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.
项目摘要/摘要
世界卫生组织警告说,由蚊媒传播的
人畜共患裂谷热病毒(RVFV)。这种新出现的病毒的后果可能是
由于预防感染和疾病的疫苗不足,情况进一步恶化。RVF是一种重要的
家畜的农业经济疾病,在非洲和中东部分地区流行。进一步
鉴于能够传播RVFV的蚊子种类在欧洲和
美洲。绵羊裂谷热病最显著的特征是胎儿丢失的浪潮(即所谓的流产
风暴“)席卷了成群的怀孕动物,那里的自然流产率可以高达
高达90%。家畜接种疫苗保护动物,同时减少RVFV的传播到
人民。成功开发轮状病毒家畜疫苗的障碍包括:1)疫苗毒株往往
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侵袭的疫苗
在预防怀孕期间垂直传播方面并不总是有效的。这些障碍代表着一个重大的
疫苗开发领域的差距。RVFV减毒活疫苗毒株的机制是
在子宫内垂直传播,以及母体免疫反应所需的保护
发育中的胎儿,目前还不清楚。没有对临床上的垂直传播潜力进行系统评估
已经进行了相关的减毒活疫苗试验。为了解决这一领域的差距,我们建议使用
RVFV垂直传播与妊娠晚期胎鼠死亡的实验动物模型。RVFV
直接感染大鼠的胎盘,引起出血和炎症,并导致胎儿畸形
包括宫内胎儿死亡,即使在没有疾病迹象的怀孕水坝中也是如此。此提案将使用
用妊娠大鼠模型测试目前裂谷热疫苗候选垂直传播机制(S),胎儿
保护,并确定胎儿保护的母体免疫相关因素。我们还将进行一次
RVFV强毒株与弱毒株对猪胎盘外植体透过率的比较分析
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量化数据
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因素。完成
这些研究将改变RVFV疫苗开发的范式,首次提供一种
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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