Low-dose Challenge Model With Enterotoxigenic E Coli

Diarrhea Clinical Trial

Official title: Validation of Low-dose ETEC Challenge Model in U.S. Adults and Re-challenge of Immune Subjects With a Homologous ETEC Strain (H10407)

Status Completed

Clinical Trial 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.

Clinical Trial 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. ;

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Prevention

Related Conditions & MeSH terms

• Diarrhea

• NCT number: NCT00844493
• Study type: Interventional
• Source: Johns Hopkins Bloomberg School of Public Health
• Status: Completed
• Phase: Phase 1
• Start date: February 2009
• Completion date: June 2013