The role of antibodies in infant TB prevention

摘要 提案摘要 该提案描述了一个为期5年的培训和研究计划，将允许丽莎克兰默，医学博士，公共卫生硕士建立在 她在全球儿科TB/HIV和分子流行病学方面的背景，并获得了免疫学方面的关键技能， 先进的生物统计学为了成为一名独立的研究者，专注于了解免疫 在母婴免疫学中具有独特优势的儿童预防结核病的机制，克兰默博士将 发展额外的技能：1）体液和先天免疫学方法，2）先进的纵向数据分析， （3）疫苗学。Cranmer博士将利用她在肯尼亚的大量实地研究经验， 母婴配对的队列，并将获得超过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中开展分子流行病学研究和疫苗试验的经验。 利用这些资源，Cranmer博士将发展专业知识，领导未来的母亲结核病疫苗试验， 婴儿。 研究计划 在结核病流行环境中，暴露于艾滋病毒的未感染婴儿患结核分枝杆菌的风险高出20倍以上 (Mtb)与未感染艾滋病毒的婴儿相比，多达40%的结核分枝杆菌感染婴儿发展为结核病 发病率和死亡率高的疾病。目前预防高浓缩铀婴儿结核分枝杆菌感染的战略，包括 卡介苗接种和初级异烟肼预防性治疗尚未成功。为了设计新的 为了制定预防战略，Cranmer博士将评估抗体在保护高浓缩铀婴儿免受结核分枝杆菌感染方面的作用 感染，并检查母体HIV暴露是否导致婴儿Mtb抗体介导的先天性 免疫力Cranmer博士将评估Mtb抗体水平或抗体依赖性细胞吞噬作用是否 在母婴配对中，ADCP/抗体依赖性细胞毒性（ADCC）功能将提供保护 抗婴儿结核杆菌感染（目标1）。然后，她将比较Mtb抗体介导的免疫（例如抗体 功能和先天免疫细胞因子表达），以了解易感性增加的潜在机制 肯尼亚高浓缩铀婴儿中结核分枝杆菌感染（目标2）。提出的目标旨在产生新的数据 这将提高我们对结核病发病机制认识，并为创新公共卫生的发展提供信息 预防婴儿结核病感染的战略，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.