Low-dose Challenge Model With Enterotoxigenic E Coli
Condition: Diarrhea
MeSH terms: Diarrhea
Study type: Interventional
Phase: Phase 1

Summary: 
      This study will validate a model for testing new vaccines designed to protect against
      intestinal infections with enterotoxigenic Escherichia coli (ETEC). ETEC is one of the most
      common causes of diarrhea in developing countries and is a common cause of travelers
      diarrhea. Vaccines are now being developed and their development will be facilitated if we
      have a valid model for testing these vaccines in human volunteers. We anticipate that the new
      vaccines will be given to volunteers and they will then be given a dose of virulent ETEC
      bacteria. If the vaccine is effective, the volunteers should not development diarrhea, but if
      the vaccine is not effective, the volunteers will have diarrhea for a few days.

      During this study, we will validate a minimum dose of virulent ETEC bacteria which is
      sufficient to cause diarrhea in healthy adult volunteers and to identify conditions that can
      make this model reliable.

      We will also determine, in a follow-up group of volunteers, if being exposed to the ETEC
      bacteria previously will protect against a subsequent illness when they are exposed to the
      same bacteria a second time. We believe that the previously exposed group will be protected
      and we will study the immune response to these exposures to help design vaccines that can
      accomplish this kind of protection.
    

Detailed description: 
      This is a study in which healthy adult inpatient volunteers will be challenged with
      Escherichia coli, strain H10407 using different conditions. The study has the following
      objectives.

        1. To identify a revised set of procedures for the ETEC H10407 challenge model that will
           allow for an inoculum dose <108 organisms, and that will cause diarrhea in 50% or more
           of subjects without causing high output diarrhea, as determined by stool output volumes
           or signs and symptoms associated with hypovolemia.

        2. To measure mucosal and systemic immune responses to ETEC H10407 in naïve and immune
           subjects.

        3. To determine the extent to which recent enteric illness due to ETEC H10407will protect
           subjects against diarrhea when re-challenged with H10407.

        4. To determine the extent to which mucosal and/or systemic antibody responses following
           ETEC H10407diarrhea are predictive of protection in a re-challenge study.

      The study is divided into 4 cohorts. The first cohort will test four conditions of dose and
      buffer for the challenge. Using the conditions that appear to be best, a larger number of
      volunteers will be given this challenge to validate these conditions. The third group will be
      divided between some volunteers who had been ill during previous studies and some who have
      not been exposed before.

      Specimens will be obtained to determine the extent of excretion of the challenge strain and
      the immune responses to the challenge. These will include measures of both systemic and local
      intestinal immunity.

      Update as of May 2010:

      The clinical portion of the study has been completed and is no longer recruiting. The overall
      results were presented at two meetings including the Vaccines for Enteric Diseases in Spain
      in 2009 and the US-Japan Medical Science conference on Cholera and Enteric Disease in San
      Diego in 2009. Volunteers who received the lower dose (7 logs), along with an overnight fast
      developed diarrhea with an attack rate of >75%. Volunteers who were challenged a second time
      with this dose were protected from subsequent illness. Immunological assessment of the
      volunteers is continuing.

      Update as of November 2011 Results of the first three cohorts were published in 2011 (see
      citation below). A fourth cohort is planned to be enrolled to evaluate the virulence of an
      even lower dose of 5 and 6 logs of E coli. The same procedures will be carried out as with
      earlier cohorts.

      Update as of April 2013 Following challenge with 5 or 6 logs of strain H10407, the attack
      rates were lower (approximately 30%). Among those volunteers who did develop illness, the
      severity was the same as with higher doses. completion of these lower doses completes the
      dose response curve for H10407. For future challenge studies, 7 logs of H10407 with
      bicarbonate buffer will be used.
    

Intervention name(s): E coli strain H10407 and buffer; E coli strain H10407 and buffer; E coli strain H10407 and buffer; E coli H10407 and buffer
Intervention type(s): Biological; Biological; Biological; Biological
Intervention description(s): 7 or 8 logs of the bacteria with bicarbonate buffer; Bacteria in a dose of 8 logs with CeraVacx buffer; Bacteria in a dose of 7 logs and CeraVacx buffer; Bacteria in a dose of 8 logs with bicarbonate buffer
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Prevention
Keywords: diarrhea; vaccine; enterotoxigenic E coli; colonization factor antigen; volunteer study