The role of antibodies in infant TB prevention

摘要 建议书摘要 这份提案描述了一项为期5年的培训和研究计划，该计划将使医学博士丽莎·克兰默在公共卫生硕士学位的基础上 她在全球儿科结核病/艾滋病毒和分子流行病学方面的背景，并在免疫学和 高级生物统计学。为了成为专注于了解免疫的独立研究人员 在母婴免疫学领域具有独特优势的儿童预防结核病的机制，克兰默博士将 发展其他技能：1)体液和先天免疫学方法，2)高级纵向数据分析， (3)疫苗学。克兰默博士将利用她在肯尼亚的大量实地研究经验，使用正在进行的 母婴配对队列，将得到累积超过30年的研究人员的密切指导 在结核病/艾滋病毒高负担环境下进行分子流行病学研究和疫苗试验的经验。 利用这些资源，克兰默博士将发展专业知识，领导未来结核病疫苗在母亲和 婴儿。 研究计划 在结核病流行的环境中，暴露于艾滋病毒的未感染婴儿患结核分枝杆菌的风险高20倍 (MTB)感染与未接触艾滋病毒的未感染婴儿进行比较。高达40%感染结核杆菌的婴儿会患上结核病 发病率和死亡率都很高的疾病。预防高尿症婴儿结核分枝杆菌感染的现行战略包括 卡介苗接种和初级异烟肼预防治疗均未获成功。为了设计出新的 预防策略，克兰默博士将评估抗体在保护HEU婴儿免受结核杆菌感染方面的作用 感染，并检查母亲接触艾滋病毒是否会导致婴儿结核分枝杆菌抗体介导的先天性改变 豁免权。克兰默博士将评估结核分枝杆菌抗体水平或抗体依赖的细胞吞噬作用 母婴配对中的(ADCP)/抗体依赖的细胞毒性(ADCC)功能将提供保护 预防婴儿结核分枝杆菌感染(目标1)。然后，她将比较结核分枝杆菌抗体介导的免疫(例如抗体 功能和先天免疫细胞因子的表达)，以了解易感性增加的潜在机制 肯尼亚HEU婴儿中结核分枝杆菌感染情况(目标2)。拟议的目标旨在生成新的数据 加强我们对结核病发病机制的了解，促进创新公共卫生的发展 预防婴儿结核分枝杆菌感染的战略，包括新的母婴疫苗。

ABSTRACT Summary of Proposal This proposal describes a 5-year training and research plan that will allow Lisa Cranmer, MD, MPH to build on her background in global pediatric TB/HIV and molecular epidemiology and gain critical skills in immunology and advanced biostatistics. In order to become an independent investigator focused on understanding immune mechanisms to prevent TB in children with a unique niche in maternal-infant immunology, Dr. Cranmer will develop additional skills in: 1) humoral and innate immunology methods, 2) advanced longitudinal data analysis, and 3) vaccinology. Dr. Cranmer will leverage her substantive field research experience in Kenya using ongoing cohorts of mother-infant pairs and will receive close mentorship from researchers with over 30 cumulative years of experience performing molecular epidemiology studies and vaccine trials in high TB/HIV burden settings. Using these resources, Dr. Cranmer will develop the expertise to lead future TB vaccine trials in mothers and infants. Research Plan In TB-endemic settings, HIV-exposed uninfected infants have >20-fold higher risk of Mycobacterium tuberculosis (Mtb) infection compared to HIV-unexposed uninfected infants. Up to 40% of Mtb-infected infants develop TB disease with high morbidity and mortality. Current strategies to prevent Mtb infection in HEU infants, including BCG vaccination and primary isoniazid preventive therapy, have not been successful. In order to design new prevention strategies, Dr. Cranmer will evaluate the role of antibodies in protection of HEU infants from Mtb infection, and examine if maternal HIV exposure leads to changes in infant Mtb antibody-mediated innate immunity. Dr. Cranmer will evaluate if Mtb antibody levels or antibody-dependent cellular phagocytosis (ADCP)/antibody-dependent cellular cytotoxicity (ADCC) function in mother-infant pairs will confer protection against infant Mtb infection (Aim 1). She will then compare Mtb antibody-mediated immunity (e.g. antibody function and innate immune cytokine expression) to understand potential mechanisms of increased susceptibility to Mtb infection among Kenyan HEU infants (Aim 2). The proposed aims are designed to generate novel data that enhance our understanding of TB pathogenesis and inform development of innovative public health strategies to prevent infant Mtb infection, including new maternal and infant vaccines.