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

• 批准号: 8209098
• 负责人: Kenneth L. Roland
• 金额: $ 19.06万
• 依托单位: ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/8209098
• 关键词: Acids; Animal Model; Attenuated; Bacteria; Bacterial Vaccines; Bicarbonates; Buffers; Bypass; Development; Disease; Dose; Enterobacteriaceae; Environment; Genes; Genome; Genotype; Goals; Heterophile Antigens; Human; Immune response; Immunity; In Vitro; Infection; Intestines; Legal patent; Life; Modeling; Mus; Oral; Organism; Outcome; Process; Recombinants; Resistance; Salmonella; Salmonella Vaccines; Salmonella typhi; Salmonella typhimurium; Signal Transduction; Simulate; Stomach; System; Testing; Tissues; Up-Regulation; Vaccination; Vaccines; Virulence; base; cost; design; enteric pathogen; immunogenicity; improved; in vivo; microorganism; mouse model; oral vaccine; pathogen; public health relevance; research study; resistant strain; tool; vaccine candidate

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 值为宿主提供了感染的保护屏障，必须克服该屏障才能使口服疫苗有效。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 值还可以作为传入细菌的信号，导致许多基因上调，从而促进其与宿主的相互作用。重组减毒沙门氏菌疫苗是引发强烈粘膜和体液免疫反应的有效且廉价的方法。然而，许多伤寒沙门氏菌疫苗比野生型菌株对酸更敏感，且功效较差。目前的策略依赖于中和或绕过胃酸的方法，这可能会导致疫苗刺激强烈免疫反应的能力降低。我们将研究增强疫苗株耐酸性的方法，以消除中和或绕过胃的低pH环境的需要。我们将修改现有的沙门氏菌耐酸系统以上调其表达和活性，并从其他细菌导入两个耐酸系统。我们将在几种不同的减毒、酸敏感沙门氏菌菌株中评估这些系统在体外增强耐酸性的能力。我们将开发一种“低 pH 值”小鼠系统，在其中模拟人胃的 pH 值，为我们提供一个体内系统来测试耐酸菌株。我们将评估耐酸性对口服鼠伤寒沙门氏菌菌株免疫原性的影响，该菌株的基因型与目前一些重组和非重组伤寒沙门氏菌候选疫苗相似。增加耐酸性是减少伤寒沙门氏菌活疫苗有效剂量和增强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重组减毒沙门氏菌活疫苗有望为多种疾病提供低成本、口服、终身的保护。然而，虽然在动物模型中有效，但由于疫苗的免疫反应较差，人体试验的结果令人失望。该项目的目标是通过增强对人胃低pH环境的抵抗力来增强口服沙门氏菌活疫苗的免疫原性。