Living in the post-Zika world: Impact of interactions between dengue and Zika viruses on diagnostics, antibody dynamics, and correlates of disease risk

生活在后寨卡世界：登革热和寨卡病毒之间的相互作用对诊断、抗体动态和疾病风险相关性的影响

• 批准号: 10615774
• 负责人: Eva Harris
• 金额: $ 100.24万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-13 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10615774
• 关键词: Address; Aedes; Affect; Age; Algorithms; Americas; Antibodies; Antibody Response; Antibody-mediated protection; Antigens; Area; Biological Assay; Biophysics; Characteristics; Child; Childhood; Clinical Data; Cohort Studies; Communities; Companions; Culicidae; Data; Data Analyses; Dengue; Dengue Hemorrhagic Fever; Dengue Infection; Dengue Shock Syndrome; Dengue Vaccine; Dengue Virus; Detection; Development; Diagnostic; Disease; Disease Outcome; E protein; Engineering; Ensure; Enzyme-Linked Immunosorbent Assay; Epidemic; Epidemiology; Epitopes; Evaluation; Flavivirus; Flavivirus Infections; Future; Guillain Barré Syndrome; Household; Immune; Immunity; Immunologics; Individual; Infection; Kinetics; Knowledge; Lateral; Latin America; Licensing; Licensure; Life; Machine Learning; Masks; Measures; Mediating; Methods; Modeling; Monoclonal Antibodies; Nicaragua; Nicaraguan; Pathogenesis; Pathogenicity; Phase; Polysaccharides; Population; Populations at Risk; Predisposition; Prevalence; Prospective, cohort study; Recording of previous events; Research; Risk; Running; Sampling; Sampling Studies; Sensitivity and Specificity; Serology; Serology test; Seroprevalences; Serotyping; Serum; Severities; Severity of illness; Specificity; System; Testing; Time; Vaccine Clinical Trial; Vaccines; Virus; Work; ZIKA; ZIKV disease; ZIKV infection; Zika Virus; Zika virus vaccine; assay development; cohort; companion diagnostics; congenital zika syndrome; cross reactivity; design; diagnostic assay; disease transmission; disorder risk; e Antigens; env Gene Products; epidemic preparedness; epidemiologic data; epidemiological model; epidemiology study; experimental study; future epidemic; improved; infection risk; innovation; insight; novel; novel vaccines; pandemic disease; programs; public health research; response; sex; tool; transmission process; vaccine efficacy; vaccine evaluation; vaccine safety; vaccine trial; viral transmission

SUMMARY Worldwide, over 3 billion people are at risk of infection and disease caused by dengue virus 1-4 (DENV1-4) and Zika virus (ZIKV), both potentially severe flaviviral diseases transmitted by Aedes mosquitoes. The devastating effects of endemic dengue across the tropics and subtropics are well documented. The recent Zika pandemic galvanized research as Zika swept across Latin America. Three years after the peak of the Zika pandemic, major dengue epidemics have started to re-occur; however, the future of flaviviral disease across areas with widespread ZIKV immunity is unknown. In this R01, we propose to develop new tools and address key knowledge gaps in flaviviral transmission and immunological interactions between DENV and ZIKV to understand how widespread ZIKV immunity impacts subsequent dengue disease and to inform evaluation of dengue and Zika clinical vaccine trials and post-licensure studies. Based on our serological, epidemiological, and clinical data to date, our overall hypothesis is that DENV1-4 and ZIKV are antigenically closely related and that immune interactions mutually affect transmission and disease severity. We will address this hypothesis with the ongoing Pediatric Dengue Cohort Study (PDCS, 2004-present), a community-based prospective cohort study in Managua, Nicaragua, following ~4,000 children, now in its 17th year. Samples from the PDCS, as well as companion studies in Managua, provide documented infection and disease data, as well as banked serum samples for over a decade before the arrival of ZIKV. The proposed study extends the cohort, ensuring that we are able to fully document the interactions of these viruses from the pre- to post-Zika eras. In Aim 1, we will develop innovative serologic tools based on glycan-fusion-loop-masked envelope proteins and new algorithms to distinguish DENV and ZIKV infection histories, critical for vaccination and epidemiological studies of dengue and Zika. We will then test our hypothesis that pre-existing ZIKV immunity can enhance disease severity caused by DENV3 but protect against DENV1. In Aim 2, we will measure changes in anti-DENV and anti-ZIKV antibody-mediated immunity over time, estimate annual changes in protective and enhancing population immunity to each virus, collect entomological data, and use modeling approaches to evaluate popula- tion susceptibility to DENV and ZIKV infection and the potential for future epidemics by incorporating immunolo- gical and entomological data. In Aim 3, we will identify determinants of protective and disease-enhancing anti- body-mediated immunity of prior DENV infection on Zika and prior ZIKV infection on dengue disease and severity. With support of expert collaborators, we will use state-of-the-art tools (e.g., new monoclonal antibodies, innovative flavivirus antigens, and antibody Fc profiling) to analyze specific infection histories and uncover potential immune correlates. Overall, this program will define new vaccine companion diagnostic assays, the dynamics of the antibody response to DENV and ZIKV, and correlates of protection and pathogenesis for dengue and Zika, which should be useful for the development and evaluation of dengue and Zika vaccines.

概括 Worldwide, over 3 billion people are at risk of infection and disease caused by dengue virus 1-4 (DENV1-4) and Zika virus (ZIKV), both potentially severe flaviviral diseases transmitted by Aedes mosquitoes. The devastating effects of endemic dengue across the tropics and subtropics are well documented. The recent Zika pandemic galvanized research as Zika swept across Latin America. Three years after the peak of the Zika pandemic, major dengue epidemics have started to re-occur; however, the future of flaviviral disease across areas with widespread ZIKV immunity is unknown. In this R01, we propose to develop new tools and address key knowledge gaps in flaviviral transmission and immunological interactions between DENV and ZIKV to understand how widespread ZIKV immunity impacts subsequent dengue disease and to inform evaluation of dengue and Zika clinical vaccine trials and post-licensure studies. Based on our serological, epidemiological, and clinical data to date, our overall hypothesis is that DENV1-4 and ZIKV are antigenically closely related and that immune interactions mutually affect transmission and disease severity.我们将解决 该假设通过正在进行的小儿登革热队列研究（PDCS，2004-Tresent），这是一个基于社区的 在尼加拉瓜Managua的前瞻性队列研究中，已有约4,000名儿童，现在是17年。来自 PDC以及Managua的同伴研究也提供了记录的感染和疾病数据 在Zikv到达之前，作为储存的血清样品已有十多年了。拟议的研究扩展了队列， 确保我们能够充分记录这些病毒从Zika之前到Zika时代的相互作用。在 AIM 1，我们将开发基于聚糖融合环遮盖的包络蛋白的创新血清学工具和 区分DENV和ZIKV感染历史的新算法，对于疫苗接种至关重要 登革热和寨卡研究。然后，我们将测试我们的假设，即现有的ZIKV免疫可以增强 DENV3引起的疾病严重程度，但可以防止DENV1。在AIM 2中，我们将衡量抗Denv的变化 随着时间的流逝，抗ZIKV抗体介导的免疫力，估计保护性的年变化和增强 对每种病毒的种群免疫，收集昆虫学数据，并使用建模方法来评估Popula- 对DENV和ZIKV感染的敏感性，以及通过纳入免疫的潜力 基因和昆虫学数据。在AIM 3中，我们将确定保护性和增强疾病的抗疾病的决定因素 身体介导的先前DENV感染对Zika的免疫力和对登革热疾病的先前ZIKV感染和 严重程度。在专家合作者的支持下，我们将使用最先进的工具（例如，新的单克隆抗体， 创新的黄病毒抗原和抗体FC分析）以分析特定的感染历史并发现 潜在的免疫相关。总体而言，该程序将定义新的疫苗伴侣诊断测定法， 抗体对DENV和ZIKV的抗体反应的动力学，以及保护和发病机理的相关性 登革热和Zika，这对于登革热和寨卡疫苗的开发和评估应该有用。

项目成果

Protection against symptomatic dengue infection by neutralizing antibodies varies by infection history and infecting serotype.

• DOI: 10.1038/s41467-023-44330-8
• 发表时间: 2024-01-09
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Bos, Sandra;Graber, Aaron L.;Cardona-Ospina, Jaime A.;Duarte, Elias M.;Zambrana, Jose Victor;Ruiz Salinas, Jorge A.;Mercado-Hernandez, Reinaldo;Singh, Tulika;Katzelnick, Leah C.;de Silva, Aravinda;Kuan, Guillermina;Balmaseda, Angel;Harris, Eva
• 通讯作者: Harris, Eva