Age in dengue antibody response and risk after primary natural infection

项目摘要/摘要 登革热是困扰我们世界的最流行的媒介传播病毒。2010年，估计有390个 全世界有100万感染者，其中25%是有症状的。登革热的发病机制很复杂。 因为存在四种血清型。感染一种血清型可以保护个体免受未来的伤害 感染相同的血清型，但随后感染不同的血清型会增加患上 有症状的疾病，包括可能危及生命的登革热出血热和登革热休克 综合症。在流行国家，儿童感染和疾病的风险最大。一种免疫疫苗是 对保护人口至关重要，但对儿童进行的大型减毒活疫苗试验表明，年龄较小的人 与未来的感染和严重疾病相关，独立于其他变量。接种疫苗是一种关联 对自然感染，在以前没有接触过的人中，与许多血清型交叉反应的抗体 预防多种登革热血清型，但都是短暂的。持久的保护很可能来自于 针对一种登革热血清型的一小部分持久抗体。是什么决定了生产 这些类型特异性抗体和它们所针对的病毒表位还不是很清楚。免疫学 需要结合纵向观察数据的研究才能了解保护性抗体 儿童原发自然登革热感染后的反应。 这项研究将解决年龄、抗体质量和登革热感染或疾病之间的关系。这个 拟议的研究将利用之前从正在进行的纵向观察中收集的数据和血清 尼加拉瓜马那瓜的儿童登革热队列研究。使用最先进的重组病毒 在这一独一无二的数据集中，该提案旨在1)比较 抗体靶向的表位在已知的登革2型登革热儿童中存在差异 感染和2)评估登革热再感染的风险，无论是年龄较小的儿童还是年龄较大的儿童 登革热感染。结果将确定抗体特异性和亲和力的差异在年轻和 并为未来在该人群中接种登革热病毒疫苗的政策决策提供信息 可能还有其他拉美国家。 通过完成这些研究目标，学员将获得一套独特的高级技能 流行病学方法、病毒学和免疫学研究，包括对复杂性的分析和解释 免疫学和纵向数据。病毒学、免疫学和流行病学方面的专家导师将支持 学员成功完成建议的研究、相关培训计划和医学博士学位 北卡罗来纳大学教堂山分校。这项F30奖学金将对申请者的发展起到至关重要的帮助作用 未来的跨学科内科医生-科学家，在病毒学、免疫学和 传染病流行病学。

PROJECT SUMMARY/ABSTRACT Dengue is the most prevalent vector-borne virus plaguing our world. In 2010, there were an estimated 390 million infections worldwide, 25% of which were symptomatic. The pathogenesis of dengue is complex because of the existence of four serotypes. Infection with one serotype protects the individual against future infections of the same serotype, but subsequent infection with a different serotype increases the risk of symptomatic disease, which includes potentially life-threatening dengue hemorrhagic fever and dengue shock syndrome. In endemic countries, children are most at risk of infection and disease. An immunizing vaccine is crucial for population protection but large trials of live-attenuated vaccine in children show that younger age is associated with future infection and severe disease independent of other variables. Vaccination is a correlate to natural infection, where in previously unexposed individuals, antibodies that cross-react to many serotypes protect against multiple dengue serotypes but are short-lived. Long-lasting protection most likely comes from a small fraction of durable antibodies that are specific to one dengue serotype. What determines the production of these type-specific antibodies and the viral epitopes that they target is not well understood. Immunologic studies incorporating longitudinal observational data are needed to understand protective antibody responses after primary natural dengue infection in children. This study will address relationships between age, antibody quality, and dengue infection or disease. The proposed research will utilize previously collected data and sera from an ongoing longitudinal observational study, the Pediatric Dengue Cohort Study in Managua, Nicaragua. Using state-of-the-art recombinant viral techniques and epidemiologic methods in this one-of-a-kind dataset, the proposal aims to 1) compare how epitopes targeted by antibodies vary in younger and older children with known dengue serotype 2 infection and 2) assess the risk of dengue reinfection in younger and older children with prior natural dengue infection. The results will establish the variation in antibody specificity and avidity in younger and older children and inform future policy decisions regarding vaccination against dengue virus in this population and possibly other Latin American countries. Through the completion of these research aims the trainee will gain a unique set of skills in advanced epidemiologic methods, virology, and immunology research, including analysis and interpretation of complex immunologic and longitudinal data. Expert mentors in virology, immunology, and epidemiology will support the trainee’s successful completion of the proposed research, associated training plan, and MD/PhD degree at the University of North Carolina at Chapel Hill. This F30 fellowship will critically aid the applicant’s development as a future interdisciplinary physician-scientist practicing at the intersection of virology, immunology, and infectious disease epidemiology.