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: 10673312
• 负责人: Amy L Hartman
• 金额: $ 48.33万
• 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/10673312
• 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; Persons; 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.

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