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.

项目概要 登革热病毒（DENV）对人类死亡和疾病造成重大且不受控制的负担，疫苗 由于我们对登革热病毒多血清型防护的理解存在严重差距，发展受到阻碍 产生、持续并随后在免疫学测定中被鉴定为重症的最大风险。 登革热疾病伴随继发感染而发生，登革热病毒疫苗需要提供针对以下情况的保护： 我们之前的研究已经证明，至少同时使用两种血清型可以最大限度地提高疗效和安全性。 通过随时间累积的连续暴露，可以自然地实现持久的多类型免疫力 因此，我们的目标是确定儿童感染登革热病毒传播的影响。 最早的黄病毒暴露对形成 DENV 体液免疫表型和亚型临床结果的影响 频繁的 DENV 暴露，为保护的免疫相关性产生了重要的基准。 为了实现这一目标，我们将利用一项正在进行的长期多代家庭队列研究 该队列于 2015 年利用 NIH P01 建立。 和美国国防部资助，并已招募了 500 个家庭的 3000 多名原发性 DENV 感染者。 迄今为止，已在 814 名未接触过登革热病毒的儿童中得到确认，到年底还有更多的儿童得到确认。 研究期为 2028 年，标志着连续监测 13 年的事件感染。 我们每季度采样一次，以检测血清转化情况并积极监测急性登革热疾病。 将通过胎盘移植和母乳喂养将母体传递的免疫力水平与以下风险联系起来： 750 名母婴夫妇（包括 500 名之前登记的和 250 名新注册的双人组）（目标 1）接下来，我们将继续对登革热病毒幼稚儿童进行长期随访。 识别与预防疾病相关的同种型和抗原特异性 DENV 抗体表型 最后，我们将讨论非 DENV 黄病毒暴露（日本脑病）。 alitis 病毒 [JEV] 疫苗接种、寨卡病毒感染、JEV 感染）对随后登革热疾病风险的影响，定义 暴露后时间、感染前抗体表型和 JEV 疫苗类型的影响（目标 3）。 这些活动与 NIAID 的使命是一致的，即更好地了解、治疗并最终预防感染。 该应用的创新在于使用定制多重面板来分析 DENV 抗体。 唾液，允许频繁的纵向采样，并使用先进的建模技术来重建 免疫动力学和识别亚临床感染的成功完成研究目标将代表着一个重要的目标。 在确定针对登革热的持久、多血清型保护的免疫相关性方面取得了重大进展 gue 疾病，为诊断、分类、DENV 疫苗和免疫疗法提供关键基准。