Human Challenge Model Refinement With Enterotoxigenic Escherichia Coli Strain B7A

Study Overview
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Brief Summary
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The purpose of this study is to determine the safe and optimal dose and regimen (fasting duration) for administering the challenge ETEC strain B7A, a CS6 expressing ETEC strain. Additionally, an assessment of homologous protection following rechallenge with B7A will be assessed.

Detailed Description
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Enterotoxigenic Escherichia coli (ETEC) is the most common causes of infectious diarrhea in children in resource limited countries, and is also a frequent cause of traveler's diarrhea in civilian and military travelers to endemic countries. ETEC strains express one or both of two enterotoxins (heat labile toxin (LT) and heat stable toxin (ST)) that cause help the bacteria cause the main symptom of watery diarrhea. They also express a variety of colonization factors (CF) that help them attach to the intestinal wall. Each colonization factor has one or more surface antigens (CS). Vaccines and treatments to prevent ETEC disease are under development. Some of these target specific enterotoxins or colonization factors. For over 40 years, we have used ETEC human challenge studies to understand the ETEC disease process, immune response, and more recently, to determine whether treatments or vaccines are protective or effective in mitigating disease. One concern about these challenge study is the use of high doses of bacteria given may overwhelm the protective efficacy of the vaccine or treatment. Several strains of ETEC have been used in these challenge studies; a frequently used strain is B7A (CS6+, LT+, ST+. O148:H28). This study will explore the optimal dosing strategy for B7A, in order to minimize the dose of ETEC necessary to produce disease in healthy adult volunteers. There will be two inpatient admissions. The first will examine 4 dosing and fasting regimens in healthy volunteers. The second admission will include volunteers who became ill during the first admission, as well as a new group of volunteers. This second admission will validate the optimal dose from the first admission, as well as to determine if previous infection with B7A ETEC will protect against a new infection. Trying to understand the immune response to this challenge organism may help us optimize vaccine design and delivery to protect people from this infection.

Official Title
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Human Challenge Model Refinement for B7A, An Enterotoxigenic Escherichia Coli (ETEC) Challenge Strain That Expresses CS6

Conditions
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Healthy Volunteer

Intervention / Treatment
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* Biological: ETEC strain B7A (O148:H28 CS6+ LT+ST+) (Lot 0481) in Buffer


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female between 18 and 50 years of age, inclusive. General good health, without clinically significant medical history, physical examination findings or clinical laboratory abnormalities per clinical judgment of the PI. Completion of a training session and demonstration of comprehension of the protocol procedures and knowledge of ETEC-associated illness by passing a written examination. Willingness to participate after informed consent obtained. Availability for the study duration, including all planned follow-up visits. Negative pregnancy test with understanding to not become pregnant during the study or within three months following last scheduled study visit. Exclusion Criteria: Presence of a significant medical condition which in the opinion of the investigator precludes participation in the study. Significant abnormalities in screening hematology or serum chemistry as determined by PI or PI in consultation with the research monitor and sponsor. Evidence of confirmed infection with HIV, Hepatitis B, or Hepatitis C. Evidence of Immunoglobulin A (IgA) deficiency (serum IgA < 7 mg/dL or below the limit of detection of assay). Evidence of current excessive alcohol consumption or drug dependence (a targeted drug screen may be used to evaluate at the clinician's discretion). Evidence of impaired immune function. Recent vaccination or receipt of an investigational product (within 30 days before receipt of challenge). Any other criteria which, in the investigator's opinion, would compromise the ability of the subject to participate in the study, the safety of the study, or the results of the study. History of microbiologically confirmed ETEC or cholera infection in last 3 years. Occupation involving handling of ETEC or Vibrio cholerae currently, or in the past 3 years. Symptoms consistent with Travelers' Diarrhea concurrent with travel or planned travel to countries where ETEC infection is endemic. Vaccination for or ingestion of ETEC, cholera, or E coli heat labile toxin within 3 years prior to dosing. Any prior experimental infection with ETEC strain B7A. Abnormal stool pattern. Regular use of laxatives, antacids, or other agents to lower stomach acidity. Use of any medication known to affect the immune function. Known allergy to two of the following antibiotics: ciprofloxacin, trimethoprim-sulfamethoxazole, and amoxicillin.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1 group A<br>Volunteers will receive 8 logs of E. coli strain B7A after overnight fast | Biological: ETEC strain B7A (O148:H28 CS6+ LT+ST+) (Lot 0481) in Buffer<br>* ETEC Bacteria<br>|
| Experimental: Cohort 1 group B<br>Volunteers will receive 9 logs of E. coli strain B7A after 90 minute fast | Biological: ETEC strain B7A (O148:H28 CS6+ LT+ST+) (Lot 0481) in Buffer<br>* ETEC Bacteria<br>|
| Experimental: Cohort 1 group C<br>Volunteers will receive 9 logs of E. coli strain B7A after overnight fast | Biological: ETEC strain B7A (O148:H28 CS6+ LT+ST+) (Lot 0481) in Buffer<br>* ETEC Bacteria<br>|
| Experimental: Cohort 1 group D<br>Volunteers will receive 10 logs of E. coli strain B7A after 90 minute fast | Biological: ETEC strain B7A (O148:H28 CS6+ LT+ST+) (Lot 0481) in Buffer<br>* ETEC Bacteria<br>|
| Experimental: Cohort 2 group A<br>subjects from Cohort 1 who met primary endpoint will receive optimal regimen as determined by analysis after Cohort 1. | Biological: ETEC strain B7A (O148:H28 CS6+ LT+ST+) (Lot 0481) in Buffer<br>* ETEC Bacteria<br>|
| Experimental: Cohort 2 group B<br>Naive subjects who will receive optimal regimen as determined by analysis after Cohort 1 | Biological: ETEC strain B7A (O148:H28 CS6+ LT+ST+) (Lot 0481) in Buffer<br>* ETEC Bacteria<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Safety- Solicited Symptoms Related to Challenge Administration | Solicited symptoms (vomiting, abdominal pain, bloating, lightheadedness, anorexia, generalized myalgia, arthralgias, abdominal cramping, constipation, nausea, malaise, headache, flatulence) | 6 days post-challenge | 
| Moderate-severe Diarrhea | Moderate-severe diarrhea post challenge defined as moderate diarrhea: 4 to 5 loose/liquid stools or 401-800 of loose/liquid stool in any 24-hour period Severe diarrhea greater than or equal to 6 loose/liquid stools or greater than 800 g of loose/liquid stools in any 24-hour period | 5 days post challenge (Cohort 1 and Cohort 2 group B) 7 days post challenge (Cohort 2 Group A) | 
| Moderate-severe Diarrhea in Subjects Receiving Homologous Rechallenge | Moderate-severe diarrhea post-challenge defined as Moderate diarrhea: 4 to 5 loose/liquid stools or 401-800g of loose/liquid stool in any 24- hour period Severe diarrhea: greater than or equal to 6 loose/liquid stools or greater than 800 g of loose/liquid stool in any 24-hour period | 7 days post-challenge | 
| Number of Participants With Safety -Solicited Symptoms Unrelated to Challenge Administration | Safety solicited symptoms unrelated to challenge administration (vomiting, abdominal pain, bloating, lightheadedness, anorexia, generalized myalgia, arthralgias, abdominal cramping, constipation, nausea, malaise, headache, flatulence) | 6 days post-challenge | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Immune Response to Challenge (Serology) |  | 28 days post challenge | 
| Immune Response to Challenge | Antibody in Lymphocyte Supernatant (ALS) Immunoglobin G (IgG) (CS6) coli surface antigen 6 Immunoglobin G (IgG) heat labile Toxin (LT) Immunoglobin G (IgG) (LPS) Lipopolysaccharide Immunoglobin A (IgA) (CS6) coli surface antigen 6 Immunoglobin A (IgA) heat labile Toxin (LT) Immunoglobin A (IgG) (LPS) Lipopolysaccharide | 6 days post challenge | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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enteritis, Challenge, Enterotoxigenic, CS6, ETEC, Escherichia coli