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

项目2-项目概要/摘要 该项目的目标是了解预先存在的登革热病毒免疫（野生型和 寨卡病毒（ZIKV）是寨卡病毒的一种。理解再- 登革热免疫与随后的ZIKV感染之间的关系是重要的，因为它已经被证明是一种免疫。 假设与ZIKV感染相关的不良后果的意外高发生率 怀孕期间感染登革热病毒可能是先前感染四种血清型之一的结果。 （DENV）.四种DENV血清型之一的原发感染对继发感染具有保护作用 相同的血清型不同血清型的二次感染可导致病情加重 这是由于交叉反应性抗体促进增强的病毒复制和偏斜的免疫应答。 DENV和ZIKV在包膜蛋白（这些增强抗体的主要靶标）中足够相似， ZIKV理论上可以作为"第五" DENV血清型起作用。这已经被一些人探索过了。 程度，但报告一直有争议，一些团体报告交叉保护，而 其他人则报告说，这有可能加剧疾病。重要的是，这一点尚未在 怀孕的背景。因此，通过这个NIH/NIAD P01，我们将使用我们的非人灵长类动物模型 ZIKV感染的严重程度，以评估母亲和胎儿在怀孕期间是否感染ZIKV 因之前接触过登革病毒而增强。有两个具体目标： 具体目标1。定义既往DENV感染对孕产妇和新生儿严重程度的影响 妊娠猕猴中的ZIKV感染。 具体目标2。确定既往DENV疫苗接种对孕产妇和新生儿疾病严重程度的影响 妊娠猕猴中的ZIKV感染。 在这些研究中，我们将对比母体病毒血症、免疫反应和胎儿结局， 在项目1中用ZIKV相同地感染DENV-未接受过治疗的个体。我们诱导DENV特异性 免疫应答包括暴露于野生型DENV和主要的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是循环在 登革病毒高流行的许多地方和2）登革疫苗目前被许可使用，或 在ZIKV传播的地区，许可证即将颁发。疫苗接种创造了一个场景， 人口将对DENV免疫。是否用Dengvaxia®免疫的个体-其中 个体同时暴露于所有四种DENV血清型-可导致更严重的ZIKV疾病 不明这些实验的结果将为流行病学上的一个问题提供重要的答案。 相关问题;在ZIKV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?