One Health Vaccine Development for Bovine and Human Schistosomiasis
一种针对牛和人类血吸虫病的健康疫苗的开发
基本信息
- 批准号:10430376
- 负责人:
- 金额:$ 7.65万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-08-21 至 2023-05-31
- 项目状态:已结题
- 来源:
- 关键词:AdjuvantAdultAlhydrogelAnimalsAntibodiesAntigensAreaAutopsyBiochemicalBody WeightBuffaloesCattleChemistryChildDataDermisDevelopmentDiseaseElectron MicroscopyFarming environmentFecesFemaleFibrosisFormulationGranulomatousHealthHumanIL17 geneIL4 geneIgEIgG1IgG2IgG4Immune responseImmunofluorescence ImmunologicImmunologic EpidemiologyIndividualInfectionInflammationInterferon Type IIInterleukin-1 betaInterleukin-10Interleukin-13Labor ForcesLinkMeasuresMicroscopicMorbidity - disease rateMusOutcomeOutputParasitesParatropomyosinPeripheral Blood Mononuclear CellPharmaceutical PreparationsPhasePhilippinesPlatyhelminthsPraziquantelPrevalenceProductionProductivityResistanceRiceRodentRodent ModelSafetySchistosomaSchistosoma japonicumSchistosoma mansoniSchistosomiasisSchistosomiasis japonicaSerumSiteTNF geneTestingToxicologyVaccinatedVaccinationVaccinesWater BuffaloWorkanti-IgEbasechemotherapycohortcytokineefficacy evaluationefficacy trialeggexperimental studyfollow-uphealth applicationhealth economicsimprovedmalenovelphase 2 studyphase II trialpreventprimary outcomeprogramsresponsescreeningsecondary outcometransmission processvaccine developmentvaccine trial
项目摘要
The overall aim of this One Health application is to accelerate the development of paramyosin (rSj97) and a newly discovered antigen (rSj68) as vaccines against human and bovine schistosomiasis japonica. Schistosomiasis, caused by three principle species of dioecious trematodes (flatworms), currently infects over 250 million individuals, results in 1.53 million DALYs lost per annum 1, and contributes to poor health and economic stagnation in endemic areas 2. Although schistosomiasis is effectively treated with praziquantel (PZQ), rapid reinfection with rebound morbidity precludes effective control based on chemotherapy alone and justifies current efforts to develop vaccines for these parasites. Most importantly, Schistosoma japonicum is a zoonosis with domesticated water buffalo (the key labor force for rice farming) suffering from the disease, as well as constituting a critical reservoir for continuing transmission to humans. In our recent work, we show that buffalo residing in our field site in Leyte, the Philippines have a prevalence of infection of 97%- underscoring the importance of these species for transmission to humans. Paramyosin was originally identified as the parasite target of antibodies generated in mice protectively vaccinated with S. mansoni schistosomula or adult worm extract 3. Our group conducted the pivotal study linking paramyosin and protection in S. japonicum 4. In four independent experiments, vaccination of mice with biochemically purified paramyosin (Sj97) resulted in 62%-86% (all P < 0.001) reduction in worm burden following cercarial challenge. We have conducted extensive immuno-epidemiology studies of Sj97 in a treatment-reinfection cohort of 616 S. japonicum infected individuals 5. We demonstrate a 30 to 41% lower intensity of reinfection (all P < 0.05) after praziquantel treatment in individuals with high Th2/Th1 cytokine ratios measured in PBMCs stimulated with Sj97. In this same cohort, we recently demonstrated that individuals with IgE but not IgG4 responses to rSj97 had a 77% lower intensity of reinfection at 12 months compared to individuals with IgG4 but not IgE responses, even after adjusting for potential confounders (p=0.016) 6. We identified rSj68 using a novel differential screening approach to identify parasite antigens recognized by antibodies expressed by resistant, but not susceptible children 7. By immunofluorescence and immunogold electron microscopy, rSj68 localizes to the tegument and gastro-dermis of adult male and female worms. In a holoendemic site in the Philippines, individuals with high titer IgE anti-rSj68 had a 58% lower intensity of reinfection over 12 months of follow-up compared to individuals without these antibodies (n=616, P < 0.001). In the current application, we propose to accelerate the development of paramyosin and rSj68 as vaccines for human and bovine schistosomiasis by conducting safety and efficacy trials in water buffaloes. We will focus our studies on adjuvants that have already been tested and found safe in humans and animals, thus accelerating our development efforts toward a Phase I vaccination study in humans and Phase II studies in bovines. The deliverables of this program will be an adjuvant optimized, bivalent schistosome vaccine that is ready for human Phase I and bovine Phase II trials with safety data to support an FDA IND application. This vaccine would have a tremendous impact on One Health objectives, including: 1) improved animal health, 2) improved animal productivity, 3) improved farm output, 4) decreased transmission of schistsosomaisis to humans, and 5) improved human health due to both direct (human vaccination) and indirect (buffalo vaccination) effects.
One Health应用程序的总体目标是加速副肌球蛋白(rSj 97)和新发现的抗原(rSj 68)的开发,作为抗人和牛日本血吸虫病的疫苗。 由雌雄异株吸虫(扁形虫)的三种主要物种引起的血吸虫病目前感染了超过2.5亿人,导致每年损失153万DALs 1,并导致流行地区的健康状况不佳和经济停滞2。虽然血吸虫病是有效的治疗吡喹酮(PZQ),快速再感染与反弹的发病率排除了有效的控制基础上单独化疗,并证明目前的努力,为这些寄生虫的疫苗开发。最重要的是,日本血吸虫是一种人畜共患疾病,驯养的布法罗(水稻种植的主要劳动力)患有这种疾病,并构成继续传播给人类的关键水库。在我们最近的工作中,我们表明,布法罗居住在我们的外地网站在莱特,菲律宾有97%的感染率-强调这些物种传播给人类的重要性。 副肌球蛋白最初被鉴定为在用S.曼氏童虫或成虫提取物3.本课题组进行了副肌球蛋白与S.山茱萸4.在四个独立的实验中,用生化纯化的副肌球蛋白(Sj 97)接种小鼠导致尾蚴攻击后的蠕虫负荷减少62%-86%(均P < 0.001)。我们对616例治疗-再感染队列中的Sj 97进行了广泛的免疫流行病学研究。日本血吸虫感染者5.我们证明,在用Sj 97刺激的PBMC中测量的Th 2/Th 1细胞因子比率高的个体中,吡喹酮治疗后再感染强度降低30%至41%(所有P < 0.05)。在同一队列中,我们最近证明,与IgG 4但无IgE应答的个体相比,对rSj 97有IgE但无IgG 4应答的个体在12个月时的再感染强度低77%,即使在调整潜在混杂因素后(p=0.016)6。 我们确定了rSj 68使用一种新的差异筛选方法,以确定寄生虫抗原的抗体所表达的抗性,但不敏感的儿童7。通过免疫荧光和免疫金电子显微镜,rSj 68定位于成虫的皮层和胃真皮的男性和女性。在菲律宾的一个完全流行的地点,与没有这些抗体的个体相比,具有高滴度IgE抗rSj 68的个体在12个月的随访中再感染强度降低了58%(n=616,P < 0.001)。 在当前的应用中,我们建议通过在水牛中进行安全性和有效性试验来加速副肌球蛋白和rSj 68作为人和牛血吸虫病疫苗的开发。我们将把研究重点放在已经过测试并在人类和动物中发现安全的佐剂上,从而加快我们在人类I期疫苗研究和牛II期疫苗研究方面的开发工作。 该计划的可交付成果将是一种佐剂优化的二价血吸虫疫苗,已准备好进行人体I期和牛II期试验,并提供安全数据以支持FDA IND申请。该疫苗将对“一个健康”目标产生巨大影响,包括:1)改善动物健康,2)改善动物生产力,3)改善农场产量,4)减少裂体病向人类的传播,以及5)由于直接(人类疫苗接种)和间接(布法罗疫苗接种)效应而改善人类健康。
项目成果
期刊论文数量(0)
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Jonathan D. Kurtis其他文献
Acquired von Willebrand disease: Management of labor and delivery with intravenous dexamethasone, continuous factor concentrate, and immunoglobulin infusion
- DOI:
10.1016/j.ajog.2004.09.020 - 发表时间:
2005-06-01 - 期刊:
- 影响因子:
- 作者:
Heather S. Lipkind;Jonathan D. Kurtis;Raymond Powrie;Marshall W. Carpenter - 通讯作者:
Marshall W. Carpenter
Jonathan D. Kurtis的其他文献
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{{ truncateString('Jonathan D. Kurtis', 18)}}的其他基金
Identifying the targets of protective immunity to severe falciparum malaria
确定严重恶性疟疾的保护性免疫目标
- 批准号:
10893666 - 财政年份:2023
- 资助金额:
$ 7.65万 - 项目类别:
Tfh responses to novel vaccine candidates and protection from pediatric falciparum malaria
Tfh 对新型候选疫苗的反应以及对小儿恶性疟疾的保护
- 批准号:
9977935 - 财政年份:2017
- 资助金额:
$ 7.65万 - 项目类别:
One Health Vaccine Development for Bovine and Human Schistosomiasis
一种针对牛和人类血吸虫病的健康疫苗的开发
- 批准号:
10019231 - 财政年份:2017
- 资助金额:
$ 7.65万 - 项目类别:
Tfh responses to novel vaccine candidates and protection from pediatric falciparum malaria
Tfh 对新型候选疫苗的反应以及对小儿恶性疟疾的保护
- 批准号:
10227778 - 财政年份:2017
- 资助金额:
$ 7.65万 - 项目类别:
Tfh responses to novel vaccine candidates and protection from pediatric falciparum malaria
Tfh 对新型候选疫苗的反应以及对小儿恶性疟疾的保护
- 批准号:
9750040 - 财政年份:2017
- 资助金额:
$ 7.65万 - 项目类别:
One Health Vaccine Development for Bovine and Human Schistosomiasis
一种针对牛和人类血吸虫病的健康疫苗的开发
- 批准号:
10189672 - 财政年份:2017
- 资助金额:
$ 7.65万 - 项目类别:
PfSEA-1 based vaccines for falciparum malaria
基于 PfSEA-1 的恶性疟疾疫苗
- 批准号:
9330056 - 财政年份:2014
- 资助金额:
$ 7.65万 - 项目类别:
PfSEA-1 based vaccines for falciparum malaria
基于 PfSEA-1 的恶性疟疾疫苗
- 批准号:
8817017 - 财政年份:2014
- 资助金额:
$ 7.65万 - 项目类别:
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