This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. S. dysenteriae 1 is the cause of epidemic bacillary dysentery, a major contributor to childhood and adult morbidity and mortality in developing nations, and to travelers visiting these areas. Our goal is to develop a vaccine to prevent this disease. An effective S. dysenteriae 1 vaccine could be beneficial to inhabitants of developing countries, to travelers, and to US soldiers deployed to nations at risk. This protocol is designed to evaluate safety and immunogenicity of 3 different doses of a new live oral attenuated S. dysenteriae 1 vaccine candidate in small numbers of human subjects. The optimal dose will subsequently be tested in larger numbers of subjects in later protocols, with the ultimate intent of an efficacious, licensed, FDA-approved product for widespread use. ` WRSd1 is a live attenuated S. dysenteriae type 1 vaccine candidate derived from a wild-type S. dysenteriae type 1 strain first isolated from Guatemala. The attenuating deletions include the virG (also termed the icsA) gene on the virulence plasmid, and the stxA and stxB genes on the chromosome that encode the A and B subunit of the holotoxin, referred to as the Shiga toxin. The virG(icsA) gene is responsible for intra- and intercellular spread of the bacterium in colonic epithelium (Hale, 1991). Its absence confers loss of the ability to induce keratoconjunctivitis in the Sereny test (guinea pig model), and presumably colitis in humans. The Shiga toxin is responsible for the systemic clinical manifestations of Hemolytic Uremic Syndrome (HUS) and renal failure (Nakao and Takeda, 2000). Together, these attenuations are expected to result in a markedly less virulent bacterium that retains the ability to invade the epithelium and induce a protective immune response. This study is designed as a non-placebo-controlled clinical trial in a total of 40 subjects. Five groups of 8 subjects each will be admitted sequentially at intervals of no less than 2 weeks to the General Clinical Research Ward (Osler 5) of the Johns Hopkins Hospital for a period of 9 to 11 days. Each group will have baseline stool, blood, serum, and urine samples taken, then be vaccinated with a single oral dose of WRSd1 given with bicarbonate buffer. The 1st group of 8 will receive 103 colony-forming units (cfu) of WRSd1, the 2nd group 104 cfu, the 3rd group 105 cfu, the 4th 106 cfu and the 5th 107 cfu. Each group will be monitored daily after vaccination for symptoms and signs of illness, and stools will be collected for characterization and culture. On study day 8, subjects will begin treatment with oral ciprofloxacin, 500 mg tablets, one tablet BID x 3 days, or Bactrim DS one BID x 5 days or Amoxicillin, 500 mg TID x 5 days and will be discharged on day 9 to 11. Subjects will have whole blood drawn for antibody secreting cell assays (ASC's) on days 0 (prior to vaccination), 7 and 9; and will return on days 14 and 28 for additional blood collection for serum and for stool collections. Data will be analyzed in terms of prevalence of adverse events by severity, prevalence of 3-fold increase in immunoglobulins (Ig), and increases in ASC's > 3 standard deviations beyond mean baseline values. In addition to the specimens listed above, blood and urine will be collected to determine clinical laboratory values during screening and on days 14 and 28.
Showing the most recent 10 out of 1014 publications
