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

摘要 全球有超过 30 亿人面临感染登革热病毒 1-4 (DENV1-4) 和疾病的风险 寨卡病毒 (ZIKV)，两种由伊蚊传播的潜在严重黄病毒疾病。毁灭性的 地方性登革热对热带和亚热带地区的影响已有详细记录。最近的寨卡病毒大流行 随着寨卡病毒席卷拉丁美洲，刺激了研究。寨卡大流行高峰三年后，主要 登革热疫情开始再次发生；然而，黄病毒病跨地区的未来 广泛的 ZIKV 免疫力尚不清楚。在本 R01 中，我们建议开发新工具并解决关键问题 DENV 和 ZIKV 之间的黄病毒传播和免疫相互作用方面的知识差距 了解广泛传播的 ZIKV 免疫力如何影响随后的登革热疾病并告知 评估登革热和寨卡疫苗临床试验和许可后研究。根据我们的血清学检测， 迄今为止的流行病学和临床数据，我们的总体假设是 DENV1-4 和 ZIKV 具有抗原性 密切相关，并且免疫相互作用相互影响传播和疾病严重程度。我们将解决 这一假设与正在进行的儿科登革热队列研究（PDCS，2004 年至今）是一项基于社区的研究 在尼加拉瓜马那瓜开展的前瞻性队列研究，对约 4,000 名儿童进行了跟踪研究，现已进入第 17 个年头。样品来自 PDCS 以及马那瓜的配套研究提供了记录的感染和疾病数据，以及 在 ZIKV 出现之前，血清样本已经储存了十多年。拟议的研究扩展了队列， 确保我们能够完整记录从前寨卡时代到后寨卡时代这些病毒的相互作用。在 目标 1，我们将开发基于聚糖融合环掩蔽包膜蛋白的创新血清学工具 区分 DENV 和 ZIKV 感染史的新算法对于疫苗接种和流行病学至关重要 登革热和寨卡病毒的研究。然后我们将检验我们的假设，即预先存在的 ZIKV 免疫力可以增强 由 DENV3 引起的疾病严重程度，但可预防 DENV1。在目标 2 中，我们将测量抗 DENV 的变化 和抗 ZIKV 抗体介导的免疫力随着时间的推移，估计保护性和增强性的年度变化 群体对每种病毒的免疫力，收集昆虫学数据，并使用建模方法来评估群体 通过整合免疫学，评估对 DENV 和 ZIKV 感染的易感性以及未来流行病的可能性 地理和昆虫学数据。在目标 3 中，我们将确定保护性和增强疾病的抗病毒药物的决定因素。 先前感染登革热病毒（DENV）对寨卡病毒和先前感染寨卡病毒（ZIKV）对登革热的身体介导免疫 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）来分析特定的感染历史并揭示 潜在的免疫相关性。总体而言，该计划将定义新的疫苗伴随诊断检测方法， 抗体对 DENV 和 ZIKV 反应的动态，以及保护和发病机制的相关性 登革热和寨卡病毒，这对于登革热和寨卡疫苗的开发和评估应该有用。

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.