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.

项目摘要/摘要 世界卫生组织警告蚊子出生造成的未决公共卫生紧急情况 人畜共动性病原体裂谷发烧病毒（RVFV）。这种新兴病毒的后果可能是 因预防感染和疾病的疫苗不足而加剧。 RVF是重要的 驯化牲畜的农业经济疾病，在非洲和中东地区是内在的。更远 鉴于在欧洲发现能够传输RVFV的蚊子和 美洲。绵羊RVF疾病最引人注目的特征是胎儿损失的一波（称为“流产） 风暴”）通过孕妇群的甜食，赞助堕胎率可以达到很高 为90％。牲畜的疫苗接种可保护动物，同时减少RVFV的传播 人们。 RVFV牲畜疫苗成功发展的障碍包括：1）疫苗菌株经常 引起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 并不总是有效防止怀孕期间的垂直传播。这些障碍代表了一个专业 疫苗开发领域的差距。 RVFV的活疫苗菌株的机制是 垂直传播在子宫内，以及保护所需的母体免疫反应 发展胎儿，尚不清楚。没有系统地评估临床上的垂直传输潜力 已经进行了相关的活疫苗。为了解决该领域的这一差距，我们建议使用 晚期妊娠大鼠RVFV垂直传播和胎儿死亡的实验啮齿动物模型。 RVFV 直接感染大鼠的胸骨，引起出血和感染，并导致胎儿畸形 即使在没有疾病迹象的怀孕大坝中，也包括胎儿内死亡。该建议将使用 怀孕的大鼠模型测试当前RVF疫苗候选物的垂直传播机制 保护和鉴定胎儿保护的母体免疫相关性。我们还将进行 病毒和减弱RVFV菌株的比较分析，从 相关物种鉴定感染的细胞和结构靶标。我们的总体假设是感染 带有RVFV的孕妇大鼠实时销售疫苗将提供有关疫苗安全的临床前定量数据 用于发展胎儿，胎儿的有效性以及胎儿保护的关键孕妇相关性。完成 在这些研究中，将首次提供RVFV疫苗开发的范式 临床相关LAV的垂直传输潜力的机械解释。