Rabbit model to assess reactogenicity and immunogenicity of Salmonella vaccines

描述（由申请人提供）：减毒活沙门氏菌作为疫苗载体具有很大的潜力，可以传递来自各种病原生物的抗原，从而引发保护性免疫反应。虽然使用小鼠接种的减毒肠炎沙门氏菌血清型伤寒沙门氏菌菌株设计的策略已经证明了这种潜力，但当这些相同的策略转移到肠炎沙门氏菌血清型伤寒沙门氏菌菌株时，所产生的菌株在给人接种时往往是反应性的或免疫原性差的。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性疫苗。缺乏可靠的口服动物模型来研究伤寒沙门氏菌的反应原性，阻碍了该领域疫苗的开发。在一定程度上，兔已被用于评价反应原性，但目前没有一种模型涉及成年兔口服疫苗。我们观察到，一些减毒宿主限制性沙门氏菌血清型在成年家兔口服时具有反应性。在此基础上，我们将建立成年兔口腔模型，检测宿主限制性沙门氏菌疫苗载体（如伤寒沙门氏菌）的反应原性。我们将建立特定的参数和相关性来定义沙门氏菌疫苗的反应原性。该兔口服模型也可用于评估沙门氏菌疫苗的免疫原性，并可能提供比小鼠鼻内模型更好的人类免疫原性图像。我们将建立和定义口服免疫家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体试验之前测试各种基因操作对反应原性和免疫原性影响的方法，扩大我们目前对伤寒沙门氏菌疫苗的了解。

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.