SAFETY AND IMMUNOGENICITY OF TY800 CARRYING HETEROLOGOUS ANTIGENS

Massachusetts General Hospital, Boston MA

Investigators

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Abstract

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.