感染 在低风险和高风险怀孕背景下的疾病和疫苗。

PROJECT SUMMARY / ABSTRACT Acute respiratory infections are the leading cause of mortality among neonates globally, particularly among low birthweight infants from pregnancies complicated by prematurity or placental insufficiency. Maternal immuniza- tion, the vaccination of pregnant women to enhance antibody transported across the placenta to the fetus, is utilized increasingly as an infection prevention strategy to protect neonates from pathogens such as influenza, and may be critical as new vaccines against SARS-CoV-2 are developed. This proposal aims to better eluci- date transplacental antibody transfer in low- and high-risk pregnancies, specifically those with prematurity or placental insufficiency, which is not known. It also describes a research training program that will allow me to become an independent physician-scientist with a translational research program focusing on infectious diseases and vaccines in pregnancy. This proposal builds upon my training in high-risk obstetrics and global health, and provides a detailed plan to improve my knowledge of virology, immunology, vaccinology, cohort studies and statistical analysis. It incorporates the expertise of an outstanding mentorship team, including experts in infectious diseases, immunology, pathology, statistics, and computational biology who are dedicated to the success of this project and the development of my career as an independent clinical researcher. The first aim of this proposal involves establishing normal and high-risk pregnancy cohorts and quantifying transplacental antibody transfer in the context of pregnancies resulting in both normal and low birth weight infants, including those complicated by placental insufficiency leading to small for gestational age infants or prematurity. I will compare quantity of transplacental antibody transfer of total IgG, influenza- and SARS-CoV- 2- specific antibodies, and expression of neonatal Fc receptor in placentas. I will also compare neonatal immunity against influenza among women who did and did not receive influenza vaccine during pregnancy, allowing the opportunity to develop multivariable models and adjust for multiple clinical covariates. For my second aim, I will characterize antibody profiles and transplacental transfer in the same cohorts using a systems serology approach to determine biophysical and effector functions of maternal and fetal immunology. Through accomplishing the aims in this proposal, I will contribute significantly to our knowledge of maternal immunizations, maternal and neonatal immune interactions and neonatal immunity against influenza and SARS-CoV-2. Improved understanding and characterization of transplacental antibody transfer in the context of maternal immunizations may provide insight in the optimization and individualization of vaccine delivery and timing in high-risk pregnancies and, ultimately, has the potential to improve neonatal survival globally. This proposal will allow me to develop a unique set of cross-disciplinary skills and expertise in order to transition to independence as a physician scientist with a larger research program specializing in respiratory infectious diseases and vaccines within the context of low- and high-risk pregnancies.