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

总结 在世界范围内，超过30亿人处于由登革病毒1-4（DENV 1 -4）引起的感染和疾病的风险中， 寨卡病毒（ZIKV）是由伊蚊传播的两种可能严重的黄病毒性疾病。的毁灭性 地方性登革热在热带和亚热带地区的影响已有详细记载。最近的寨卡大流行 随着寨卡病毒席卷拉丁美洲，在寨卡大流行高峰期三年后， 登革热疫情已开始重新发生;然而，黄病毒病在各地区的未来， 广泛的ZIKV免疫性是未知的。在本R 01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与ZIKV之间的免疫相互作用方面的知识空白， 了解广泛的ZIKV免疫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， 根据迄今为止的流行病学和临床数据，我们的总体假设是DENV 1 -4和ZIKV是抗原性的。 它们密切相关，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童登革热队列研究（PDCS，2004年至今），一个基于社区的 在尼加拉瓜马那瓜进行的前瞻性队列研究，跟踪了约4，000名儿童，现已进入第17年。样本 PDCS以及在马那瓜进行的相关研究也提供了有记录的感染和疾病数据， 在ZIKV到来之前的十多年里，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寨卡病毒爆发前到爆发后的相互作用。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免疫力可以增强ZIKV的免疫力。 疾病严重程度由DENV 3引起，但可以预防DENV 1。在目标2中，我们将测量抗DENV 和抗ZIKV抗体介导的免疫力随时间的变化，估计保护性和增强性免疫力的年度变化。 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免疫力。 对DENV和ZIKV感染的易感性以及通过结合免疫学方法在未来流行的可能性， 地理和昆虫学资料。在目标3中，我们将确定保护性和疾病增强性抗- 先前DENV感染对Zika和先前ZIKV感染对登革热的身体介导免疫， 严重性。在专家合作者的支持下，我们将使用最先进的工具（例如，新的单克隆抗体， 创新的黄病毒抗原和抗体Fc谱）来分析特定的感染史， 潜在的免疫相关性。总的来说，该计划将定义新的疫苗伴随诊断测定， 对DENV和ZIKV的抗体应答的动力学，以及对DENV和ZIKV的保护和发病机制的相关性。 登革热和寨卡病毒，这应该是有用的登革热和寨卡疫苗的开发和评估。

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.