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

描述(申请人提供)：登革热在世界范围内导致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。推动这些转变的机制还没有被很好地理解。这项拟议的工作将对泰国过去25年的病毒进行测序，并表征这些病毒的抗原性关系。人类将对抗原性相近的病毒产生免疫反应，从而保护个人免受这两种病毒的侵袭。对于病毒 在抗原性上相距遥远，感染一种病毒不会导致对另一种病毒的免疫。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。感染一种登革热病毒会导致对抗原性相似病毒的保护，但当接触到其他抗原性更远的病毒时，可能会使个人容易出现严重后果。免疫的影响可能会随着时间的推移而变化，最初是提供保护，然后是风险。这些相互作用可以对正在传播的登革热病毒施加选择性压力。这可能是一些血统被赶到灭绝，而另一些则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，抗原地图学，我们将描述登革热病毒在过去25年中的变化。我们将使用一项已进行了12年的队列研究的样本，确定一个人的抗原组合，或一个人对其具有免疫力的抗原，是否可以预测他们患登革热的风险。最后，我们将建立与泰国观察到的模式很好匹配的模型。与公共卫生的相关性了解登革热的遗传变异是如何出现并取代现有变异的，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，了解它们对传播的登革热病毒的影响对于它们的最佳使用、持续效力和人口安全至关重要。

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.