Rabbit model to assess reactogenicity and immunogenicity of Salmonella vaccines

描述（由申请方提供）：减毒活沙门氏菌作为疫苗载体具有很大的潜力，可递送来自各种病原生物体的抗原以引发保护性免疫应答。虽然使用减毒的肠道沙门氏菌血清型鼠伤寒菌株给药的策略已经证明了这种潜力，当这些相同的策略转移到肠道沙门氏菌血清型伤寒时，所得菌株在给药于人时通常是反应原性的或免疫原性差。现有口服S.鼠伤寒沙门氏菌/小鼠模型或鼻内S.伤寒/小鼠模型既不能检测也不能预测反应原性疫苗。缺乏可靠的口腔动物模型来研究S.伤寒反应原性阻碍了这一领域的疫苗开发。家兔已在有限程度上用于评价反应原性，但目前的模型均未涉及成年家兔经口接种疫苗。我们观察到，一些减毒宿主限制性沙门氏菌血清型口服给药成年兔时，反应原性。基于这一观察，我们将建立一个口服成年兔模型来检测宿主限制性沙门氏菌疫苗载体的反应原性，如沙门氏菌。伤寒我们将建立特定的参数和相关性，以确定沙门氏菌疫苗的反应原性。该口服兔模型也可用于评价沙门氏菌疫苗的免疫原性，并可提供比小鼠鼻内模型更好的人体免疫原性图片。我们将建立和定义口服免疫家兔的免疫应答与临床试验中观察到的人类免疫应答的历史数据之间的相关性。该动物模型将扩大我们目前对S.伤寒疫苗通过提供一种在人体试验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。

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.