Dengue vaccine and viral evolution in rural Thailand

描述（由申请方提供）：本提案的总体目标是检查泰国北方儿童中引入四价减毒活登革病毒疫苗对自然发生的地方性野生型登革病毒的进化后果。登革病毒在过去200年中演变为四种不同的血清型和一种重要的人类病原体，产生称为登革出血热（DHF）的严重疾病。登革热被认为是一个新出现的全球公共卫生问题。它是世界上亚热带和热带地区引起人类疾病的最常见的虫媒病毒，估计每年发生超过5000万例DV感染，其中有数十万例DHF病例，超过20，000例死亡。DHF是住院和残疾调整生命年（DAF）的主要原因。提供针对所有四种登革热血清型的保护的登革热疫苗是高度优先的，并且基于节省的每名登革热患者的成本，具有高度的成本效益。目前尚不清楚疫苗接种对自然发生的登革热病毒的进化有何影响。疫苗接种可能会在人类宿主及其载体内创造一个天然登革热病毒相对低传播的环境，从而增加随机事件，使新的登革热病毒基因型出现。在这项申请中，美国和泰国的一个经验丰富的大学和军事研究人员跨学科小组建议进行协调研究，以确定接种候选减毒活四价疫苗对野生型登革热病毒疫苗相关遗传变化的影响，以及这些变化如何决定住院儿童的DHF风险，在接种疫苗和周围人群及其蚊媒中的特定型登革热病毒传播。在泰国北方甘榜府疫苗试验期间将进行协调研究，以分离野生型登革热病毒，并在患有严重登革热疾病的住院儿童中检查人群的遗传多样性，对其社区进行聚类调查，并通过综合密集的病媒监测，在病媒人群中进行遗传多样性检查。第一个登革热疫苗有效性研究的现场测试提供了一个独特的机会来研究这种疫苗对野生型登革热病毒的进化后果，其结果将对未来登革热疫苗的设计和登革热疫苗有效性试验的进行产生长期影响。公共卫生相关性：这项研究计划涉及在美国和泰国进行的研究，以了解四价登革减毒活疫苗将如何影响登革流行国家自然发生的野生型登革病毒的演变。

DESCRIPTION (provided by applicant): The overall objective of this proposal is to examine the evolutionary consequences of introducing a tetravalent live-attenuated dengue virus vaccine into children in Northern Thailand on naturally occurring endemic wild-type dengue virus. Dengue virus has evolved over the last 200 years as four distinct serotypes and an important human pathogen producing severe illness known as dengue hemorrhagic fever (DHF). Dengue is considered an emerged global public health problem. It is the most common arbovirus causing human disease in subtropical and tropical regions of the world and estimated that over 50 million DV infections occur each year with several hundred thousand cases of DHF, and over 20,000 deaths. DHF is a major cause of hospitalization and disability adjusted life-years (DALYs). A dengue vaccine that offers protection against all four dengue serotypes is a high priority and based on cost per DALYs saved, highly cost- effective. It is not known what the effects of vaccination will do on the evolution of naturally occurring dengue viruses. Vaccination may create an environment of relative low-transmission of natural dengue virus, within the human host and its vector, thereby increasing stochastic events that will allow new dengue virus genotypes to emerge. In this application, an experienced interdisciplinary team of university and military investigators in the US and Thailand proposes to conduct coordinated studies to determine the effect vaccination with a candidate live-attenuated tetravalent vaccine will have on vaccine related genetic changes on wild-type dengue virus and how these changes will determine risk for DHF in hospitalized children, serotype-specific dengue virus transmission in the vaccinated and surrounding population, and in its mosquito vector. Coordinated studies will be performed during the vaccine trial in Kamphaeng Phet Province, Northern Thailand, to isolate wild-type dengue virus and examine genetic diversity in the population, in hospitalized children with severe dengue illness and cluster investigation of their neighborhoods, and through integrated intensive vector surveillance, in the vector population. The field testing of the first dengue vaccine efficacy study offers a unique opportunity to study the evolutionary consequences of this vaccine on wild-type dengue virus with findings that will have long-term impact on the design of future dengue vaccines and conduct of dengue vaccine efficacy trials. PUBLIC HEALTH RELEVANCE: This research proposal involves studies in the United States and Thailand to understand how the tetravalent live-attenuated dengue vaccine will affect the evolution of naturally occurring wild-type dengue virus in a country endemic for dengue.