Safety Study of Chimeric Vaccine to Prevent ETEC Diarrhea

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Escherichia Coli Infection

Intervention / Treatment
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* Biological: Recombinant fimbrial adhesin dsc14CfaE-sCTA2/LTB5
* Biological: Recombinant fimbrial adhesin dscCfaE
* Biological: Modified E. coli heat labile enterotoxin LTR192G


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A-1<br>Recombinant fimbrial adhesin dscCfaE: 1 ug of dscCfaE ID on study days 0, 21 and 42 | Biological: Recombinant fimbrial adhesin dscCfaE<br> <br> * Other names: dscCfaE;|
| Experimental: Group A-2<br>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<br> <br> * Other names: Chimera;|
| Experimental: Group A-3<br>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<br> <br> * Other names: LTR192G;|
| Experimental: Group B-1<br>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<br> <br> * Other names: dscCfaE;Biological: Modified E. coli heat labile enterotoxin LTR192G<br> <br> * Other names: LTR192G;|
| Experimental: Group B-2<br>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<br> <br> * Other names: Chimera;Biological: Modified E. coli heat labile enterotoxin LTR192G<br> <br> * Other names: LTR192G;|
| Experimental: Group C-1<br>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<br> <br> * Other names: dscCfaE;Biological: Modified E. coli heat labile enterotoxin LTR192G<br> <br> * Other names: LTR192G;|
| Experimental: Group C-2<br>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<br> <br> * Other names: Chimera;Biological: Modified E. coli heat labile enterotoxin LTR192G<br> <br> * Other names: LTR192G;|
| Experimental: Group D-1<br>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<br> <br> * Other names: dscCfaE;Biological: Modified E. coli heat labile enterotoxin LTR192G<br> <br> * Other names: LTR192G;|
| Experimental: Group D-2<br>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<br> <br> * Other names: dscCfaE;Biological: Modified E. coli heat labile enterotoxin LTR192G<br> <br> * Other names: LTR192G;|

What is the study measuring?
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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 |