Dose-Finding Study of CS19 Expressing ETEC Challenge Strains
Summary
This will be a strain and dose-finding study in which CS19-ETEC strain WS0115A will be administered at a starting inoculum of 5 x 108 colony forming units (cfu) to 5 subjects as the initial step to establish a human disease model. If an 80% attack rate (AR) for predefined diarrheal disease is achieved without high output diarrhea, the same inoculum will be given to 5 - 10 more subjects for confirmation of AR. If an 80% AR is not achieved, AR and severity of disease will be evaluated to determine if the dose should be increased. The same sequence may be conducted with DS26-1 as necessary. If the WS0115A strain causes high output diarrhea, the dose will be adjusted down and further dose characterization continued. An iterative process will be used to select the optimal strain and dose with each step reviewed and approved by the medical monitor.
Description
This is a phase 1, open-label, strain and dose-finding study designed to establish a human challenge modelfor CS19-ETEC that causes a > 80% attack rate without causing high output diarrhea. This study design is identical to that of the CS17 challenge model recently completed. Two strains of CS19-ETEC isolated from human diarrheal cases have been identified and characterized. Each clinical isolate was used to generate a cGMP MCB and procedures were established to create a fresh inoculum to administer orally in a sodium bicarbonate solution for challenge. Refer to Section 8 for full details on the isolation and preparation of these strains.
CS19-ETEC strain WS0115A (toxin phenotype of LT+ ST+ and serotype O114:H-) will be the lead strain and will be administered orally to an initial cohort of 5 subjects. This strain was isolated from the stool of a 12-month-old Egyptian girl suffering from watery diarrhea identified during a surveillance study conducted in Abees, Egypt from 1993 to 1995 by investigators at the Naval Medical Research Unit-3 (NAMRU-3), Cairo, Egypt. A negative microbiologic work-up for copathogens (other bacterialenteropathogens, rotavirus, Giardia lamblia, Entamoeba histolytica, and Cryptosporidium) supports that the isolated WS0115A strain was pathogenic in this child. Since this strain has an LT+ST+ toxin phenotype, it is the preferred strain to lead in testing the challenge model, since heterologous protection by bovine milk IgG anti-CsbD against an LT+ST+ phenotype would offer a more robust test of the protection afforded by anti-colonization. The alternate strain, CS-19 ETEC strain DS26-1 (toxin phenotype LT+ST-;serotype O8:H9) was isolated in 1990 at the U.S. Navy Forward Laboratory from a U.S. soldier with diarrhea while on deployment to Saudi Arabia during Operation Desert Shield. A negative microbiologic work-up for copathogens (Salmonella typhi, Vibrio cholerae, Giardia lamblia or Entamoeba histolytica)supports that the isolated DS26-1 strain was pathogenic in this individual. Each clinical isolate was used to generate a cGMP master cell bank and procedures were established to create a fresh inoculum to administer orally in a sodium bicarbonate solution for challenge. Refer to Section 8 for full details on the isolation and preparation of these strains.
Study Design
Allocation: Non-Randomized, Control: Uncontrolled, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Screening
Conditions
Travelers' Diarrhea
Intervention
CS19 expressing ETEC strain
Location
Center for Immunization Research - Johns Hopkins Bloomberg School of Public Health
Baltimore
Maryland
United States
21205
Status
Recruiting
Source
Johns Hopkins Bloomberg School of Public Health
Results (where available)
Links
- Source: http://clinicaltrials.gov/show/NCT00564863
- Information obtained from ClinicalTrials.gov on July 15, 2010
Medical and Biotech [MESH] Definitions
Bovine Virus Diarrhea-mucosal Disease
Acute disease of cattle caused by the bovine viral diarrhea viruses (DIARRHEA VIRUSES, BOVINE VIRAL). Often mouth ulcerations are the only sign but fever, diarrhea, drop in milk yield, and loss of appetite are also seen. Severity of clinical disease varies and is strain dependent. Outbreaks are characterized by low morbidity and high mortality.
Enteropathogenic Escherichia Coli
Strains of ESCHERICHIA COLI characterized by attaching-and-effacing histopathology. These strains of bacteria intimately adhere to the epithelial cell membrane and show effacement of microvilli. In developed countries they are associated with INFANTILE DIARRHEA and infantile GASTROENTERITIS and, in contrast to ETEC strains, do not produce ENDOTOXINS.
Enterotoxigenic Escherichia Coli
Strains of ESCHERICHIA COLI that produce or contain at least one member of either heat-labile or heat-stable ENTEROTOXINS. The organisms colonize the mucosal surface of the small intestine and elaborate their enterotoxins causing DIARRHEA. They are mainly associated with tropical and developing countries and affect susceptible travelers to those places.
Diarrhea Virus 2, Bovine Viral
A species of PESTIVIRUS causing systemic infections including BOVINE VIRUS DIARRHEA-MUCOSAL DISEASE and BOVINE HEMORRHAGIC SYNDROME in cattle and some other cloven-hoofed animals. There are several strains and two biotypes: cytopathic (rare) and non-cytopathic. The severity of disease appears to be strain dependent. Cytopathogenic effects do not correlate with virulence as non-cytopathic BVDV-2 is associated only with Hemorrhagic Disease, Bovine.
Rotavirus Infections
Infection with any of the rotaviruses. Specific infections include human infantile diarrhea, neonatal calf diarrhea, and epidemic diarrhea of infant mice.
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