Increased resistance to low pH to improve Salmonella vaccine immunogenicity
增强对低 pH 值的抵抗力,提高沙门氏菌疫苗的免疫原性
基本信息
- 批准号:8209098
- 负责人:
- 金额:$ 19.06万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2011
- 资助国家:美国
- 起止时间:2011-01-01 至 2013-12-31
- 项目状态:已结题
- 来源:
- 关键词:AcidsAnimal ModelAttenuatedBacteriaBacterial VaccinesBicarbonatesBuffersBypassDevelopmentDiseaseDoseEnterobacteriaceaeEnvironmentGenesGenomeGenotypeGoalsHeterophile AntigensHumanImmune responseImmunityIn VitroInfectionIntestinesLegal patentLifeModelingMusOralOrganismOutcomeProcessRecombinantsResistanceSalmonellaSalmonella VaccinesSalmonella typhiSalmonella typhimuriumSignal TransductionSimulateStomachSystemTestingTissuesUp-RegulationVaccinationVaccinesVirulencebasecostdesignenteric pathogenimmunogenicityimprovedin vivomicroorganismmouse modeloral vaccinepathogenpublic health relevanceresearch studyresistant straintoolvaccine candidate
项目摘要
DESCRIPTION (provided by applicant): The low pH of the stomach provides the host with a protective barrier to infection and must be overcome to allow oral vaccines to be effective. Salmonella and other enteric bacteria have developed strategies to surmount this harsh environment. In Salmonella, low pH also serves as a signal to the incoming bacterium resulting in the up regulation of a number of genes that facilitate its interaction with the host. Recombinant attenuated Salmonella vaccines are an effective and inexpensive way to elicit strong mucosal and humoral immune responses. However, many Salmonella Typhi vaccines are more sensitive to acid than the wild-type strain and have poor efficacy. Current strategies rely on ways to neutralize or by-pass stomach acid, which may result in reduction of the vaccine's ability to stimulate a strong immune response. We will investigate ways to enhance the acid resistance of vaccine strains to eliminate the need for neutralizing or bypassing the low pH environment of the stomach. We will modify an existing Salmonella acid resistance system to up regulate its expression and activity and import two acid resistance systems from other bacteria. We will evaluate these systems in several different attenuated, acid sensitive Salmonella strains for the ability to confer increased acid resistance in vitro. We will develop a 'low pH' mouse system in which we will model the pH of the human stomach providing us with an in vivo system to test the acid-resistant strains. We will evaluate the effects of acid-resistance on the immunogenicity of orally administered S. Typhimurium strains with genotypes similar to some current recombinant and non-recombinant S. Typhi vaccine candidates. Increasing acid resistance represents a means to reduce the efficacious dose and enhance the immunogenicity of live S. Typhi vaccines.
PUBLIC HEALTH RELEVANCE: Effective live recombinant attenuated Salmonella vaccines expressing heterologous antigen genes hold the promise of providing low cost, orally administered, life-long protection against a variety of diseases. However, while effective in animal models, the results from human trials have been disappointing due to poor immune responses in vaccines. The goal of this project is to enhance the immunogenicity of live, oral Salmonella vaccines by increasing resistance to the low pH environment of the human stomach.
描述(由申请人提供):胃的低pH值为宿主提供了保护性感染的保护障碍,必须克服以允许口服疫苗有效。沙门氏菌和其他肠道细菌已经制定了克服这种恶劣环境的策略。在沙门氏菌中,低pH值也是传入细菌的信号,导致了许多基因的调节,这些基因促进了其与宿主的相互作用。重组衰减的沙门氏菌疫苗是引起强粘膜和体液免疫反应的有效且廉价的方法。但是,许多沙门氏菌鼠伤寒比野生型菌株对酸更敏感,并且功效差。当前的策略依赖于中和胃酸的方法,这可能会导致疫苗刺激强烈免疫反应的能力。我们将研究增强疫苗菌株的酸耐药性,以消除中和或绕过胃的低pH环境的需求。我们将修改现有的沙门氏菌耐药性系统以提高其表达和活性,并从其他细菌中进口两个酸性系统。我们将在几种不同的酸敏感敏感沙门氏菌菌株中评估这些系统,以便在体外赋予酸耐药性。我们将开发一种“低pH”小鼠系统,在该系统中,我们将对人胃的pH进行建模,从而为我们提供一个体内系统来测试耐酸菌株。我们将评估耐酸对口服孢子链球菌菌株的免疫原性的影响,其基因型类似于某些当前的重组和非重组链球菌候选疫苗。抗酸性的增加代表了减少有效剂量并增强活孢链球菌疫苗的免疫原性的一种手段。
公共卫生相关性:表达异源抗原基因的有效活体重组成的沙门氏菌疫苗有望提供低成本,口服,终身保护各种疾病。但是,尽管在动物模型中有效,但由于疫苗的免疫反应不佳,人类试验的结果令人失望。该项目的目的是通过增加对人胃低pH环境的耐药性来增强现场口服沙门氏菌疫苗的免疫原性。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(1)
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Kenneth L. Roland其他文献
Kenneth L. Roland的其他文献
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Targeting Peyer's Patches To Improve Salmonella Typhi Vaccine Immunogenicity
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9089926 - 财政年份:2015
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$ 19.06万 - 项目类别:
Increased resistance to low pH to improve Salmonella vaccine immunogenicity
增强对低 pH 值的抵抗力,提高沙门氏菌疫苗的免疫原性
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