Live-attenuated Rift Valley fever vaccines: comparative mechanisms of trans-placental transmission and vaccine efficacy for developing fetuses

项目摘要/摘要 世界卫生组织警告说，由蚊媒传播的 人畜共患裂谷热病毒(RVFV)。这种新出现的病毒的后果可能是 由于预防感染和疾病的疫苗不足，情况进一步恶化。RVF是一种重要的 家畜的农业经济疾病，在非洲和中东部分地区流行。进一步 鉴于能够传播RVFV的蚊子种类在欧洲和 美洲。绵羊RVF病最显著的特征是胎儿丢失的浪潮(即所谓的“流产” 风暴“)席卷了成群的怀孕动物，那里的自然流产率可以高达 高达90%。家畜接种疫苗保护动物，同时减少RVFV的传播到 人民。成功开发轮状病毒家畜疫苗的障碍包括：1)疫苗毒株往往 导致怀孕动物的胎儿感染和死亡，以及2)保护成年动物免受疾病侵袭的疫苗 在预防怀孕期间垂直传播方面并不总是有效的。这些障碍代表着一个重大的 疫苗开发领域的差距。RVFV减毒活疫苗毒株的机制是 在子宫内垂直传播，以及母体免疫反应所需的保护 发育中的胎儿，目前还不清楚。没有对临床上的垂直传播潜力进行系统评估 已经进行了相关的减毒活疫苗试验。为了解决这一领域的差距，我们建议使用 RVFV垂直传播与妊娠晚期胎鼠死亡的实验动物模型。RVFV 直接感染大鼠的胎盘，引起出血和炎症，并导致胎儿畸形 包括宫内胎儿死亡，即使在没有疾病迹象的怀孕水坝中也是如此。此提案将使用 用妊娠大鼠模型测试目前裂谷热疫苗候选垂直传播机制(S)，胎儿 保护，并确定胎儿保护的母体免疫相关因素。我们还将进行一次 RVFV强毒株与弱毒株对猪胎盘外植体透过率的比较分析 相关物种，以确定感染的细胞和结构目标。我们的总体假设是感染 接种RVFV减毒活疫苗的怀孕大鼠将提供疫苗安全性的临床前量化数据 对于发育中的胎儿，对胎儿的功效，以及胎儿保护的关键母体相关因素。完成 这些研究将改变RVFV疫苗开发的范式，首次提供一种 临床相关LAV垂直传播潜力的机制解释。

PROJECT SUMMARY/ABSTRACT The World Health Organization warns of a pending public health emergency caused by mosquito-borne zoonotic pathogen Rift Valley fever virus (RVFV). The consequences of this emerging virus could be exacerbated by insufficient vaccines for prevention of infection and disease. RVF is an important agroeconomic illness of domesticated livestock and is endemic in Africa and parts of the Middle East. Further spread is likely given that mosquito species capable of transmitting RVFV are found in Europe and the Americas. The most striking feature of RVF disease in sheep is a wave of fetal loss (known as an “abortion storm”) that sweeps through herds of pregnant animals, where spontaneous abortion rates can reach as high as 90%. Vaccination of livestock protects animals while simultaneously reducing the spread of RVFV to people. Obstacles in the successful development of RVFV livestock vaccines include: 1) vaccine strains often cause fetal infection and death in pregnant animals, and 2) vaccines that protect adult animals from disease are not always effective at preventing vertical transmission during pregnancy. These hurdles represent a major gap in the vaccine development field. The mechanisms by which live-attenuated vaccine strains of RVFV are vertically transmitted in utero, as well as the maternal immune response required for the protection of developing fetuses, are not known. No systematic evaluation of the vertical transmission potential of clinically- relevant live attenuated vaccines has been performed. To address this gap in the field, we propose to use an experimental rodent model of RVFV vertical transmission and fetal death in late-gestation pregnant rats. RVFV directly infects the placenta in rats, causes hemorrhage and inflammation, and results in fetal malformations including intrauterine fetal death even in pregnant dams without signs of disease. This proposal will use the pregnant rat model to test current RVF vaccine candidates for the mechanism(s) of vertical transmission, fetal protection, and identification of maternal immune correlates of fetal protection. We will also conduct a comparative analysis of virulent and attenuated RVFV strains for permissivity of placental explants from relevant species to identify cellular and structural targets of infection. Our overall hypothesis is that infection of pregnant rats with RVFV live-attenuated vaccines will provide pre-clinical quantitative data on vaccine safety for developing fetuses, efficacy for the fetuses, and critical maternal correlates of fetal protection. Completion of these studies will change the paradigm of RVFV vaccine development by providing, for the first time, a mechanistic explanation for the vertical transmission potential of clinically relevant LAVs.