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

项目概要/摘要 世界卫生组织警告说，由蚊子传播的 人畜共患病病原体裂谷热病毒（RVFV）。这种新兴病毒的后果可能是 由于预防感染和疾病的疫苗不足而加剧。裂谷热是一个重要的 家畜的农业经济疾病，在非洲和中东部分地区流行。进一步 鉴于在欧洲发现了能够传播RVFV的蚊子物种， 美洲.羊裂谷热病最显著的特征是胎儿大量丢失（称为“流产 风暴”）席卷了成群的怀孕动物，在那里，自然流产率可能高达 90%。牲畜接种疫苗可保护动物，同时减少RVFV的传播， 人RVFV家畜疫苗成功开发的障碍包括：1）疫苗株通常 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的疫苗 并不总是有效地防止怀孕期间的垂直传播。这些障碍代表了一个主要的 疫苗研发领域的差距。RVFV减毒活疫苗株的作用机制 在子宫内垂直传播，以及保护 发育中的胎儿，尚不清楚。没有对临床上- 相关的减毒活疫苗已经研制成功。为了解决该领域的这一差距，我们建议使用 RVFV垂直传播和妊娠晚期妊娠大鼠胎儿死亡的实验啮齿动物模型。RVFV 直接感染大鼠胎盘，引起出血和炎症，并导致胎儿畸形 包括子宫内胎儿死亡，甚至在没有疾病迹象的怀孕母鼠中。本提案将使用 妊娠大鼠模型，以测试目前的裂谷热候选疫苗的垂直传播机制，胎儿 保护和鉴定母体免疫与胎儿保护的相关性。我们亦会进行一项 RVFV强毒株和弱毒株对胎盘组织的感染作用比较分析 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， 接种RVFV减毒活疫苗的孕鼠将提供疫苗安全性的临床前定量数据 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性。完成 这些研究将改变RVFV疫苗开发的范式，首次提供了一个 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.