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 在世界范围内，超过30亿人面临由登革热病毒1-4(DENV1-4)和 寨卡病毒(ZIKV)，这两种潜在的严重黄病毒疾病都是由伊蚊传播的。毁灭性的 地方性登革热对热带和亚热带的影响是有据可查的。最近的寨卡病毒大流行 随着寨卡病毒席卷拉丁美洲，引发了研究。寨卡病毒大流行高峰三年后，主要 登革热疫情已经开始重新出现；然而，黄病毒病在有 寨卡病毒的广泛免疫力尚不清楚。在本R01中，我们建议开发新工具并解决关键问题 在黄病毒传播和DENV和ZIKV之间免疫相互作用方面的知识差距 了解广泛传播的寨卡病毒免疫如何影响后续的登革热疾病，并告知 评估登革热和寨卡病毒临床疫苗试验和许可后研究。根据我们的血清学结果， 到目前为止的流行病学和临床数据，我们的总体假设是DENV1-4和ZIKV是抗原性的 密切相关，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(PDDC，2004年至今)是一项基于社区的研究 尼加拉瓜马那瓜的前瞻性队列研究，跟踪调查了约4,000名儿童，目前已进入第17个年头。样品来自 疾病预防控制中心以及马那瓜的配套研究也提供了记录在案的感染和疾病数据。 作为保存了十多年的血清样本，在ZIKV到来之前。这项拟议的研究扩大了队列， 确保我们能够完整地记录这些病毒从寨卡病毒时代之前到后寨卡时代的相互作用。在……里面 目标1，我们将开发基于糖链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。然后我们将测试我们的假设，即预先存在的ZIKV免疫可以增强 由DENV3引起的疾病严重性，但对DENV1具有保护作用。在目标2中，我们将测量抗登革热病毒的变化 和抗ZIKV抗体介导的免疫随着时间的推移，估计每年的变化保护和增强 对每种病毒的种群免疫，收集昆虫学数据，并使用建模方法评估种群- 对DENV和ZIKV感染的易感性以及加入免疫球蛋白的未来流行的可能性。 地理和昆虫学数据。在目标3中，我们将确定保护性和增强性抗病的决定因素 寨卡病毒前期感染和登革热前期感染的机体免疫 严肃性。在专家合作者的支持下，我们将使用最先进的工具(例如，新的单抗， 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 潜在的免疫相关性。总体而言，该计划将定义新的疫苗配套诊断分析，即 猪传染性法氏囊病病毒和寨卡病毒抗体应答的动态变化及其保护作用与发病机制的关系 这将有助于登革热和寨卡病毒疫苗的开发和评估。

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.