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

连接抗原

• 批准号: 8801344
• 负责人: Derek A Cummings
• 金额: $ 78.93万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-11 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8801344
• 关键词: Age; Antigenic Diversity; Antigenic Variation; Antigens; Archives; Case-Control Studies; Cercopithecus pygerythrus; Cohort Studies; Dengue; Dengue Virus; Development; Disease; Distant; Extinction (Psychology); Future; Genetic; Genetic Variation; Genome; Genotype; Human; Immune response; Immunity; Incidence; Individual; Infection; Integration Host Factors; Lead; Licensing; Life; Link; Location; Maps; Measures; Modeling; Morbidity - disease rate; Neutralization Tests; Outcome; Pattern; Population; Public Health; Risk; Risk Estimate; Safety; Sampling; Seasons; Serotyping; Serum; Severity of illness; System; Techniques; Testing; Thailand; Time; Vaccines; Variant; Viral; Virus; Work; burden of illness; case control; experience; genetic variant; member; model building; mortality; pathogen; pressure; prospective; public health relevance; rural area; tool; transmission process

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.

描述（由申请人提供）：登革热在全球范围内引起明显的发病率和死亡率。病例中的大幅增加通常与主要血清型和/或基因型的转移有关。驱动这些转移的机制尚不清楚。拟议的工作将从泰国开始的过去25年开始序列病毒，并表征这些病毒的抗原关系。人类将对抗原上的病毒产生免疫反应，这些病毒彼此接近，可以保护个体免受两种病毒的侵害。对于病毒 抗原远处的感染不会导致对另一种的免疫力。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。一种登革热病毒感染会导致抗原上相似的病毒的保护，但是当暴露于其他抗原更遥远的病毒时，可能会使个体诱发患者的严重预后。免疫的影响会随着时间的流逝而改变，最初提供保护，然后提供风险。这些相互作用可以在循环的登革热病毒上施加选择性压力。这可能是某些谱系被驱动到灭绝而另一些持续存在的原因之一。使用新工具来表征病毒的抗原关系，抗原制图，我们将在过去25年中表征登革热病毒的变化。我们将确定一个抗原投资组合或个人具有免疫力的抗原是使用同类研究中的样本来预测其Dengu疾病风险的风险。最后，我们将建立适合泰国模式的模型。与公共卫生有关，了解登革热的遗传变异如何出现并取代现有变体将有助于我们预测未来的发生率，准备监视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。了解这些疫苗的影响，如果它们得到许可和广泛使用，对循环登革热病毒的影响对于它们的最佳使用，持续疗效和人口安全至关重要。