Rabbit model to assess reactogenicity and immunogenicity of Salmonella vaccines

用于评估沙门氏菌疫苗反应原性和免疫原性的兔模型

• 批准号: 8490135
• 负责人: Kenneth L. Roland
• 金额: $ 19.25万
• 依托单位: ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8490135
• 关键词: Adult; Animal Experiments; Animal Model; Antigens; Attenuated; Attenuated Vaccines; Bacteremia; Bacteria; Cellular Immunity; Clinical Trials; Data; Development; Diarrhea; Disease; Fever; Genes; Goals; Health; Heterophile Antigens; Human; Human Volunteers; Humoral Immunities; Immune response; Knowledge; Life; Living Costs; Malaise; Measures; Modeling; Mucosal Immunity; Mus; Mutation; Oral; Oral Administration; Organism; Oryctolagus cuniculus; Outcome; Recombinants; Reliance; Route; Salmonella; Salmonella Vaccines; Salmonella enterica; Salmonella paratyphi; Salmonella typhi; Salmonella typhimurium; Surface; Symptoms; Testing; Tissues; Typhoid Fever; Vaccines; Virulence; Work; attenuation; base; cost; genetic manipulation; immunogenic; immunogenicity; improved; insight; mouse model; pathogen; public health relevance; tool; vaccine development; vector; vector vaccine

DESCRIPTION (provided by applicant): Live attenuated Salmonella hold great potential as vaccine vectors to deliver antigens from a variety of pathogenic organisms to elicit a protective immune response. While strategies devised using attenuated Salmonella enterica serovar Typhimurium strains administered to mice has demonstrated this potential, when these same strategies are transferred to Salmonella enterica serovar Typhi, the resulting strains are often reactogenic or poorly immunogenic when administered to humans. One weakness of the existing oral S. Typhimurium/mouse model or the intranasal S. Typhi/mouse model is that neither detects nor predicts reactogenic vaccines. The lack of a reliable oral animal model to study S. Typhi reactogenicity has hampered vaccine development in this field. Rabbits have been used to a limited extent to evaluate reactogenicity, but none of the current models involve oral administration of the vaccine to adult rabbits. We observed that some attenuated host restricted Salmonella serovars are reactogenic when orally administered to adult rabbits. Based on this observation, we will develop an oral adult rabbit model to detect reactogenicity of host-restricted Salmonella vaccine vectors, such as S. Typhi. We will establish specific parameters and correlates to define reactogenicity in Salmonella vaccines. This oral rabbit model can also be used to evaluate the immunogenicity of Salmonella vaccines and may provide a better picture of immunogenicity in humans than the mouse intranasal model. We will establish and define correlates between immune responses in orally immunized rabbits with historical data on human immune responses observed in clinical trials. This animal model will expand our current knowledge of S. Typhi vaccines by providing a means to test the effects of a wide variety of genetic manipulations on reactogenicity and immunogenicity prior to testing in humans.

描述（由申请人提供）：减毒活沙门氏菌作为疫苗载体具有巨大的潜力，可以传递来自多种病原生物的抗原以引发保护性免疫反应。虽然使用给予小鼠的减毒肠沙门氏菌血清型伤寒菌株设计的策略已证明了这种潜力，但当将这些相同的策略转移到伤寒沙门氏菌血清型时，所得菌株在给予人类时通常具有反应原性或免疫原性较差。现有的口服伤寒沙门氏菌/小鼠模型或鼻内伤寒沙门氏菌/小鼠模型的一个弱点是既不能检测也不能预测反应原疫苗。缺乏可靠的口腔动物模型来研究伤寒沙门氏菌反应原性，阻碍了该领域的疫苗开发。兔子已在有限程度上用于评估反应原性，但目前的模型均不涉及对成年兔子口服疫苗。我们观察到，一些减毒宿主限制性沙门氏菌血清型在给成年兔口服给药时具有反应原性。基于这一观察，我们将开发一种口服成年兔模型来检测宿主限制性沙门氏菌疫苗载体（例如伤寒沙门氏菌）的反应原性。我们将建立具体参数和相关性来定义沙门氏菌疫苗的反应原性。这种兔口腔模型还可用于评估沙门氏菌疫苗的免疫原性，并且可能比小鼠鼻内模型提供更好的人类免疫原性图片。我们将建立并定义口服免疫兔子的免疫反应与临床试验中观察到的人类免疫反应的历史数据之间的相关性。该动物模型将提供一种在人体测试之前测试各种基因操作对反应原性和免疫原性的影响的方法，从而扩展我们目前对伤寒沙门氏菌疫苗的了解。