Dengue vaccine and viral evolution in rural Thailand

描述(申请人提供)：这项建议的总体目标是研究将四价减毒登革热病毒疫苗引入泰国北部儿童对自然发生的地方性野生型登革热病毒的进化后果。登革热病毒在过去200年中演变为四种不同的血清型，是一种产生严重疾病的重要人类病原体，称为登革出血热(DHF)。登革热被认为是一个新出现的全球公共卫生问题。它是在世界亚热带和热带地区导致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，数十万例DHF病例，20,000多人死亡。DHF是住院和伤残调整寿命年(DALY)的主要原因。提供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，并基于节省的每DALYs的成本，具有很高的成本效益。目前尚不清楚接种疫苗将对自然发生的登革热病毒的进化产生什么影响。接种疫苗可能会在人类宿主及其媒介内创造一个自然登革热病毒传播相对较低的环境，从而增加随机事件，从而使新的登革热病毒基因型得以出现。在这项申请中，一个由美国和泰国的大学和军方研究人员组成的经验丰富的跨学科团队提议进行协调研究，以确定候选减毒四价疫苗接种将对野生型登革热病毒的疫苗相关基因变化的影响，以及这些变化将如何确定住院儿童发生登革热的风险、接种疫苗和周围人群及其蚊子媒介中的血清特异性登革热病毒传播的风险。在疫苗试验期间，将在泰国北部的Kamphaeng Phet省进行协调研究，以分离野生型登革热病毒，检查人群中的遗传多样性，对患有严重登革热疾病的住院儿童进行研究，对他们的社区进行集群调查，并通过综合的密集病媒监测，在病媒人群中进行研究。首个登革热疫苗效力研究的现场测试为研究该疫苗对野生型登革热病毒的进化后果提供了一个独特的机会，其结果将对未来登革热疫苗的设计和登革热疫苗效力试验的进行产生长期影响。公共卫生相关性：这项研究提案涉及在美国和泰国进行的研究，以了解四价减毒登革热疫苗将如何影响一个登革热地方性国家自然产生的野生型登革热病毒的演变。

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.