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.

项目摘要 登革热病毒（DENV）引起人类死亡和疾病的严重且不受限制的烧伤，并用疫苗烧伤 在我们了解对DENV的多种型保护的理解时，发展的限制差距受到关键差距的阻碍 在免疫学测定中产生，持续和随后鉴定出来。作为严重的最大风险 登革热疾病发生在继发性感染时，DENV疫苗将需要为AT产生保护 至少两种血清型仅仅是为了最大程度地提高效率和安全性。我们先前的研究表明 通过随时间累积的顺序暴露，可以自然实现耐用的多种免疫组织化学 在高流血区域进行DENV传播。彼此之间，我们的目标是定义孩子的影响 最早的黄病毒暴露于塑造DENV体液免疫表型和亚se-临床结果 Quent DENV暴露，为保护剂生成重要的基准。 为了解决这一目标，我们将利用正在进行的长期多代家庭队列研究 DENV在泰国的Kamphaeng Phet的传播。该队列成立于2015年，利用NIH P01 和美国国防部的资金，已在500个家庭中招募了3000多名个人。 432原发性DENV感染 迄今为止已确定了814名未经人口的儿童，在结束前还需要确定更多 2028年的研究期，标志着13年的连续监视。通过 季度抽样以检测血清转化和通过主动监测急性登革热疾病。我们 通过占地转移和母乳喂养，将与母体转让的免疫学水平联系起来 登革热感染的登革热疾病，有750个母亲二元组（包括500个以前入围的 250个新入选的二元组（AIM 1）。接下来，我们将继续对丹夫的儿童进行长期跟进 识别与保护与疾病有关的同种型和抗原特异性DENV抗体表型 主要DENV感染（AIM 2）。最后，我们将联系非Denv Flavivivirus暴露（日本脑 Alitis病毒[JEV]疫苗接种，Zika病毒感染，JEV感染），以随后的登革热疾病风险 自暴露，感染前抗体表型和JEV疫苗类型以来的时间影响（AIM 3）。 这些活动与Niaid的使命是一致 疾病。该应用程序在使用自定义多路复用面板进行分析DENV抗体方面具有创新性 唾液，允许经常纵向采样，并使用先进的建模技术重建 免疫动力学并鉴定亚临床感染。成功完成学习目标将代表 便携式促进确定耐用，多型保护的免疫相关性，以防止DEN- 猜猜疾病，为诊断，分类和DENV疫苗和免疫疗法提供关键的基准。