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
基本信息
- 批准号:10356824
- 负责人:
- 金额:$ 63.29万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:Abortion RatesAddressAdultAfricaAmericasAnimal DiseasesAnimalsAttenuatedAttenuated Live Virus VaccineAttenuated VaccinesBiological Response ModifiersCellsCulicidaeDataDevelopmentDiseaseDisease OutbreaksEconomicsEuropeEvaluationFemaleFetal DeathFetal DevelopmentFetusHemorrhageHumanImmuneImmune responseInduced AbortionInfectionInfection preventionInflammationLivestockMaternal-Fetal TransmissionMiddle EastModelingMosquito-borne infectious diseaseOutcomePathologyPersonsPlacentaPredispositionPregnancyProductionRattusRift Valley FeverRift Valley fever virusRodent ModelSheepSpontaneous abortionStructureTestingTimeTropismVaccinationVaccinesVertical TransmissionViral Load resultVirulentVirusVirus DiseasesWorld Health OrganizationZoonosesabortionclinically relevantcomparativefetalfetal infectionfetal losshealth assessmentmalformationmature animalmosquito-bornenext generationnovel vaccinespathogenpermissivenesspre-clinicalpregnantprepregnancypreventpublic health emergencysafety assessmenttransmission processvaccine candidatevaccine developmentvaccine efficacyvaccine safety
项目摘要
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.
项目总结/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
为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
相关物种以识别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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Amy L Hartman其他文献
Amy L Hartman的其他文献
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{{ truncateString('Amy L Hartman', 18)}}的其他基金
Mechanisms of Neuronal Infection by Prototype Emerging Bunyaviruses
原型新兴布尼亚病毒感染神经元的机制
- 批准号:
10728597 - 财政年份:2023
- 资助金额:
$ 63.29万 - 项目类别:
Comparative Analysis of Bunyavirus Neuropathogenesis
布尼亚病毒神经发病机制的比较分析
- 批准号:
10675190 - 财政年份:2022
- 资助金额:
$ 63.29万 - 项目类别:
Role of the novel entry factor Lrp1 in in vivo tropism and pathogenesis of Rift Valley fever virus
新型进入因子Lrp1在裂谷热病毒体内趋向性和发病机制中的作用
- 批准号:
10447151 - 财政年份:2021
- 资助金额:
$ 63.29万 - 项目类别:
Role of the novel entry factor Lrp1 in in vivo tropism and pathogenesis of Rift Valley fever virus
新型进入因子Lrp1在裂谷热病毒体内趋向性和发病机制中的作用
- 批准号:
10286235 - 财政年份:2021
- 资助金额:
$ 63.29万 - 项目类别:
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 - 财政年份:2020
- 资助金额:
$ 63.29万 - 项目类别:
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 - 财政年份:2020
- 资助金额:
$ 63.29万 - 项目类别:
Neuroprotective anti-inflammatory drugs as a novel combination therapy for neurological Rift Valley Fever
神经保护性抗炎药物作为神经裂谷热的新型联合疗法
- 批准号:
9915980 - 财政年份:2017
- 资助金额:
$ 63.29万 - 项目类别:
Mechanisms of Neuropathogenic Rift Valley Fever in a Novel Rat Model
新型大鼠模型中神经致病性裂谷热的机制
- 批准号:
9002103 - 财政年份:2015
- 资助金额:
$ 63.29万 - 项目类别:
Mechanisms of Neuropathogenic Rift Valley Fever in a Novel Rat Model
新型大鼠模型中神经致病性裂谷热的机制
- 批准号:
8891769 - 财政年份:2015
- 资助金额:
$ 63.29万 - 项目类别:
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