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）：登革热在全世界范围内造成显着的发病率和死亡率。病例的大幅增加通常与主要血清型和/或基因型的变化有关。推动这些转变的机制尚不清楚。拟议的工作将对过去 25 年来自泰国的病毒进行测序，并表征这些病毒的抗原关系。人类会对抗原上彼此接近的病毒产生免疫反应，从而保护个体免受这两种病毒的侵害。对于病毒 由于抗原性较远，感染一种病毒不会导致对另一种病毒产生免疫力。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。感染一种登革热病毒可以预防抗原相似的病毒，但当接触其他抗原较远的病毒时，可能会使个体面临严重的后果。免疫力的影响会随着时间的推移而变化，最初提供保护，然后带来风险。这些相互作用可以对循环的登革热病毒施加选择性压力。这可能是一些谱系濒临灭绝而另一些谱系却持续存在的原因之一。使用一种表征病毒抗原关系的新工具——抗原制图术，我们将表征过去 25 年登革热病毒的变化。我们将使用已进行超过 12 年的队列研究样本来确定个体抗原组合或个体具有免疫力的抗原是否可以预测其患登革热疾病的风险。最后，我们将建立非常适合在泰国观察到的模式的模型。与公共卫生的相关性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。了解这些疫苗（如果它们获得许可并广泛使用）对传播登革热病毒的影响对于其最佳使用、持续功效和人群安全至关重要。