Safety Study of Chimeric Vaccine to Prevent ETEC Diarrhea

A Phase 1 Dose Escalating Study of Two Enterotoxigenic Escherichia Coli Prototype Adhesin-based Vaccines With or Without Modified Heat-labile Enterotoxin by Intradermal or Transcutaneous Immunization

The purpose of the study is to determine if immunization with a chimeric E. coli protein, dsc14CfaE-sCT2/LTB5, is safe and immunogenic when administered by vaccination under the skin.

Study Overview

• Status: Completed
• Conditions: Escherichia Coli Infection
• Intervention / Treatment: Biological: Recombinant fimbrial adhesin dscCfaE; Biological: Recombinant fimbrial adhesin dsc14CfaE-sCTA2/LTB5; Biological: Modified E. coli heat labile enterotoxin LTR192G

Detailed Description

The purpose of the study is to evaluate the safety and immunogenicity of dsc14cfaEsCTA2/LTB5 (Chimera) and dscCfaE administered with and without LTR192G by intradermal (ID) immunization and to gather additional data on the administration of dsCfaE and LTR192G via transcutaneous immunization (TCI) route. If vaccines are found to be safe and adequately immunogenic in humans, a down-selection would occur and a phase 2b vaccination/challenge study would be undertaken to further evaluate vaccine safety and allow a preliminary assessment of efficacy of one of these candidates by the ID or TCI route. With favorable evidence for safety, immunogenicity, efficacy, complemented by advances in standard methodology to combine multiple adhesins with an appropriate LT enterotoxoid form, a multivalent vaccine would be constructed and evaluated for further clinical development.

• Study Type: Interventional
• Enrollment (Actual): 57
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Silver Spring, Maryland, United States, 20910
      • Walter Reed Army Institute of Research Clinical Trial Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Healthy, adult, male or female, age 18 to 45 years (inclusive) at the time of enrollment.
• Completion and review of comprehension test (achieved > 70% accuracy).
• Signed informed consent document.
• Available for the required follow-up period and scheduled clinic visits.
• Women: Negative pregnancy test with understanding (through informed consent process) to not become pregnant during the study or within three (3) months following study completion.

Exclusion Criteria:

• Health problems (for example, chronic medical conditions such as psychiatric conditions, diabetes mellitus, hypertension or any other conditions that might place the subjects at increased risk of adverse events. Study clinicians, in consultation with the PI, will use clinical judgment on a case-by-case basis to assess safety risks under this criterion. The PI will consult with the Research Monitor as appropriate.
• Clinically significant abnormalities on physical examination.
• Use of immunosuppressive medications (systemic corticosteroids or chemotherapeutics that may influence antibody development), or immunosuppressive illness, including IgA deficiency (defined by serum IgA below the detectable limit).
• Women who are pregnant or planning to become pregnant during the study period plus 3 months beyond the last study safety visit and currently nursing women.
• Participation in research involving another investigational product (defined as receipt of investigational product or exposure to invasive investigational device) 30 days before planned date of first vaccination or anytime through the last study safety visit.
• Positive blood test for HBsAg, HCV, HIV-1.
• Clinically significant abnormalities on basic laboratory screening.
• Exclusionary skin history/findings that would confound assessment or prevent appropriate local monitoring of AEs, or possibly increase the risk of an AE.
• History of chronic skin disease (clinician judgment).
• History of atopy such as active eczema.
• Acute skin infection/eruptions on the upper arms including fungal infections, severe acne or active contact dermatitis.
• Allergies that may increase the risk of AEs.
• Regular use (weekly or more often) of antidiarrheal, anti-constipation, or antacid therapy.
• Abnormal stool pattern (fewer than 3 stools per week or more than 3 stools per day) on a regular basis; loose or liquid stools on other than an occasional basis.
• Prior exposure to ETEC or Vibrio cholera.
• History of microbiologically confirmed ETEC or cholera infection.
• Travel to countries where ETEC or V. cholera or other enteric infections are endemic (most of the developing world) within two years prior to dosing clinician judgment).
• Received previous experimental ETEC or V. cholera vaccine or live ETEC or V. cholera challenge.
• Occupation involving handling of ETEC or V. cholera currently, or in the past 3 years.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: PREVENTION
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

9

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group A-1; Recombinant fimbrial adhesin dscCfaE: 1 ug of dscCfaE ID on study days 0, 21 and 42	Biological: Recombinant fimbrial adhesin dscCfaE; Other Names: dscCfaE
Experimental: Group A-2; Recombinant fimbrial adhesin dsc14CfaE-sCTA2/LTB5: 2.6 ug of Chimera ID on study days 0, 21 and 42	Biological: Recombinant fimbrial adhesin dsc14CfaE-sCTA2/LTB5; Other Names: Chimera
Experimental: Group A-3; Modified E. coli heat labile enterotoxin LTR192G: 100 ng of LTR192G ID on study days 0, 21 and 42	Biological: Modified E. coli heat labile enterotoxin LTR192G; Other Names: LTR192G
Experimental: Group B-1; Recombinant fimbrial adhesin dscCfaE and Modified E. coli heat labile enterotoxin LTR192G: 1 ug of dscCfaE + 100 ng of LTR192G ID on study days 0, 21 and 42	Biological: Recombinant fimbrial adhesin dscCfaE; Other Names: dscCfaE; Biological: Modified E. coli heat labile enterotoxin LTR192G; Other Names: LTR192G
Experimental: Group B-2; Recombinant fimbrial adhesin dsc14CfaE-sCTA2/LTB5 and Modified E. coli heat labile enterotoxin LTR192G: 2.6 ug of Chimera + 100 ng of LTR192G ID on study days 0, 21 and 42	Biological: Recombinant fimbrial adhesin dsc14CfaE-sCTA2/LTB5; Other Names: Chimera; Biological: Modified E. coli heat labile enterotoxin LTR192G; Other Names: LTR192G
Experimental: Group C-1; Recombinant fimbrial adhesin dscCfaE and Modified E. coli heat labile enterotoxin LTR192G: 5 ug of dscCfaE + 100 ng of LTR192G ID on study days 0, 21 and 42	Biological: Recombinant fimbrial adhesin dscCfaE; Other Names: dscCfaE; Biological: Modified E. coli heat labile enterotoxin LTR192G; Other Names: LTR192G
Experimental: Group C-2; Recombinant fimbrial adhesin dsc14CfaE-sCTA2/LTB5 and Modified E. coli heat labile enterotoxin LTR192G: 12.9 ug of Chimera + 100 ng of LTR192G ID on study days 0, 21 and 42	Biological: Recombinant fimbrial adhesin dsc14CfaE-sCTA2/LTB5; Other Names: Chimera; Biological: Modified E. coli heat labile enterotoxin LTR192G; Other Names: LTR192G
Experimental: Group D-1; Recombinant fimbrial adhesin dscCfaE and Modified E. coli heat labile enterotoxin LTR192G: 25 ug dscCfaE + 100 ng LTR192G ID on study days 0, 21 and 42	Biological: Recombinant fimbrial adhesin dscCfaE; Other Names: dscCfaE; Biological: Modified E. coli heat labile enterotoxin LTR192G; Other Names: LTR192G
Experimental: Group D-2; Recombinant fimbrial adhesin dscCfaE and Modified E. coli heat labile enterotoxin LTR192G: 1250 ug dscCfaE + 50 ng LTR192G TCI on study days 0, 21 and 42	Biological: Recombinant fimbrial adhesin dscCfaE; Other Names: dscCfaE; Biological: Modified E. coli heat labile enterotoxin LTR192G; Other Names: LTR192G

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety - Occurrence of Adverse Events	Occurrence of related and unrelated to vaccine AE's	1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Immune Responses to Vaccine Antigens	Number of participants with immune responses to vaccine antigens from baseline. Peripheral blood mononuclear cells (PBMCs) were collected to determine IgA antibody secreting cells (ASC) responses to dscCfaE and LTB. For each antigen, pre-and post-dosing samples were tested for total and vaccine-specific numbers of IgA-ASCs using the ELISPOT assay. A positive IgA-ASC response was defined as a > 2-fold increase over the baseline value of the ASC per 10^6 PBMC, when the number of ASC was >0.5 per 10^6 in the baseline sample. When the number of baseline ASCs was less than 0.5 per 10 PBMC, a subject was considered a responder if the post-vaccination value was greater than 1.0 per 10^6 PBMC.	baseline and post dose
Antigen-Specific IgA Geometric Mean Titers	Antigen-Specific IgA Geometric Mean Titers as defined by Fecal IgA. Final Clinical Study Report (FCSR) highlighted titer numbers only; no numbers for measure of dispersion/precision were given; no explanation as to why standard deviation information is not present in the FCSR.	Day 0, 21,42, 56, 70

Collaborators and Investigators

• Sponsor: U.S. Army Medical Research and Development Command
• Investigators: Principal Investigator: Ramiro L. Gutierrez, MD, MPH, Enteric Diseases Department, Naval Medical Research Center

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2012
• Primary Completion (Actual): June 1, 2014
• Study Completion (Actual): June 1, 2015

Study Registration Dates

• First Submitted: July 11, 2012
• First Submitted That Met QC Criteria: July 16, 2012
• First Posted (Estimate): July 19, 2012

Study Record Updates

• Last Update Posted (Actual): February 12, 2021
• Last Update Submitted That Met QC Criteria: February 10, 2021
• Last Verified: February 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infections; Gram-Negative Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Enterobacteriaceae Infections; Escherichia coli Infections
• Other Study ID Numbers: S-12-07 (Other Identifier: Sponsor); NMRC.2012.0005 (Other Identifier: Naval Medical Research Center Institutional Review Board); 1924 (Other Identifier: Walter Reed Army Institute of Research Institutional Review Board)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED