Age in dengue antibody response and risk after primary natural infection

项目总结/摘要 登革热是世界上最流行的病媒传播病毒。2010年，估计有390个 全世界有100万例感染，其中25%是有症状的。登革热的发病机制复杂 因为存在四种血清型。一种血清型的感染可以保护个体免受未来的感染。 同一血清型感染，但随后感染不同血清型会增加 有症状的疾病，包括可能危及生命的登革出血热和登革休克 综合征在流行国家，儿童最容易受到感染和患病。免疫疫苗是 对人群保护至关重要，但在儿童中进行的大型减毒活疫苗试验表明， 与未来感染和严重疾病相关，与其他变量无关。接种疫苗与 自然感染，在以前未暴露的个体中，与许多血清型交叉反应的抗体 预防多种登革热血清型，但寿命短。持久的保护最有可能来自于 一小部分持久的抗体对一种登革热血清型具有特异性。是什么决定了生产 对这些类型特异性抗体和它们所靶向的病毒表位的了解还不是很清楚。免疫 需要结合纵向观察数据的研究来了解保护性抗体 儿童原发性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。的 拟议的研究将利用以前收集的数据和血清从一个正在进行的纵向观察 尼加拉瓜马那瓜的儿童登革热队列研究。利用最先进的重组病毒 技术和流行病学方法在这个独一无二的数据集，该提案旨在1）比较如何 已知登革热血清型2的年幼和年长儿童中抗体靶向的表位不同 感染和2）评估登革热再感染的风险，在年幼和年长的儿童与先前的自然 登革热感染。结果将确定年轻人和老年人中抗体特异性和亲合力的变化， 年龄较大的儿童，并为今后有关在这一人群中接种登革热病毒疫苗的政策决定提供信息 可能还有其他拉丁美洲国家。 通过完成这些研究目标，受训者将获得一套独特的技能， 流行病学方法，病毒学和免疫学研究，包括分析和解释复杂的 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 学员成功完成拟议的研究，相关的培训计划，并在MD/博士学位 位于查佩尔山的北卡罗来纳州大学。这个F30奖学金将对申请人的发展起到关键性的帮助， 一个未来的跨学科的医生，科学家在病毒学，免疫学， 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.