Multivalent Vaccines Effective Against MDR Salmonella

项目摘要--RP2 非伤寒沙门氏菌(NTS)如鼠伤寒沙门氏菌和肠炎沙门氏菌通常会引起 自限性胃肠炎。据估计，NTS在全球范围内造成9400万例病例和15.5万人死亡 年。而由其他重要肠道病原体引起的疾病的发生率已经降低。 由于FoodNet发起的干预措施，美国沙门氏菌病的发病率一直保持在 同样的数字，据报道2014年每10万人中有7452人感染。NTS不成比例地影响到非常 年轻人和老年人。我们的总体目标是开发疫苗，以提供对NTS疾病的广泛保护。 这项建议寻求建立在我们以前工作的基础上，我们已经培育了活的减毒鼠伤寒沙门氏菌，S. 肠炎疫苗、新港沙门氏菌疫苗和病毒性沙门氏菌疫苗。这个项目的主要目标是展示我们的活疫苗 可广泛预防NTS胃肠炎，并在潜在目标中有效 人口。为了实现这些目标，我们提出了以下目标：目标1.确定候选人是否还活着 减毒非伤寒沙门氏菌(B群鼠伤寒沙门氏菌、D群肠炎沙门氏菌、Virchow沙门氏菌 [血清组C1]和S.Newport[血清组C2])疫苗可以预防胃肠炎；目的2.识别 对我们的候选减毒鼠伤寒沙门氏菌的机械性或非机械性相关保护 疫苗；目的3.预测减毒活疫苗在目标人群中的性能；目的4.评估 一种减毒沙门氏菌活疫苗的多价配方，并确定诱导的抗体是否 对包括耐药沙门氏菌在内的临床菌株有效。在这个项目结束时，我们 预计我们将证明我们的候选NTS疫苗可以介导对 胃肠炎，我们将确定机械性和非机械性的保护相关性。我们也 预计我们已经确定我们的口服活疫苗是否产生了目前识别的抗体 循环中的抗生素耐药菌株。最后，我们将证明我们的疫苗具有免疫原性。 人口。如果我们成功，这些结果将为启动未来的第一阶段临床试验铺平道路。

Project summary – RP2 Non-typhoidal Salmonella (NTS) such as Salmonella Typhimurium and Salmonella Enteritidis generally cause self-limiting gastroenteritis. NTS is estimated to cause 94 million cases and 155,000 deaths worldwide each year. Whereas the incidence of disease caused by other important enteric pathogens have been reduced consequent to interventions initiated by FoodNet, the incidence of Salmonella disease in the U.S. has remained the same and was reported to be 7452 infections per 100,000 in 2014. NTS disproportionally affects the very young and the elderly. Our overall goal is to develop vaccines to provide broad protection against NTS disease. This proposal seeks to build on our previous work where we have developed live attenuated S. Typhimurium, S. Enteritidis, S. Newport and S. Virchow vaccines. The main goals of this project are to show that our live vaccines can provide broad protection against NTS gastroenteritis and that they will be effective in potential target populations. To achieve these goals, we propose the following aims: Aim 1. Determine whether candidate live attenuated non-typhoidal Salmonella (S. Typhimurium [serogroup B], S. Enteritidis [serogroup D], S. Virchow [serogroup C1] and S. Newport [serogroup C2]) vaccines can protect against gastroenteritis; Aim 2. To identify a mechanistic or non-mechanistic correlate of protection for our candidate live attenuated S. Typhimurium vaccine; Aim 3. To predict performance of live attenuated NTS vaccines in target populations; Aim 4. To evaluate a multivalent formulation of live attenuated Salmonella vaccines and determine whether elicited antibodies are effective against clinical strains including antibiotic-resistant Salmonella. At the conclusion of this project, we anticipate that we will have shown that our candidate NTS vaccines can mediate protection against gastroenteritis and we will have identified mechanistic and non-mechanistic correlates of protection. We also anticipate that we will have determined whether our live oral vaccines produce antibodies that recognize currently circulating antibiotic-resistant strains. Finally, we will have shown that our vaccines are immunogenic in target populations. If we are successful, these results will pave the way for initiating future Phase 1 clinical trials.