Defining correlates of protection from dengue illness in a long-term cohort study of multigenerational house-holds in Thailand

在泰国多代家庭的长期队列研究中定义预防登革热疾病的相关性

• 批准号: 10639298
• 负责人: Kathryn B Anderson
• 金额: $ 71.07万
• 依托单位: UPSTATE MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-10 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10639298
• 关键词: Acute; Address; Antibodies; Antibody titer measurement; Antigens; Arboviruses; Area; Benchmarking; Breast Feeding; Cessation of life; Child; Clinical; Cohort Studies; Communicable Diseases; Custom; Dengue; Dengue Infection; Dengue Vaccine; Dengue Virus; Development; Diagnostic; Disease; Enrollment; Environment; Exposure to; Family; Flavivirus; Funding; Future; Generations; Goals; Health; Household; Human; Humoral Immunities; Immune; Immunity; Immunoglobulin G; Immunologics; Immunology procedure; Immunotherapy; Incidence; Individual; Infant; Infection; Japanese encephalitis virus; Kinetics; Knowledge; Locales; Longitudinal cohort study; Longterm Follow-up; Malaria; Maps; Maternally-Acquired Immunity; Mediating; Mission; Modeling; Mothers; National Institute of Allergy and Infectious Disease; Outcome; Pathogenesis; Phenotype; Population Surveillance; Pregnant Women; Recording of previous events; Research; Risk; Safety; Saliva; Sampling; Serotyping; Shapes; Specimen; Techniques; Testing; Thailand; Time; Triage; United States National Institutes of Health; Vaccinated; Vaccination; Vaccine Therapy; Vaccines; Virus Diseases; ZIKV infection; Zika Virus; cohort; cross reactivity; efficacy trial; expectation; immunogenicity; innovation; mathematical model; placental transfer; prenatal; prevent; primary outcome; protective effect; secondary infection; seroconversion; severe dengue; tool; vaccine development; viral transmission; ward

PROJECT SUMMARY Dengue viruses (DENV) cause a significant and unchecked burden of human death and disease, with vaccine development hindered by critical gaps in our understanding of how multi-serotypic protection against DENV is generated, sustained, and subsequently identified in immunological assays. As the greatest risk for severe dengue illness occurs with secondary infection, DENV vaccines will need to generate protection against at least two serotypes simultaneously to maximize efficacy and safety. Our prior studies have demonstrated that durable, multi-typic immunity can be achieved naturally, through sequential exposures accumulated over time in hyperendemic areas for DENV transmission. Accordingly, our objective is to define the impacts of a child’s earliest flavivirus exposures in shaping DENV humoral immune phenotypes and clinical outcomes of subse- quent DENV exposures, generating important benchmarks for immune correlates of protection. To address this objective, we will leverage an ongoing long-term multigenerational family cohort study for DENV transmission in Kamphaeng Phet, Thailand. The cohort was established in 2015, leveraging NIH P01 and US DOD funds, and has enrolled over 3000 individuals within 500 families. 432 primary DENV infections have been identified among 814 DENV-naïve children to date, with more to be identified by the end of the study period in 2028 and marking 13 years of continuous surveillance. Incident infections are identified through quarterly sampling to detect seroconversions and through active surveillance for acute dengue illnesses. We will relate levels of maternally-transferred immunity, through placental transfer and breastfeeding, to risks of dengue illness with primary DENV infection in 750 mother-infant dyads (including 500 previously-enrolled and 250 newly-enrolled dyads) (Aim 1). Next, we will continue our long-term follow-up of DENV-naïve children and identify isotype- and antigen-specific DENV antibody phenotypes associated with protection from illness with post-primary DENV infection (Aim 2). Finally, we will relate non-DENV flavivirus exposures (Japanese enceph- alitis virus [JEV] vaccination, Zika virus infection, JEV infection) to risks of subsequent dengue illness, defining effects of time since exposure, pre-infection antibody phenotypes, and JEV vaccine type (Aim 3). These activities are consistent with NIAID’s mission to better understand, treat, and ultimately prevent infec- tious diseases. The application is innovative in using a custom multiplex panel for profiling DENV antibodies in saliva, permitting frequent longitudinal sampling, and in using advanced modeling techniques to reconstruct immune kinetics and identify subclinical infections. Successful completion of study aims will represent an im- portant advancement towards identifying immune correlates of durable, multi-serotypic protection against den- gue illness, providing critical benchmarks for diagnostics, triage, and DENV vaccines and immuno-therapies.

项目总结 登革热病毒(DENV)给人类的死亡和疾病造成了巨大的和无节制的负担，疫苗 发展受阻，因为我们对DENV的多血清型保护是如何理解的严重差距 产生、维持并随后在免疫学检测中被鉴定。作为严重感染的最大风险 登革热疾病发生时会发生二次感染，DENV疫苗需要对At产生保护作用 同时至少有两种血清型，以最大限度地提高疗效和安全性。我们之前的研究已经证明 通过随时间积累的连续暴露，可以自然获得持久的、多种类型的免疫力 在DENV传播的高流行区。因此，我们的目标是定义儿童的影响 早期黄病毒暴露在形成DENV体液免疫表型和亚型临床转归中的作用 量化DENV暴露，为免疫保护相关性产生重要基准。 为了实现这一目标，我们将利用正在进行的长期多代家庭队列研究 泰国Kamphaeng Phet的DENV传播。该队列成立于2015年，利用NIH P01 和美国国防部的基金，并已在500个家庭中登记了3000多人。432例原发登革热病毒感染 迄今已在814名DENV幼稚儿童中确认，还有更多儿童将在年底前确认 2028年为研究期，并标志着13年的连续监测。通过以下方式识别事件感染 通过每季度抽样检测血清转换和积极监测急性登革热。我们 会将通过胎盘转移和母乳喂养的母体转移免疫水平与 750名母婴中有原发性DENV感染的登革热疾病(包括500名先前登记的和 250名新加入的二联体)(目标1)。接下来，我们将继续对DENV-天真儿童进行长期跟踪和 识别与疾病保护相关的同型和抗原特异性DENV抗体表型 初发后DENV感染(目标2)。最后，我们将介绍非DENV黄病毒暴露(日本脑炎- 阿里炎病毒[乙脑]疫苗接种、寨卡病毒感染、乙脑病毒感染)对后续登革热疾病风险的影响，定义 暴露时间、感染前抗体表型和乙脑疫苗类型的影响(目标3)。 这些活动符合NIAID更好地了解、治疗并最终预防感染的使命。 易传染的疾病。该应用程序在使用定制的多路面板来分析DENV抗体方面具有创新性 唾液，允许频繁的纵向采样，并使用先进的建模技术重建 免疫动力学和识别亚临床感染。成功完成学习目标将代表着一种信息技术-- 在识别针对登革热的持久、多血清型保护的免疫相关性方面取得了重要进展-- GUG疾病，为诊断、分类以及DENV疫苗和免疫疗法提供关键基准。