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

项目总结/摘要 急性呼吸道感染是全球新生儿死亡的主要原因，特别是在低出生率婴儿中。 妊娠合并早产或胎盘功能不全的出生体重婴儿。母体免疫- 孕妇接种疫苗以增强抗体通过胎盘转运到胎儿， 越来越多地用作感染预防策略，以保护新生儿免受流感等病原体的侵害， 并且可能是开发针对SARS-CoV-2的新疫苗的关键。该提案旨在更好地阐明- 低风险和高风险妊娠中的经胎盘抗体转移日期，特别是早产或 胎盘功能不全，这是未知的。它还描述了一个研究培训计划，使我能够 成为一个独立的医生，科学家与翻译研究计划，重点是传染病 怀孕期间的疾病和疫苗。这项建议建立在我在高风险产科和全球 健康，并提供了一个详细的计划，以提高我的知识病毒学，免疫学，疫苗学，队列 研究和统计分析。它结合了一个优秀的导师团队的专业知识，包括 传染病、免疫学、病理学、统计学和计算生物学方面的专家， 为这个项目的成功和我作为一名独立临床研究人员的职业发展干杯。 该提案的第一个目标是建立正常和高危妊娠队列， 在导致正常和低出生体重的妊娠背景下的经胎盘抗体转移 婴儿，包括并发胎盘功能不全导致小于胎龄儿的婴儿，或 早产我将比较总IgG、流感病毒和SARS-CoV的经胎盘抗体转移量， 2-特异性抗体和胎盘中新生儿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妇女的流感免疫力， 允许有机会开发多变量模型并调整多个临床协变量。为我 第二个目标，我将使用一种新的方法来描述同一队列中的抗体谱和经胎盘转移。 系统血清学方法来确定母体和胎儿免疫学的生物物理学和效应子功能。 通过实现这一建议中的目标，我将大大有助于我们对孕产妇的认识， 免疫接种、母体和新生儿免疫相互作用以及新生儿对流感的免疫力， SARS-CoV-2.在背景下改善对经胎盘抗体转移的理解和表征 母亲免疫接种的最佳化和个体化可以提供疫苗接种的最佳化和个体化的见解， 这一技术可用于高危妊娠的时机选择，并最终有可能提高全球新生儿存活率。这 我的建议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 独立作为一个医生科学家与一个更大的研究计划，专门研究呼吸道感染 在低风险和高风险怀孕的情况下，预防疾病和接种疫苗。

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.