Characterization of 3rd & 4th dengue virus infections in a pediatric cohort study

3号的特征

• 批准号: 9223558
• 负责人: Angel Lazaro Balmaseda
• 金额: $ 6.63万
• 依托单位: SUSTAINABLE SCIENCES INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9223558
• 关键词: 14 year old; Accounting; Acute; Address; Age; Avidity; B-Lymphocytes; Biological Assay; California; Characteristics; Child; Childhood; Clinical; Clinical Data; Cohort Studies; Communities; Culicidae; Data; Dengue; Dengue Hemorrhagic Fever; Dengue Infection; Dengue Shock Syndrome; Dengue Virus; Development; Disease; Enzyme-Linked Immunosorbent Assay; Epidemiology; Fever; Flow Cytometry; Health; Human; Immune response; Immunity; In Vitro; Infection; Influenza; Laboratories; Life; Longevity; Measurement; Methodology; Methods; Modeling; Nicaragua; Nicaraguan; Outcome; Public Health; Research Infrastructure; Resources; Risk; Risk Factors; Running; Sampling; Scientist; Serotyping; Serum; Signs and Symptoms; Specificity; Statistical Methods; Techniques; Time; Training; Undifferentiated; United States National Institutes of Health; Universities; Vaccination; Vaccine Design; Virus; Work; base; cohort; enzyme linked immunospot assay; experience; interest; longitudinal analysis; meetings; programs; prospective; research study; seroconversion; vaccine development; virology

DESCRIPTION (provided by applicant): Four serotypes of dengue virus (DV1-4) circulate globally, causing more human illness than any other mosquito-borne virus. DV infection results in dengue fever, an acute debilitating febrile illness, or more severe life-threatening forms of th disease. DV infection confers life-long immunity against re-infection with the same serotype, but may protect against or enhance subsequent infection with a heterologous serotype. Despite the risk and the cross-protection associated with secondary DV infections, very little is known about 2nd, 3rd, or 4th DV infections specifically, largely because cohort studies with appropriate longevity have not existed. We have a unique opportunity to leverage the ICIDR influenza cohort and existing infrastructure from previous and ongoing NIH-supported studies in Managua, Nicaragua, to extend the Pediatric Dengue Cohort Study (PDCS), now arguably the longest running continuous cohort in the dengue field. The PDCS has been ongoing since August of 2004, with high-quality laboratory, epidemiological, clinical, and operational infrastructure, together with community buy-in and support from the Nicaraguan Ministry of Health. The longevity of the cohort allows specific questions about 3rd and 4th DV infections to be addressed for the first time. The resulting data have important implications for vaccine design and understanding dengue immunopathogenesis and natural protection. We will continue to follow 3,300 children 2-14 years old in Managua and examine epidemiological, clinical, and immunological characteristics of 3rd/4th vs. 2nd DV infections. This is a unique opportunity to leverage existing research infrastructure and resources to continue a long-term prospective cohort study in Nicaragua to answer critical questions about dengue that have direct implications for vaccine development. Our data from the PDCS over the past 7 years demonstrates the feasibility of identifying sufficient repeat DV infections and obtaining the samples for Aims 1-3. The PI, Director of the National Virology Laboratory (NVL) and Director of the Nicaraguan Virology Program at the Instituto de Ciencias Sostenibles in Managua, has collaborated closely with Dr. Eva Harris at the University of California (UC), Berkeley, for over 16 years. We have preliminary data supporting all the proposed experiments and methodologies and are well- poised to perform the studies outlined. Importantly, all the proposed work will be conducted in Nicaragua, with continued scientific interaction and training with the Harris Laboratory at UC Berkeley. Aim 1 will identify repeat DV infections in the cohort and determine risk factors for infection outcome in 3rd/4th vs. 2nd DV infections. Aim 2 will use longitudinal statistical methods to evaluate clinical signs and symptoms associated with 3rd/4th DV infections as compared to 1st and 2nd infections. In Aim 3, we will characterize the B cell and humoral immune response and analyze the relation of serum avidity and breadth and quality of DV-specific B cells to DV infection number and outcome. These aims address critical concepts in the dengue field that have never been carefully characterized, and the results are highly relevant for vaccine development

描述（由申请人提供）：登革热病毒（DV1-4）的四种血清型在全球范围内传播，比任何其他蚊媒病毒造成更多的人类疾病。 DV 感染会导致登革热（一种使人衰弱的急性发热性疾病）或更严重的危及生命的疾病。 DV 感染赋予终生免疫力，防止相同血清型的再次感染，但可以预防或增强异源血清型的后续感染。尽管存在与继发性 DV 感染相关的风险和交叉保护，但人们对第二次、第三次或第四次 DV 感染知之甚少，这主要是因为尚不存在具有适当寿命的队列研究。我们有一个独特的机会，可以利用 ICIDR 流感队列和 NIH 支持的尼加拉瓜马那瓜先前和正在进行的研究的现有基础设施来扩展儿科登革热队列研究 (PDCS)，该研究现在可以说是登革热领域运行时间最长的连续队列。 PDCS 自 2004 年 8 月以来一直在进行，拥有高质量的实验室、流行病学、临床和运营基础设施，以及社区的支持和尼加拉瓜卫生部的支持。该队列的寿命较长，使得有关第三次和第四次DV感染的具体问题首次得到解决。由此产生的数据对于疫苗设计和了解登革热免疫发病机制和自然保护具有重要意义。我们将继续跟踪马那瓜的 3,300 名 2-14 岁儿童，并检查第 3 次/第 4 次与第 2 次 DV 感染的流行病学、临床和免疫学特征。这是一个独特的机会，可以利用现有的研究基础设施和资源，继续在尼加拉瓜进行长期前瞻性队列研究，以回答有关登革热的关键问题，这些问题对疫苗开发有直接影响。我们过去 7 年从 PDCS 获得的数据证明了识别足够的重复 DV 感染并获取目标 1-3 样本的可行性。该 PI 是马那瓜国家病毒学实验室 (NVL) 主任和尼加拉瓜科学研究所病毒学项目主任，与加州大学伯克利分校 (UC) 的 Eva Harris 博士密切合作超过 16 年年。我们拥有支持所有提议的实验和方法的初步数据，并且已做好执行概述的研究的准备。重要的是，所有拟议的工作都将在尼加拉瓜进行，并与加州大学伯克利分校的哈里斯实验室继续进行科学互动和培训。目标 1 将识别队列中重复的 DV 感染，并确定第 3 次/第 4 次 DV 感染与第 2 次 DV 感染的感染结果的危险因素。目标 2 将使用纵向统计方法来评估与第 1 次和第 2 次感染相比，第 3 次/第 4 次 DV 感染相关的临床体征和症状。在目标 3 中，我们将表征 B 细胞和体液免疫反应，并分析血清亲和力以及 DV 特异性 B 细胞的广度和质量与 DV 感染数量和结果的关系。这些目标解决了登革热领域从未仔细表征过的关键概念，其结果与疫苗开发高度相关