Low-dose Challenge Model With Enterotoxigenic E Coli

NCT00844493 | Completed Phase 1

• 1 other identifier: CIR259
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Diarrhea

Keywords

diarrhea; vaccine; enterotoxigenic E coli; colonization factor antigen; volunteer study

Outcome Measures

Primary Outcomes (1)

• Occurrence of moderate or severe diarrhea

  5 days

Secondary Outcomes (1)

• Antibody response to Cholera toxin b subunit, Lipopolysaccharide and colonization factor antigen

  6 months

Study Arms (4)

H10407 challenge 1

EXPERIMENTAL

7 or 8 logs of E. coli strain H10407 with CeraVacx buffer

Biological: E coli strain H10407 and buffer

H10407 challenge 2

EXPERIMENTAL

7 or 8 logs of E. coli strain H10407 with bicarbonate buffer

Biological: E coli strain H10407 and buffer

H10407 challenge 3

EXPERIMENTAL

6 logs of E. coli H10407 with bicarbonate buffer

Biological: E coli strain H10407 and buffer

H10407 challenge 4

EXPERIMENTAL

5 logs of E. coli H10407 with bicarbonate buffer

Biological: E coli H10407 and buffer

Interventions

E coli strain H10407 and buffer BIOLOGICAL

7 or 8 logs of the bacteria with bicarbonate buffer

H10407 challenge 1

E coli H10407 and buffer BIOLOGICAL

Bacteria in a dose of 8 logs with bicarbonate buffer

H10407 challenge 4

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Male or female between 18 and 45 years of age, inclusive.
• General good health, as determined by physical exam, laboratory testing, and medical history.
• Laboratory values within acceptable range for complete blood count (CBC), Alanine Aminotransferase (ALT), and serum creatinine as determined by PI.
• Demonstrate comprehension of the protocol procedures and knowledge of ETEC illness by passing a written examination (pass grade ≥ 70%)
• Able and willing to sign an informed consent.
• Available to participate for the length of the study.
• Female only: Females of childbearing potential will use an effective method of contraception during the study, including abstinence, hormonal contraception, barrier, implantables or injectables.

You may not qualify if:

• Presence of a clinically significant medical condition (including but not limited to any chronic illnesses, immunosuppressive illness, cancer, diabetes, gastrointestinal disease, such as peptic ulcer, symptoms or evidence of active gastritis or gastroesophageal reflux disease, inflammatory bowel disease)
• Evidence of immunoglobulin A (IgA) deficiency (serum IgA \<5 or limit of detection of assay)
• Evidence of HIV, hepatitis B virus (HBV), hepatitis C virus (HCV), by medical history or laboratory testing.
• Symptoms consistent with Traveler's Diarrhea concurrent with travel to countries where ETEC or cholera infection is endemic (most of the developing world) within two years prior to receipt of investigational agent, OR planned travel to endemic countries during the length of the trial.
• History of significant psychiatric illness requiring hospitalization or any suicide attempts within the past 2 years.
• History of significant drug or alcohol abuse requiring hospitalization or rehabilitation within the past 2 years.
• Evidence of significant drug abuse, as determined by the Principal Investigator, on toxicity screening.
• Fewer than 3 stools per week or more than 3 stools per day as the usual frequency; loose or liquid stools other than on an occasional basis.
• History of allergic reaction to fluoroquinolones, cotrimoxazole, or ampicillin/penicillin (excluded if allergic to two of three).
• History of diarrhea in the 2 weeks prior to receipt of investigational agent.
• Weekly use of laxatives or any agent that increases gastric pH.
• Use of antibiotics during the 7 days prior to receipt of investigational agent.
• Use of proton pump inhibitors, H2 blockers, or antacids within 48 hours of receipt of investigational agent.
• History of vaccination for or ingestion of ETEC, cholera, or heat labile toxin (LT) toxin within 5 years.\*
• History of participation in prior ETEC H10407 research studies.\*

Sponsors & Collaborators

• Johns Hopkins Bloomberg School of Public Health: lead
• PATH Vaccine Solutions: collaborator

Study Sites (1)

Center for Immunization Research, Johns Hopkins Bloomberg School of Public Heatlh

Baltimore, Maryland, 21205, United States

Location

Related Publications (8)

• McKenzie R, Bourgeois AL, Engstrom F, Hall E, Chang HS, Gomes JG, Kyle JL, Cassels F, Turner AK, Randall R, Darsley M, Lee C, Bedford P, Shimko J, Sack DA. Comparative safety and immunogenicity of two attenuated enterotoxigenic Escherichia coli vaccine strains in healthy adults. Infect Immun. 2006 Feb;74(2):994-1000. doi: 10.1128/IAI.74.2.994-1000.2006.

  PMID: 16428745 BACKGROUND

• Sack DA, Shimko J, Sack RB, Gomes JG, MacLeod K, O'Sullivan D, Spriggs D. Comparison of alternative buffers for use with a new live oral cholera vaccine, Peru-15, in outpatient volunteers. Infect Immun. 1997 Jun;65(6):2107-11. doi: 10.1128/iai.65.6.2107-2111.1997.

  PMID: 9169739 BACKGROUND

• DuPont HL, Formal SB, Hornick RB, Snyder MJ, Libonati JP, Sheahan DG, LaBrec EH, Kalas JP. Pathogenesis of Escherichia coli diarrhea. N Engl J Med. 1971 Jul 1;285(1):1-9. doi: 10.1056/NEJM197107012850101. No abstract available.

  PMID: 4996788 BACKGROUND

• Qadri F, Saha A, Ahmed T, Al Tarique A, Begum YA, Svennerholm AM. Disease burden due to enterotoxigenic Escherichia coli in the first 2 years of life in an urban community in Bangladesh. Infect Immun. 2007 Aug;75(8):3961-8. doi: 10.1128/IAI.00459-07. Epub 2007 Jun 4.

  PMID: 17548483 BACKGROUND

• Qadri F, Ahmed T, Ahmed F, Begum YA, Sack DA, Svennerholm AM; PTE Study Group. Reduced doses of oral killed enterotoxigenic Escherichia coli plus cholera toxin B subunit vaccine is safe and immunogenic in Bangladeshi infants 6-17 months of age: dosing studies in different age groups. Vaccine. 2006 Mar 6;24(10):1726-33. doi: 10.1016/j.vaccine.2005.08.110. Epub 2005 Oct 10.

  PMID: 16257098 BACKGROUND

• Qadri F, Svennerholm AM, Faruque AS, Sack RB. Enterotoxigenic Escherichia coli in developing countries: epidemiology, microbiology, clinical features, treatment, and prevention. Clin Microbiol Rev. 2005 Jul;18(3):465-83. doi: 10.1128/CMR.18.3.465-483.2005.

  PMID: 16020685 BACKGROUND

• 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.

  PMID: 21852546 RESULT

• Chakraborty S, Harro C, DeNearing B, Brubaker J, Connor S, Maier N, Dally L, Flores J, Bourgeois AL, Walker R, Sack DA. Impact of lower challenge doses of enterotoxigenic Escherichia coli on clinical outcome, intestinal colonization and immune responses in adult volunteers. PLoS Negl Trop Dis. 2018 Apr 27;12(4):e0006442. doi: 10.1371/journal.pntd.0006442. eCollection 2018 Apr.

  PMID: 29702652 DERIVED

Related Links

• resource for vaccines for Enterotoxigenic E coli
• web site for the International Centre for Diarrhoeal Disease Research, Bangladesh where much of the work on ETEC is done

MeSH Terms

Conditions

Diarrhea

Interventions

Buffers

Condition Hierarchy (Ancestors)

Signs and Symptoms, Digestive; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Laboratory Chemicals; Specialty Uses of Chemicals; Chemical Actions and Uses

Study Officials

• Clayton Harro, M.D.

  Johns Hopkins Bloomberg School of Public Health

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: PREVENTION
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 13, 2009
• First Posted: February 16, 2009
• Study Start: February 1, 2009
• Primary Completion: February 1, 2012
• Study Completion: June 1, 2013
• Last Updated: September 12, 2014

Record last verified: 2013-04

Locations

US (1)