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
人类诺如病毒(Hnov)和艰难梭菌(Cd)是急性胃肠炎的两个主要原因。
世界各地都有严重的发病率和死亡率。这两种感染(一种病毒和一种细菌)有许多共同之处
传播的相同特征;同时感染在美国尤其普遍,在高
危险人群,如接受抗生素治疗的老年患者、住院患者或患者
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很大努力,
到目前为止,市场上仍然没有单一的疫苗可用。我们开发了一种新的平台技术
通过工程设计一种益生菌酵母来对抗肠道细菌病原体,该酵母菌可以分泌多个
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艰难梭菌的靶向。这样做的总体目标是
项目是产生分泌抗Cd毒素和hNoV的mSdAb的SB菌株,产生原理证明
相关动物疾病模型的疗效数据,并开发临床兼容的干燥和
包被Sb-mSdAb菌株。我们假设口服Sb-mSdAb菌株分泌
针对hNoV和CD毒素的mSdAb将防止其单独或同时感染。为了检验这一假设,
我们提出了以下三个具体目标:1)工程SB-mSdAb株(SB-aNoVCd)分泌
针对Cd毒素和hNov的VHH融合。2)测定SB-aNoVCd菌株的预防效果
人新城疫病毒和环糊精在诺生菌猪体内的感染。3)开发支持酵母喷雾干燥的配方,
封装。完成建议的翻译活动后,我们将产生销售线索SB-aNoVCd
菌株及其在小鼠和灵知生菌猪体内的特性,这是最适合的动物
人新城疫病毒感染和疾病模型。关键的原则性疗效数据是否应该生成,未来扩大
将有理由将更多的VHH纳入产生广泛有效的铅免疫预防措施
抗CD和hNOV胃肠炎酵母菌的菌株和最终商品化
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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