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: 8607893
• 负责人: Kenneth L. Roland
• 金额: $ 23.14万
• 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 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8607893
• 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）：作为疫苗向量的活衰减沙门氏菌具有从各种致病生物传递抗原的巨大潜力，以引起保护性免疫反应。虽然使用衰减的肠道肠肺卫生菌株制定的策略表明了这种潜力，但是当这些相同的策略被转移到肠道肠typhi的沙门氏菌时，当施用的菌株通常是反应菌或对人类施用的不良免疫原性的。现有口服鼠伤寒链球菌/小鼠模型或鼻内链球菌/小鼠模型的一个弱点是，既不能检测也不预测反应疫苗。缺乏可靠的口腔动物模型来研究S.鼠伤寒链球菌的反应生成性阻碍了该领域的疫苗发育。兔子已在有限的程度上用于评估反应生成性，但是当前的模型均未涉及将疫苗施用到成年兔子。我们观察到，在口服成年兔子时，一些减弱的宿主限制性沙门氏菌血清射手具有反应源。基于这一观察结果，我们将开发一种口腔成人兔模型，以检测宿主限制的沙门氏菌疫苗载体（例如Typhi）的反应生成性。我们将建立特定的参数，并相关以定义沙门氏菌疫苗中的反应生成性。该口腔兔模型也可用于评估沙门氏菌疫苗的免疫原性，并且可以比小鼠鼻内模型更好地看出人类免疫原性的情况。我们将建立和定义口服免疫兔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。该动物模型将通过提供一种在人类测试之前测试各种遗传操纵对反应生成性和免疫原性的影响的方法来扩展我们当前对斑链球菌疫苗的知识。