Dose-Finding Study of CS19 Expressing ETEC Challenge Strains
Condition: Travelers' Diarrhea
MeSH terms: Diarrhea
Study type: Interventional
Phase: Phase 1

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.
    

Detailed 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.
    

Intervention name(s): CS19 expressing ETEC strain
Intervention type(s): Biological
Intervention description(s): Wild type ETEC strain expressing the colonization faction CS19, and LT and ST enterotoxins.
Intervention model: Single Group Assignment
Intervention model description: This is a phase 1, open-label, strain and dose-finding study designed to establish a human challenge model for CS19-ETEC that causes a > 80% attack rate without causing high output diarrhea. 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.
Masking: None (Open Label)
Primary purpose: Other
Keywords: Diarrhea; ETEC