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

裂谷热减毒活疫苗：经胎盘传播的比较机制和疫苗对发育中胎儿的功效

• 批准号: 10113532
• 负责人: Amy L Hartman
• 金额: $ 63.46万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10113532
• 关键词: Abortion Rates; Address; Adult; Africa; Americas; Animal Diseases; Animals; Attenuated; Attenuated Live Virus Vaccine; Attenuated Vaccines; Biological Response Modifiers; Cells; Cellular Structures; Culicidae; Data; Development; Disease; Disease Outbreaks; Europe; Evaluation; Female; Fetal Death; Fetal Development; Fetus; Health; Hemorrhage; Human; Immune; Immune response; Induced Abortion; Infection; Infection prevention; Inflammation; Livestock; Maternal-Fetal Transmission; Middle East; Modeling; Mosquito-borne infectious disease; Outcome; Pathology; Placenta; Predisposition; Pregnancy; Production; Rattus; Rift Valley Fever; Rift Valley fever virus; Rodent Model; Safety; Sheep; Spontaneous abortion; Testing; Time; Tropism; Vaccination; Vaccines; Vertical Disease Transmission; Viral Load result; Virulent; Virus; Virus Diseases; World Health Organization; Zoonoses; abortion; base; clinically relevant; comparative; fetal; fetal infection; fetal loss; in utero; malformation; mature animal; mosquito-borne; next generation; novel vaccines; pathogen; pre-clinical; pregnant; prepregnancy; prevent; public health emergency; transmission process; vaccine candidate; vaccine development; vaccine efficacy; vaccine safety

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.

项目概要/摘要 世界卫生组织警告称，蚊子传播的公共卫生紧急事件尚未解决 人畜共患病病原体裂谷热病毒（RVFV）这种新出现的病毒的后果可能是。 RVF 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。 鉴于在欧洲和其他地区发现了能够传播裂谷热病毒的蚊子种类，该病毒很可能会传播 美洲绵羊裂谷热病最显着的特征是胎儿流失浪潮（称为“流产”）。 风暴”）席卷怀孕动物群，自然流产率高达 90% 的牲畜接种疫苗可以保护动物，同时减少 RVFV 的传播。 成功开发RVFV家畜疫苗的障碍包括：1）疫苗毒株经常存在。 导致怀孕动物胎儿感染和死亡，以及 2) 保护成年动物免受疾病侵害的疫苗 这些障碍并不总是能有效预防怀孕期间的垂直传播。 RVFV减毒活疫苗株的机制存在空白。 在子宫内垂直传播，以及保护胎儿所需的母体免疫反应 尚无对临床上垂直传播潜力的系统评估。 为了解决这一领域的空白，我们建议使用相关的减毒活疫苗。 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。 直接感染大鼠胎盘，引起出血和炎症，导致胎儿畸形 包括宫内胎儿死亡，即使是在没有疾病迹象的怀孕母鼠中。 怀孕大鼠模型，用于测试当前候选RVF疫苗的垂直传播机制、胎儿 保护，并确定胎儿保护的母体免疫相关性。 RVFV 强毒株和减毒株对胎盘外植体容许度的比较分析 相关物种来识别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定量数据 对胎儿发育的影响、对胎儿的功效以及胎儿保护完成的重要母体相关因素。 这些研究首次提供了一种方法，将改变 RVFV 疫苗开发的范式 临床相关 LAV 垂直传播潜力的机制解释。