Rabbit model to assess reactogenicity and immunogenicity of Salmonella vaccines

描述(由申请人提供)：活的减毒沙门氏菌作为疫苗载体具有巨大的潜力，可以传递来自各种病原体的抗原，以引起保护性免疫反应。虽然使用减毒伤寒沙门氏菌血清型给小鼠的策略已经证明了这种潜力，但当这些相同的策略被转移到伤寒沙门氏菌时，所产生的菌株在给药给人类时通常是反应性的或免疫原性差的。现有的口服鼠伤寒沙门氏菌/小鼠模型或鼻腔注射伤寒沙门氏菌/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性，阻碍了该领域的疫苗开发。兔在一定程度上被用来评估反应性，但目前的模型中没有一种涉及成年兔口服疫苗。我们观察到一些减毒的宿主限制性沙门氏菌血清型在给成年兔口服时具有反应性。基于这一观察结果，我们将建立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的反应性，如伤寒沙门氏菌。我们将建立特定的参数和相关性来确定沙门氏菌疫苗的反应性。这种口服兔模型也可以用来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的图像。我们将根据临床试验中观察到的人类免疫反应的历史数据，建立和定义口服免疫兔子的免疫反应之间的相关性。这一动物模型将扩大我们目前对伤寒疫苗的了解，提供一种手段，在人类试验之前测试各种基因操作对反应性和免疫原性的影响。

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.