Dengue vaccine and viral evolution in rural Thailand

描述（由申请人提供）：本提案的总体目标是研究向泰国北部儿童引入四价登革热病毒减毒活疫苗对自然发生的野生型登革热病毒的进化后果。在过去200年里，登革热病毒已演变为四种不同的血清型和一种重要的人类病原体，可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虫媒病毒，据估计，每年发生5000多万例DV感染，其中有几十万例登革出血热，死亡人数超过2万人。DHF是住院和残疾调整生命年（DALYs）的主要原因。一种能够预防所有四种登革热血清型的登革热疫苗是一个高度优先事项，并且基于节省的每个伤残调整生命年的成本，具有很高的成本效益。目前尚不清楚疫苗接种将对自然发生的登革热病毒的进化产生什么影响。疫苗接种可能在人类宿主及其媒介中创造一种天然登革热病毒传播相对较低的环境，从而增加了使新的登革热病毒基因型出现的随机事件。在这一申请中，一个由美国和泰国的大学和军事研究人员组成的经验丰富的跨学科团队建议进行协调研究，以确定使用候选四价减毒活疫苗接种疫苗对疫苗相关的野生型登革热病毒遗传变化的影响，以及这些变化如何决定住院儿童登革出血热的风险，以及疫苗接种者和周围人群中血清型特异性登革热病毒的传播。在它的蚊子载体中。将在泰国北部坎彭佩省进行疫苗试验期间进行协调研究，以分离野生型登革热病毒并检查人群中的遗传多样性，在患有严重登革热疾病的住院儿童中进行调查，并对其社区进行聚集性调查，并通过综合强化病媒监测在病媒人群中进行调查。首次登革热疫苗效力研究的实地试验为研究这种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，其研究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开展产生长期影响。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，以了解四价减毒登革热活疫苗如何影响登革热流行国家自然发生的野生型登革热病毒的进化。

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.