Preventing norovirus and Clostridium difficile gastroenteritis by engineered probiotic yeast Saccharomyces boulardii secreting multi-specific single-domain antibodies
通过分泌多特异性单域抗体的工程益生菌布拉酵母菌预防诺如病毒和艰难梭菌胃肠炎
基本信息
- 批准号:10320907
- 负责人:
- 金额:$ 60.86万
- 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:2020-01-22 至 2024-12-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAnimal Disease ModelsAnimal ModelAntibiotic ResistanceAntibiotic TherapyAntibioticsAntibodiesBindingBody Weight decreasedCarbohydratesCharacteristicsChromosomal InsertionClinicClinicalClostridium difficileCommunicable DiseasesDNA cassetteDataDevelopmentDiarrheaDiseaseDoseDried YeastDrug or chemical Tissue DistributionEncapsulatedEngineered ProbioticsEngineeringEnteralErythrocytesExcipientsFamily suidaeFormulationFutureGastroenteritisGenesGenomeGnotobioticGoalsHandHealth care facilityHemagglutinationHumanIn VitroIndividualInfectionInfection preventionInflammationIntestinal SecretionsIntestinesLeadLong-Term CareMediatingMethodsMonitorMorbidity - disease rateMusNorovirusOralOral AdministrationPatientsPrevention strategyPreventiveProbioticsProcessProductionProphylactic treatmentSaccharomycesSiteSymptomsTechnologyTestingTherapeuticToxinTraveler&aposs diarrheaVaccinesVariantViralViral Load resultVirulence FactorsVirus-like particleYeastsagedantibiotic-associated diarrheaantitoxinbasecapsulecommercializationenteric pathogengut microbiotahigh risk populationin vivomicrobiotamicrobiota transplantationmortalitynanobodiesnovelpassive antibodiespathogenpathogenic bacteriapreventscale uptooltransmission processvaccine accessvaccine development
项目摘要
Abstract
Human norovirus (hNoV) and Clostridium difficile (CD) represent two leading causes of acute gastroenteritis
worldwide with significant morbidity and mortality. The two infections (one viral and one bacterial) share many of
the same characteristics of transmission; and concurrent infections are particularly prevalent in the US in high-
risk populations, such as aged patients undergoing antibiotic treatments, hospitalized patients, or patients
staying in long-term care facilities. Despite great efforts in the development of vaccines against both infections,
to date there is still no single vaccine available on the market. We have developed a novel platform technology
against enteric bacterial pathogens by engineering a probiotic yeast, Saccharomyces boulardii, to secrete multi-
specific single-domain (VHH) antibodies, directly targeting bacterial virulence factors at the intestinal site of
infection. We have successfully applied this technology to target Clostridium difficile. The overall objective of this
project is to generate Sb strains secreting mSdAbs against both CD toxins and hNoV, generate proof-of-principle
efficacy data in relevant animal disease models, and develop clinic-compatible formulations for drying and
encapsulating the Sb-mSdAb strains. We hypothesize that oral administration of Sb-mSdAb strains secreting
mSdAb against hNoV and CD toxins will prevent their individual or concurrent infections. To test this hypothesis,
we propose to accomplish the following 3 specific aims: 1) Engineer Sb-mSdAb strains (Sb-aNoVCd) secreting
VHH fusions against both CD toxins and hNoVs. 2) Determine preventive efficacy of Sb-aNoVCd strains against
infections with hNoV and CD in gnotobiotic pigs. 3) Develop a formulation supporting yeast spray drying and
encapsulation. With the completion of proposed translational activities, we will have generated lead Sb-aNoVCd
strains and evaluated in vivo characteristics in mice and in gnotobiotic pigs which is the most appropriate animal
model of hNoV infection and disease. Should the key proof-of-principle efficacy data generated, future scale-up
efforts will be justified to include additional VHHs for generating broadly efficacious lead immunoprophylactic
strains and eventual commercialization of the yeast products against CD and hNoV gastroenteritis for which we
currently have no prophylaxis or vaccines.
摘要
人诺如病毒(hNoV)和艰难梭菌(CD)代表急性胃肠炎的两个主要原因
发病率和死亡率都很高。这两种感染(一种是病毒性的,一种是细菌性的)有许多共同点,
相同的传播特征;并发感染在美国特别普遍,
风险人群,如接受抗生素治疗的老年患者、住院患者或
住在长期护理机构。尽管在开发针对这两种感染的疫苗方面做出了巨大努力,
到目前为止,市场上仍然没有单一的疫苗。我们开发了一种新的平台技术
针对肠道细菌病原体,通过工程化益生菌酵母,布拉酵母,分泌多-
特异性单域(VHH)抗体,直接靶向肠道部位的细菌毒力因子,
感染我们已经成功地将该技术应用于靶向艰难梭菌。本报告的总体目标
项目是产生分泌抗CD毒素和hNoV的mSdAb的Sb菌株,产生原理验证
在相关动物疾病模型中的疗效数据,并开发临床相容的制剂用于干燥和
包封Sb-mSdAb菌株。我们假设口服分泌Sb-mSdAb的菌株
抗hNoV和CD毒素的mSdAb将预防其单独或并发感染。为了验证这个假设,
我们提出实现以下3个具体目标:1)分泌Sb-mSdAb的工程菌株(Sb-aNoVCd)
针对CD毒素和hNoV两者的VHH融合物。2)确定Sb-aNoVCD菌株对以下疾病的预防效力:
hNoV和CD感染在gnotobiotic猪。3)开发支持酵母喷雾干燥的配方,
封装随着拟定翻译活动的完成,我们将生成铅锑-aNoVCD
菌株,并在小鼠和最合适的动物无菌猪中评价体内特性
hNoV感染和疾病的模型。如果产生了关键的原理验证有效性数据,
为了产生广泛有效的先导免疫预防,
菌株和最终商业化的酵母产品对CD和hNoV胃肠炎,我们
目前还没有预防措施或疫苗。
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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Hanping Feng其他文献
Hanping Feng的其他文献
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{{ truncateString('Hanping Feng', 18)}}的其他基金
Characterization of neutralizing antitoxins and epitopes in Clostridium difficile patients
艰难梭菌患者中和抗毒素和表位的特征
- 批准号:
10549285 - 财政年份:2020
- 资助金额:
$ 60.86万 - 项目类别:
Preventing norovirus and Clostridium difficile gastroenteritis by engineered probiotic yeast Saccharomyces boulardii secreting multi-specific single-domain antibodies
通过分泌多特异性单域抗体的工程益生菌布拉酵母菌预防诺如病毒和艰难梭菌胃肠炎
- 批准号:
10540345 - 财政年份:2020
- 资助金额:
$ 60.86万 - 项目类别:
Characterization of neutralizing antitoxins and epitopes in Clostridium difficile patients
艰难梭菌患者中和抗毒素和表位的特征
- 批准号:
10319522 - 财政年份:2020
- 资助金额:
$ 60.86万 - 项目类别:
Probiotic yeast secreting single-domain antibodies to prevent Clostridium difficile and Campylobacter jejuni disease
益生菌酵母分泌单域抗体来预防艰难梭菌和空肠弯曲菌疾病
- 批准号:
10364713 - 财政年份:2019
- 资助金额:
$ 60.86万 - 项目类别:
Probiotic yeast secreting single-domain antibodies to prevent Clostridium difficile and Campylobacter jejuni disease
益生菌酵母分泌单域抗体来预防艰难梭菌和空肠弯曲菌疾病
- 批准号:
10584482 - 财政年份:2019
- 资助金额:
$ 60.86万 - 项目类别:
A Novel Humanized Tetra-specific Antibody against Clostridium difficile Infection
一种抗艰难梭菌感染的新型人源化四特异性抗体
- 批准号:
10432036 - 财政年份:2017
- 资助金额:
$ 60.86万 - 项目类别:
A Novel Humanized Tetra-specific Antibody against Clostridium difficile Infection
一种抗艰难梭菌感染的新型人源化四特异性抗体
- 批准号:
9362547 - 财政年份:2017
- 资助金额:
$ 60.86万 - 项目类别:
Toxemia and systemic disease in Clostridium difficile infection
艰难梭菌感染的毒血症和全身性疾病
- 批准号:
8664002 - 财政年份:2013
- 资助金额:
$ 60.86万 - 项目类别:
Epithelium, dendritic cells, and Clostridium difficile associated colitis
上皮、树突状细胞和艰难梭菌相关结肠炎
- 批准号:
7887611 - 财政年份:2010
- 资助金额:
$ 60.86万 - 项目类别:
Development of Vaccines against Clostridium difficile Infection
艰难梭菌感染疫苗的研制
- 批准号:
7903007 - 财政年份:2010
- 资助金额:
$ 60.86万 - 项目类别:
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