Previous exposure to dengue as a risk factor for Zika during pregnancy

项目摘要 登革热病毒（DENV）在美洲的许多地区流行，其中寨卡病毒（ZIKV）正在出现。这些 两种病毒在遗传和抗原性上密切相关，因此对DENV的免疫可能影响结果 ZIKV感染本项目的目标是了解预先存在的DENV免疫诱导的影响， 通过在怀孕期间感染ZIKV或接种ZIKV疫苗来预防ZIKV感染。这个问题很重要，因为 假设，与ZIKV感染相关的不良后果的意外高发生率， 怀孕可能是先前感染四种DENV血清型之一的结果。原发性感染 一种DENV血清型对相同血清型的二次感染具有保护性。继发感染 不同血清型的抗体可能导致疾病加重，因为交叉反应、中和不足的抗体可能促进病毒复制增强和免疫应答偏斜。DENV和ZIKV相似 ZIKV在包膜蛋白（这些增强抗体的主要靶点）中的含量足以使ZIKV理论上 作为“第五”DENV血清型起作用。这在一定程度上已经被探索过，但争议仍然存在，因为 一些团体报告了交叉保护，而另一些团体则报告了增强疾病的可能性。 重要的是，DENV和ZIKV之间的相互作用尚未在妊娠环境中探索， 尽管先天性ZIKV感染与出生缺陷有关。因此，通过这个NIH/ NIAD R 01我们将使用我们的ZIKV感染的非人灵长类动物模型来评估妊娠期间母体和胎儿ZIKV感染的严重程度是否因先前暴露于DENV而增强。有两 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， DENV未感染个体同样感染ZIKV。我们诱导DENV特异性免疫应答的策略包括暴露于野生型DENV和领先的DENV候选疫苗Sanofi Pasteur's Dengvaxia®。这些研究至关重要，因为1）ZIKV在许多地方传播， DENV是高流行性的，2）Dengvaxia®目前已获得使用许可，并获得其他DENV疫苗的许可 在ZIKV病毒传播的地区，根据定义，大规模疫苗接种活动将增加 登革病毒免疫的流行。是否使用Dengvaxia®免疫-同时暴露 个体感染所有四种DENV血清型-可导致更严重的ZIKV疾病是未知的。的结果 这些实验将为流行病学相关问题提供重要答案;在ZIKV也共同流行的情况下，接种登革热疫苗是否安全？

Project Summary Dengue virus (DENV) is endemic in many regions of the Americas where Zika virus (ZIKV) is emerging. These two viruses are closely related genetically and antigenically, so immunity to DENV may influence the outcome of ZIKV infection. The goal of this project is to understand the impact of pre-existing DENV immunity induced by infection or vaccination on ZIKV infection during pregnancy. This question 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 DENV serotypes. Primary infection with one DENV serotype is protective against secondary infection with the same serotype. Secondary infection with a different serotype can lead to enhanced disease because cross-reactive, inadequately neutralizing, antibodies can facilitate enhanced viral replication and skewed immune responses. DENV and ZIKV are similar enough in the envelope protein (the major target of these enhancing antibodies) that ZIKV could theoretically function as a “fifth” DENV serotype. This has been explored to some degree, but controversy remains, as some groups have reported cross-protection while others have reported the potential for enhanced disease. Critically, interactions between DENV and ZIKV have not been explored in the setting of pregnancy, even though congenital ZIKV infection is associated with birth defects. Accordingly, through this NIH/ NIAD R01 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. 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) Dengvaxia® is currently licensed for use, and licensure of other DENV vaccines is imminent, in areas where ZIKV is circulating. By definition, large-scale vaccination campaigns will increase the prevalence of DENV immunity. Whether immunization with Dengvaxia®—which simultaneously exposes an individual 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?