LINKING ANTIGENIC & GENETIC VARIATION OF DENGUE TO INDIVIDUAL AND POPULATION RISK

描述（由申请人提供）：登革热在全球范围内造成严重的发病率和死亡率。病例的大幅增加往往与主要血清型和/或基因型的转变有关。驱动这些转变的机制还没有得到很好的理解。拟议的工作将对泰国过去25年的病毒进行测序，并描述这些病毒的抗原关系。人类将对抗原性彼此接近的病毒产生免疫反应，这将保护个体免受两种病毒的侵害。是否有病毒 抗原性远的，感染一种不会导致对另一种的免疫。登革热 病毒通过我们的免疫反应以几种不同的方式相互作用。感染一种登革病毒可保护个体免受抗原性相似的病毒的侵害，但当暴露于其他抗原性更远的病毒时，可使个体易患严重后果。免疫力的影响会随着时间的推移而改变，最初提供保护，然后是风险。这些相互作用可以对传播的登革热病毒施加选择性压力。这可能是一些血统被驱赶到灭绝而另一些血统继续存在的原因之一。使用一种新的工具来描述病毒的抗原关系，抗原制图，我们将描述过去25年来登革热病毒的变化。我们将使用来自已进行>12年的队列研究的样本，确定个体抗原组合或个体具有免疫力的抗原是否可预测其登谷病风险。最后，我们将建立符合泰国观察到的模式的模型。了解登革热的遗传变异如何出现并取代现有变异将有助于我们预测未来的发病率，准备监测系统并了解个人风险的驱动因素。目前正在开发多种候选登革热疫苗。如果这些疫苗获得许可并广泛使用，了解它们对传播登革热病毒的影响对其最佳使用，持续有效性和人群安全至关重要。

DESCRIPTION (provided by applicant): Dengue causes significant morbidity and mortality worldwide. Large increases in cases are often associated with a shift in predominant serotypes and/or genotypes. The mechanisms that drive these shifts are not well understood. The proposed work will sequence viruses from the last 25 years from Thailand and characterize the antigenic relationship of these viruses. Humans will mount an immune response to viruses that are antigenically close to one another that will protect individuals from both viruses. For viruses that are antigenically distant, infection with one will not lead to immunity to another. The dengue viruses interact through our immune responses in several distinct ways. Infection with one dengue virus leads to protection from antigenically similar viruses, but can predispose individuals to severe outcome when exposed to other antigenically more distant viruses. The impact of immunity can change over time, initially providing protection, then risk. These interactions can exert selective pressure on circulating dengue viruses. This may be one reason that some lineages are driven to extinction while others persist. Using a new tool to characterize the antigenic relationship of viruses, antigenic cartography, we will characterize changes in dengue viruses over the last 25 years. We will determine whether an individuals antigenic portfolio, or the antigens that an individual has immunity to, is predictive of their risk of dengu disease using samples from a cohort study that has been conducted for >12 years. Finally, we will build models that fit that observed pattern in Thailand well. Relevance to Public Health Understanding how genetic variants of dengue emerge and replace existing variants will help us forecast future incidence, prepare surveillance systems and understand drivers of individual risk. Multiple candidate dengue vaccines are currently in development. Understanding the impact of these vaccines, should they become licensed and used widely, on circulating dengue viruses is critical to their optimal use, continued efficacy and population safety.