Human Challenge Model Refinement With Enterotoxigenic Escherichia Coli Strain B7A

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

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.

Study Overview

• Status: Completed
• Conditions: Healthy Volunteer
• Intervention / Treatment: Biological: ETEC strain B7A (O148:H28 CS6+ LT+ST+) (Lot 0481) in Buffer

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 47
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21205
      • Johns Hopkins Center for Immunization Research

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Male or female between 18 and 50 years of age, inclusive.
2. General good health, without clinically significant medical history, physical examination findings or clinical laboratory abnormalities per clinical judgment of the PI.
3. Completion of a training session and demonstration of comprehension of the protocol procedures and knowledge of ETEC-associated illness by passing a written examination.
4. Willingness to participate after informed consent obtained.
5. Availability for the study duration, including all planned follow-up visits.
6. Negative pregnancy test with understanding to not become pregnant during the study or within three months following last scheduled study visit.

Exclusion Criteria:

1. Presence of a significant medical condition which in the opinion of the investigator precludes participation in the study.
2. Significant abnormalities in screening hematology or serum chemistry as determined by PI or PI in consultation with the research monitor and sponsor.
3. Evidence of confirmed infection with HIV, Hepatitis B, or Hepatitis C.
4. Evidence of Immunoglobulin A (IgA) deficiency (serum IgA < 7 mg/dL or below the limit of detection of assay).
5. Evidence of current excessive alcohol consumption or drug dependence (a targeted drug screen may be used to evaluate at the clinician's discretion).
6. Evidence of impaired immune function.
7. Recent vaccination or receipt of an investigational product (within 30 days before receipt of challenge).
8. 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.
9. History of microbiologically confirmed ETEC or cholera infection in last 3 years.
10. Occupation involving handling of ETEC or Vibrio cholerae currently, or in the past 3 years.
11. Symptoms consistent with Travelers' Diarrhea concurrent with travel or planned travel to countries where ETEC infection is endemic.
12. Vaccination for or ingestion of ETEC, cholera, or E coli heat labile toxin within 3 years prior to dosing.
13. Any prior experimental infection with ETEC strain B7A.
14. Abnormal stool pattern.
15. Regular use of laxatives, antacids, or other agents to lower stomach acidity.
16. Use of any medication known to affect the immune function.
17. Known allergy to two of the following antibiotics: ciprofloxacin, trimethoprim-sulfamethoxazole, and amoxicillin.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: PREVENTION
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: SINGLE

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Cohort 1 group A; 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; ETEC Bacteria
EXPERIMENTAL: Cohort 1 group B; 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; ETEC Bacteria
EXPERIMENTAL: Cohort 1 group C; 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; ETEC Bacteria
EXPERIMENTAL: Cohort 1 group D; 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; ETEC Bacteria
EXPERIMENTAL: Cohort 2 group A; 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; ETEC Bacteria
EXPERIMENTAL: Cohort 2 group B; 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; ETEC Bacteria

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Johns Hopkins Bloomberg School of Public Health
• Collaborators: United States Department of Defense; PATH; Naval Medical Research Center

Publications and helpful links

General Publications

• Porter CK, Riddle MS, Alcala AN, Sack DA, Harro C, Chakraborty S, Gutierrez RL, Savarino SJ, Darsley M, McKenzie R, DeNearing B, Steinsland H, Tribble DR, Bourgeois AL. An Evidenced-Based Scale of Disease Severity following Human Challenge with Enteroxigenic Escherichia coli. PLoS One. 2016 Mar 3;11(3):e0149358. doi: 10.1371/journal.pone.0149358. eCollection 2016.
• Harro C, Chakraborty S, Feller A, DeNearing B, Cage A, Ram M, Lundgren A, Svennerholm AM, Bourgeois AL, Walker RI, Sack DA. Refinement of a human challenge model for evaluation of enterotoxigenic Escherichia coli vaccines. Clin Vaccine Immunol. 2011 Oct;18(10):1719-27. doi: 10.1128/CVI.05194-11. Epub 2011 Aug 18.
• Chakraborty S, Harro C, DeNearing B, Ram M, Feller A, Cage A, Bauers N, Bourgeois AL, Walker R, Sack DA. Characterization of Mucosal Immune Responses to Enterotoxigenic Escherichia coli Vaccine Antigens in a Human Challenge Model: Response Profiles after Primary Infection and Homologous Rechallenge with Strain H10407. Clin Vaccine Immunol. 2015 Nov 18;23(1):55-64. doi: 10.1128/CVI.00617-15. Print 2016 Jan.
• Isidean SD, Riddle MS, Savarino SJ, Porter CK. A systematic review of ETEC epidemiology focusing on colonization factor and toxin expression. Vaccine. 2011 Aug 26;29(37):6167-78. doi: 10.1016/j.vaccine.2011.06.084. Epub 2011 Jul 1.
• Ahmed T, Bhuiyan TR, Zaman K, Sinclair D, Qadri F. Vaccines for preventing enterotoxigenic Escherichia coli (ETEC) diarrhoea. Cochrane Database Syst Rev. 2013 Jul 5;2013(7):CD009029. doi: 10.1002/14651858.CD009029.pub2.
• McKenzie R, Porter CK, Cantrell JA, Denearing B, O'Dowd A, Grahek SL, Sincock SA, Woods C, Sebeny P, Sack DA, Tribble DR, Bourgeois AL, Savarino SJ. Volunteer challenge with enterotoxigenic Escherichia coli that express intestinal colonization factor fimbriae CS17 and CS19. J Infect Dis. 2011 Jul 1;204(1):60-4. doi: 10.1093/infdis/jir220.
• Porter CK, Riddle MS, Tribble DR, Louis Bougeois A, McKenzie R, Isidean SD, Sebeny P, Savarino SJ. A systematic review of experimental infections with enterotoxigenic Escherichia coli (ETEC). Vaccine. 2011 Aug 11;29(35):5869-85. doi: 10.1016/j.vaccine.2011.05.021. Epub 2011 May 25.
• Lamberti LM, Bourgeois AL, Fischer Walker CL, Black RE, Sack D. Estimating diarrheal illness and deaths attributable to Shigellae and enterotoxigenic Escherichia coli among older children, adolescents, and adults in South Asia and Africa. PLoS Negl Trop Dis. 2014 Feb 13;8(2):e2705. doi: 10.1371/journal.pntd.0002705. eCollection 2014 Feb.
• Lanata CF, Fischer-Walker CL, Olascoaga AC, Torres CX, Aryee MJ, Black RE; Child Health Epidemiology Reference Group of the World Health Organization and UNICEF. Global causes of diarrheal disease mortality in children <5 years of age: a systematic review. PLoS One. 2013 Sep 4;8(9):e72788. doi: 10.1371/journal.pone.0072788. eCollection 2013.

Study record dates

Study Major Dates

• Study Start (ACTUAL): April 1, 2016
• Primary Completion (ACTUAL): December 1, 2016
• Study Completion (ACTUAL): December 1, 2016

Study Registration Dates

• First Submitted: May 10, 2016
• First Submitted That Met QC Criteria: May 11, 2016
• First Posted (ESTIMATE): May 16, 2016

Study Record Updates

• Last Update Posted (ACTUAL): July 6, 2018
• Last Update Submitted That Met QC Criteria: June 6, 2018
• Last Verified: April 1, 2018

More Information

Terms related to this study

• Keywords: Challenge; Escherichia coli; ETEC; enteritis; CS6; Enterotoxigenic
• Additional Relevant MeSH Terms: Infections; Gram-Negative Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Enterobacteriaceae Infections; Escherichia coli Infections
• Other Study ID Numbers: CIR303 B7A

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Data will be published in Peer reviewed journal