A Study of Protective Immunity Against Dengue in Infants

描述(申请人提供)：世界卫生组织认为登革热是一种高度优先的新出现的病毒疾病，因为世界上有超过10亿人面临登革出血热(DHF)的风险。在菲律宾等登革热流行国家，迫切需要登革热疫苗；然而，也有重大关切，即疫苗的广泛使用可能会增加患登革热的风险。因此，确定保护性免疫的可重复相关性是至关重要的。这项建议的目标是在一项关于婴儿时期登革热病毒感染的前瞻性研究中，确定针对登革热的保护性免疫的相关性。与年龄较大的儿童不同，婴儿在原发DV感染后表现出症状登革热(包括DHF)，这种感染被预先存在的、母体获得的体液免疫所改变。婴儿期独特的免疫学条件为确定保护性免疫相关因素提供了最纯粹的环境。 该项目的第一个目标将是确定与登革热症状保护性免疫相关的血清型特异性中和抗体(Abs)水平。在感染DV前采集的菲律宾婴儿血液样本中的中和抗体滴度，以及在患病时预测的中和抗体滴度，将与疾病严重程度等级和病毒血症峰值水平相关。将测定婴儿出现症状登革热的中和抗体效价。第二个目标是描述导致婴儿DHF发病的危险因素。从发病前的血液样本中，将测量抗体中和能力的关联或感染与DHF的增强，同时控制其他潜在的协变量。协变量将包括代表病毒载量和婴儿宿主免疫反应的指标。最后，第三个目标将是加强菲律宾登革热的诊断和研究能力。一个合作的国际财团已经成立，以推动菲律宾的登革热研究。这项研究将为有效测试登革热疫苗和整个区域未来的公共卫生疫苗接种运动提供重要数据。

DESCRIPTION (provided by applicant): Dengue is considered a high priority emerging viral disease by the WHO, as over 1 billion people in the world are at risk for dengue hemorrhagic fever (DHF). In dengue endemic countries such as the Philippines, there is an urgent need for a dengue vaccine; however, there is also major concern that widespread use of a vaccine may increase the risk for DHF. Thus, it is critical that reproducible correlates of protective immunity be identified. The goal of this proposal is to identify correlates of protective immunity against dengue in a prospective study of dengue virus infections during infancy. Unlike older children, infants manifest symptomatic dengue (including DHF) following primary DV infections that are modified by pre-existing, maternally-acquired, humoral immunity. The unique immunological conditions of infancy provide the most unadulterated setting to define protective immune correlates. The first aim of this project will be to define levels of serotype-specific neutralizing antibodies (Abs) associated with protective immunity against symptomatic dengue. Neutralizing Ab titers in blood samples collected from Filipino infants before DV infection, and predicted neutralizing Ab titers at the time of illness, will be correlated with disease severity rankings and peak viremia levels. Neutralizing Ab titers at which infants developed symptomatic dengue will be determined. The second aim will be to delineate risk factors contributing to the pathogenesis of DHF in infants. From pre-illness blood samples, the association of Ab neutralizing capacity or enhancement of infection with DHF will be measured while controlling for other potential covariates. The covariates will include measures representing viral load and infant host immune responses. Finally, the third aim will be to strengthen the capacity for diagnosis and research on dengue in the Philippines. A collaborative and international consortium has been formed to advance dengue research in the Philippines. The research will generate vital data for the effective testing of dengue vaccines and future public health vaccination campaigns throughout the region.