非伤寒沙门菌能够引起全球范围的食物源性人畜共患病，禽产品是造成人沙门菌病的主要来源。来源于B1、C1、C2、D1血清群的多种沙门菌株的广泛流行使得我们急需研制高效的沙门菌多价疫苗。通过缺失某些全局调控基因来构建弱毒疫苗是目前研制多价疫苗较为成功的策略，然而这种疫苗诱发的交叉保护水平还不理想。本申请拟通过一种新策略，即靶向沙门菌主要保护性抗原O-多糖抗原，以鼠伤寒沙门菌（B1）为载体，利用延迟表达系统和宿主-质粒平衡致死系统调控表达来源于D1、C1、C2血清群的异源O-抗原，并通过缺失毒力相关基因crp/cya构建重组的沙门菌多价弱毒疫苗。我们将通过小鼠和鸡动物模型验证构建的多价疫苗能够预防B1、C1、C2、D1血清群沙门菌的感染，并通过分析揭示各血清群沙门菌的O-抗原特异性免疫应答与保护性免疫应答的相关性。本申请将为研制多价疫苗提供新思路，为开发多糖疫苗提供理论依据。

Non-typhoidal Salmonella cause food-borne zoonotic salmonellosis around the world. Contaminated poultry products are one of the major sourses of human non-typhoidal salmonellosis. The prevalent Salmonella serotypes found in poultry and food-contaminated sources maily belong to serogroups B1, D1, C2 and C1, posing an urgent need for efficient multivalent Salmonella vaccines to confer protection against most of Salmonella serovars. Live attenuated vaccines containing mutation of global regulators showed reduced colonization by homologous strains in chickens, but low protection against heterologous challenge strains. Here, we will construct a novel multivalent vaccine by expression of heterologous O polysaccharide antigens from group D1, C1, C2 in a single live S. Typhimurium strain with regulated delayed in vivo antigen synthesis and balanced-lethal vector-host system, and by mutation of crp/cya genes. The immunogenicity and protective potency will be determined in both mouse and chicken animal models, and finally the correlations between O antigen-specific immune responses and protection efficacies against several Salmonella serovars were also analyzed. The study will provide new strategies for construction of universal vaccines and theoretical basis for polysaccharide vaccines.