SAFETY AND IMMUNOGENICITY OF TY800 CARRYING HETEROLOGOUS ANTIGENS

本方案的目的是评估减毒沙门氏菌菌株用于递送与其他传染病相关的异源抗原的安全性和免疫原性。沙门氏菌长期以来一直被认为是合适的疫苗载体，因为它们可以刺激体液、细胞和粘膜免疫，并且可以口服。有希望的动物研究迄今尚未转化为临床成功，本研究的总体目标是评估刺激人类对载体抗原免疫反应的重要变量。研究人员选择了来自霍乱、旅行者腹泻、乙型肝炎病毒或幽门螺杆菌（一种部分导致胃肠道溃疡和肿瘤形成的细菌病原体）的特异性蛋白作为异源抗原。先前对GCRC的研究已经证实，Ty800（一种因特定毒力调控位点而被删除的伤寒沙门氏菌减毒株）在人单剂量时是安全的和具有免疫原性的。研究人员将设计Ty800来表达上述抗原之一，并在一小群成年志愿者中测试这些新菌株。受试者在GCRC上被密切跟踪7-10天，然后作为门诊患者，研究结果包括临床不良事件、细菌脱落的持续时间、疫苗菌血症的存在或不存在，以及对沙门氏菌抗原和工程抗原的体液和粘膜免疫反应的测量。对该研究的修改包括评估另一种血清型沙门氏菌，表达幽门螺杆菌抗原的鼠伤寒沙门氏菌。研究人员提出，鼠伤寒沙门氏菌在肠道中更持久、更有活力的定植可能会导致人类对载体抗原产生更好的免疫反应。

The purpose of this protocol is to evaluate the safety and immunogenicity of attenuated Salmonella strains for delivery of heterologous antigens related to other infectious diseases. Salmonella have long been proposed as appropriate vaccine vectors because they stimulate humoral, cellular, and mucosal immunity and may be given orally. Promising studies in animals have not to date been translated to clinical success, and the overall goal of this study is to evaluate variables important for stimulating human immune responses to vectored antigens. The investigators have chosen as heterologous antigens specific proteins from either cholera, tranveler's diarrhea, hepatitis B virus, or Helicobacter pylori, a bacterial pathogen responsible in part for gastrointestinal ulceration and tumor formation. Previous studies on the GCRC have established that Ty800, an attenuated S. typhi strain deleted for a specific virulence regulatory locus is safe and immunogenic in single doses in humans. The investigators will engineer Ty800 to express one of the mentioned antigens and test these new strains in small cohorts of adult volunteers. Subjects are followed closely on the GCRC for 7-10 days, and then as outpatients, and study outcomes include clinical adverse events, duration of bacterial shedding, presence or absence of vaccine bacteremias, and measurenment of humoral and mucosal immune responses to both Salmonella antigens and engineered antigens. Amendments to the study have included a proposal to evaluate another serotype of Salmonella, S. typhimurium expressing the Helicobacter pylori antigen. The investigators propose that the more durable and vigorous colonization of the intestine afforded by S. typhimurium may result in better human immune responses to vectored antigens.