Project 2: Dengue infection and vaccination enhancement of ZIKV in pregnancy

项目2--项目摘要/摘要 该项目的目标是了解先前存在的登革热病毒免疫(野生型和 在怀孕期间随后感染寨卡病毒(ZIKV)。理解重新-- 登革热免疫与随后的寨卡病毒感染之间的关系很重要，因为它已经 假设与寨卡病毒感染相关的不良后果的出乎意料的高比率 怀孕期间可能是先前感染过四种登革热病毒中的一种所致 (DENV)。初次感染四种DENV血清型中的一种对继发感染具有保护作用 有着相同的血清型。不同血清型的继发感染可导致病情加重 由于交叉反应抗体促进了病毒复制和扭曲的免疫反应。 DENV和ZIKV在包膜蛋白上足够相似(这些增强抗体的主要靶点是- IES)，从理论上讲，ZIKV可以作为第五种DENV血清型。这已经被一些人探索过了 学位，但这些报告一直存在争议，一些组织报告说存在交叉保护，而 其他人则报告了疾病增加的可能性。关键是，这一点还没有在 怀孕的背景。因此，通过NIH/NIAD P01，我们将使用我们的非人灵长类模型 ZIKV感染评估母婴孕期ZIKV感染严重程度 因以前接触DENV而增强。有两个具体目标： 明确目标1.明确以前的DENV感染对产妇和新生儿的严重程度的影响 妊娠猕猴中的寨卡病毒感染。 具体目标2.确定之前接种DENV疫苗对产妇和新生儿严重程度的影响 妊娠猕猴中的寨卡病毒感染。 在这些研究中，我们将比较母体病毒血症、免疫反应和胎儿结局 在项目1中感染ZIKV的DENV-幼稚个体。我们诱导DENV特异性的策略 免疫反应包括接触野生型DENV和一种领先的DENV候选疫苗- 赛诺菲巴斯德的Dengvaxia®这些研究是至关重要的，因为1)ZIKV在 目前，许多DENV高度流行和登革热疫苗的地区都获得了使用或 在ZIKV正在流通的地区，许可证即将发放。接种疫苗创造了一种情况，幼稚的人 人口将对DENV免疫。是否接种了登革热®疫苗的个人-在哪里 个人同时接触所有四种DENV血清型-可导致更严重的ZIKV疾病 是未知的。这些实验的结果将为流行病学提供重要的答案 相关问题；在寨卡病毒也共同流行的地方接种登革热疫苗安全吗？

Project 2 - Project Summary/Abstract The project goal is to understand the impact of pre-existing dengue virus immunity (both wildtype- and vaccine-derived) on subsequent Zika virus (ZIKV) infection during pregnancy. Understanding the re- lationship between dengue immunity on subsequent ZIKV infection is important because it has been hypothesized that the unexpectedly high rate of adverse consequences associated with ZIKV infection during pregnancy may be the result of previous infection with one of the four serotypes of dengue virus (DENV). Primary infection with one of the four DENV serotypes is protective against secondary infection with the same serotype. Secondary infection with a different serotype can lead to enhanced disease due to cross-reactive antibodies facilitating enhanced viral replication and skewed immune responses. DENV and ZIKV are similar enough in the envelope protein (the major target of these enhancing antibod- ies) that ZIKV could theoretically function as a “fifth” DENV serotype. This has been explored to some degree but the reports have been controversial with some groups reporting cross-protection, while others have reported the potential for enhanced disease. Critically, this has not been explored in the setting of pregnancy. Accordingly, through this NIH/NIAD P01 we will use our nonhuman primate model of ZIKV infection to evaluate whether the severity of maternal and fetal ZIKV infection during pregnancy are enhanced by previous exposure to DENV. There are two Specific Aims: Specific Aim 1. Define the impact of prior DENV infection on the severity of maternal and neonatal ZIKV infection in pregnant macaques. Specific Aim 2. Define the impact of prior DENV vaccination on the severity of maternal and neonatal ZIKV infection in pregnant macaques. In these studies, we will contrast maternal viremia, immune responses, and fetal outcomes with those in DENV-naive individuals infected identically with ZIKV in Project 1. Our strategy to induce DENV-specific immune responses includes exposure to both wildtype DENV and a leading DENV vaccine candidate- Sanofi Pasteur’s Dengvaxia®. These studies are critically important because 1) ZIKV is circulating in many locations where DENV is hyperendemic and 2) dengue vaccines currently are licensed for use or licensure is imminent in areas where ZIKV is circulating. Vaccination creates a scenario whereby a naive population will become DENV-immune. Whether individuals immunized with Dengvaxia®—where an individual is simultaneously exposed to all four DENV serotypes—can lead to more severe ZIKV disease is unknown. The results from these experiments will provide important answers to an epidemiologically relevant question; is it safe to vaccinate against dengue where ZIKV also is co-endemic?