Dose Escalating Study of a Prototype CS6 Subunit Vaccine With a Modified Heat-labile Enterotoxin From Enterotoxigenic Escherichia Coli (ETEC)

Study Overview
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Brief Summary
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This study will evaluate the safety of a prototype Coli surface antigen 6 (CS6) subunit vaccine (CssBA) alone or in combination with Escherichia coli double mutant heat labile toxin (dmLT) given by intramuscular (IM) injection.

Detailed Description
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This is an open-label clinical trial in which a total of 50 participants will receive three injections of either CssBA alone, dmLT alone or CssBA + dmLT. The vaccine will be administered via IM injection to alternating deltoid regions on days 1, 22, and 43. Each participant will receive the same dose at each vaccination dependent upon group assignment. Group A is considered a pilot group in which all 3 doses will be administered and participants monitored for safety 7 days after the third vaccination, prior to the enrollment of participants in Group B.

Official Title
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A Phase 1 Dose Escalating Study of a Prototype CS6 Subunit Vaccine With a Modified Heat-labile Enterotoxin From Enterotoxigenic Escherichia Coli (ETEC)

Conditions
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Diarrhea

Intervention / Treatment
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* Biological: CssBA
* Biological: dmLT


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 last vaccination. Exclusion Criteria: Health problems (for example, intercurrent febrile illness, chronic medical conditions such as psychiatric conditions, diabetes mellitus, hypertension or any other condition that might place the subject 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. Immunosuppressive drugs (use of systemic corticosteroids or chemotherapeutics that may influence antibody development) or illness (including immunoglobulin A [IgA] deficiency, defined by serum IgA < 7 mg/dL). Women who are pregnant or planning to become pregnant during the study period plus three (3) months beyond the last received dose 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 Hepatitis B surface antigen (HBsAg), Hepatitis C virus (HCV), human immunodeficiency virus (HIV)-1/2. Clinically significant abnormalities on basic laboratory screening. Exclusionary skin disease history/findings that would confound assessment or prevent appropriate local monitoring of adverse events (AEs), or possibly increase the risk of a local AE History of chronic skin disease (clinician judgement) 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 History of microbiologically confirmed ETEC or cholera infection in the last 3 years Travel to countries where ETEC or V. cholerae or other enteric infections are endemic (most of the developing world) within 3 years prior to dosing (clinician judgement) Symptoms consistent with Travelers' Diarrhea or concurrent with travel to countries where ETEC infection is endemic (most of the developing world) within 3 years prior to dosing, OR planned travel to endemic countries during the length of the study Vaccination for or ingestion of ETEC, cholera, or E. coli heat labile toxin within 3 years prior to dosing Occupation involving handling of ETEC or V. cholerae 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: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A1: CssBA 5 ug<br>Participants received an intramuscular injection of 5 ug CssBA on days 1, 22, and 43. | Biological: CssBA<br>* Recombinant enterotoxigenic Escherichia coli (ETEC) surface antigen 6 containing modified structural subunits A and B<br>* Other names: spd_dsc16Bntd14CssBAB7A[His]₆;|
| Experimental: Group A2: DmLT 100 ng<br>Participants received an intramuscular injection of 100 ng DmLT on days 1, 22, and 43. | Biological: dmLT<br>* Escherichia coli double mutant heat-labile toxin with mutations at amino acids 192 and 211<br>|
| Experimental: Group B: CssBA 5 ug + DmLT 100 ng<br>Participants received an intramuscular injection of 5 ug CssBA + 100 ng dmLT on days 1, 22, and 43. | Biological: CssBA<br>* Recombinant enterotoxigenic Escherichia coli (ETEC) surface antigen 6 containing modified structural subunits A and B<br>* Other names: spd_dsc16Bntd14CssBAB7A[His]₆;Biological: dmLT<br>* Escherichia coli double mutant heat-labile toxin with mutations at amino acids 192 and 211<br>|
| Experimental: Group C: CssBA 5 ug + DmLT 500 ng<br>Participants received an intramuscular injection of 5 ug CssBA + 500 ng dmLT on days 1, 22, and 43. | Biological: CssBA<br>* Recombinant enterotoxigenic Escherichia coli (ETEC) surface antigen 6 containing modified structural subunits A and B<br>* Other names: spd_dsc16Bntd14CssBAB7A[His]₆;Biological: dmLT<br>* Escherichia coli double mutant heat-labile toxin with mutations at amino acids 192 and 211<br>|
| Experimental: Group D: CssBA 15 ug + DmLT 500 ng<br>Participants received an intramuscular injection of 15 ug CssBA + 500 ng dmLT on days 1, 22, and 43. | Biological: CssBA<br>* Recombinant enterotoxigenic Escherichia coli (ETEC) surface antigen 6 containing modified structural subunits A and B<br>* Other names: spd_dsc16Bntd14CssBAB7A[His]₆;Biological: dmLT<br>* Escherichia coli double mutant heat-labile toxin with mutations at amino acids 192 and 211<br>|
| Experimental: Group E: CssBA 45 ug + DmLT 500 ng<br>Participants received an intramuscular injection of 45 ug CssBA + 500 ng dmLT on days 1, 22, and 43. | Biological: CssBA<br>* Recombinant enterotoxigenic Escherichia coli (ETEC) surface antigen 6 containing modified structural subunits A and B<br>* Other names: spd_dsc16Bntd14CssBAB7A[His]₆;Biological: dmLT<br>* Escherichia coli double mutant heat-labile toxin with mutations at amino acids 192 and 211<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Solicited Adverse Events | Solicited adverse events included vaccine site pain, vaccine site pruritus, vaccine site rash/eruption, vaccine site swelling, vaccine site tenderness, fever, headache, diarrhea, arthralgia, myalgia, malaise, nausea, and vomiting. Adverse events were assessed for severity by the investigator according to the following: Mild (Grade 1): Does not interfere with routine activities, minimal level of discomfort Moderate (Grade 2): Interferes with routine activities, moderate level of discomfort Severe (Grade 3): Unable to perform routine activities, significant level of discomfort Potentially life-threatening (Grade 4): Hospitalization or emergency room (ER) visit for potentially life-threatening event | From first vaccination to 28 days after the third vaccination, 71 days. | 
| Number of Participants With Unsolicited Adverse Events | Adverse events were assessed for severity by the investigator according to the following: Mild (Grade 1): Does not interfere with routine activities Minimal level of discomfort Moderate (Grade 2): Interferes with routine activities Moderate level of discomfort Severe (Grade 3): Unable to perform routine activities Significant level of discomfort Potentially life-threatening (Grade 4): Hospitalization or emergency room (ER) visit for potentially life-threatening event | From first vaccination to 28 days after the third vaccination, 71 days. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With a Serum Immunologic Response to Coli Surface Antigen 6 (CS6) | Serum samples were assayed for immunoglobulin G (IgG) and immunoglobulin A (IgA) antibody titers against CS6 using an enzyme-linked Immunosorbent assay (ELISA). Immunologic response was defined as a ≥ 4-fold increase in reciprocal endpoint titer between Baseline and any post-vaccination sample. | Baseline (Day 1 predose), Days 22 and 43 predose, and Day 70 | 
| Percentage of Participants With a Serum Immunologic Response to Labile Toxin | Serum samples were assayed for immunoglobulin G (IgG) and immunoglobulin A (IgA) antibody titers against labile toxin using an enzyme-linked Immunosorbent assay (ELISA). Immunologic response was defined as a ≥ 4-fold increase in reciprocal endpoint titer between Baseline and any post-vaccination sample. | Baseline (Day 1 predose), Days 22 and 43 predose, and Day 70 | 
| Percentage of Participants With a Mucosal Immunologic Response to Coli Surface Antigen 6 (CS6) | Peripheral blood mononuclear cells (PBMCs) were collected to determine antibody responses from lymphocyte supernatant against CS6 at Baseline and 7 days after each vaccination. Antibody in lymphocyte supernatant (ALS) is an indirect quantification of antibody secreting cells (ASC) activated in the mucosa that circulate in the peripheral blood about seven days post-mucosal immunization/infection. After incubation, lymphocyte supernatant was assayed for antigen-specific IgG and IgA antibodies using ELISA. A positive ALS response was defined as a four-fold rise in antibody titers between Baseline and any post vaccination sample. | Baseline (Day 1 pre-dose), Days 8 and 29 predose, and Day 50 | 
| Percentage of Participants With a Mucosal Immunologic Response to Labile Toxin | Peripheral blood mononuclear cells (PBMCs) were collected to determine antibody responses from lymphocyte supernatant against labile toxin at Baseline and 7 days after each vaccination. Antibody in lymphocyte supernatant (ALS) is an indirect quantification of antibody secreting cells (ASC) activated in the mucosa that circulate in the peripheral blood about seven days post-mucosal immunization/infection. After incubation, lymphocyte supernatant was assayed for antigen-specific IgG and IgA antibodies using ELISA. A positive ALS response was defined as a four-fold rise in antibody titers between Baseline and any post vaccination sample. | Baseline (Day 1 pre-dose), Days 8 and 29 predose, and Day 50 | 
| Geometric Mean Titer of Serum Anti-CS6 Immunoglobulin G Antibodies | Serum samples were assayed for IgG antibody titers against CS6 using an enzyme-linked Immunosorbent assay (ELISA). | Days 1, 22, and 43 pre-vaccination, and Day 70 | 
| Geometric Mean Titer of Serum Anti-CS6 Immunoglobulin A Antibodies | Serum samples were assayed for IgA antibody titers against CS6 using an enzyme-linked Immunosorbent assay (ELISA). | Days 1, 22, and 43 pre-vaccination, and Day 70 | 
| Geometric Mean Titer of Serum Anti-LT Immunoglobulin G Antibodies | Serum samples were assayed for IgG antibody titers against labile toxin using an enzyme-linked Immunosorbent assay (ELISA). | Days 1, 22, and 43 pre-vaccination, and Day 70 | 
| Geometric Mean Titer of Serum Anti-LT Immunoglobulin A Antibodies | Serum samples were assayed for IgA antibody titers against labile toxin using an enzyme-linked Immunosorbent assay (ELISA). | Days 1, 22, and 43 pre-vaccination, and Day 70 | 
| Geometric Mean Titer of Antibody Lymphocyte Supernatant Anti-CS6 Immunoglobulin G Antibodies | Lymphocyte supernatant was assayed for IgG antibody titers against CS6 using ELISA. | Days 1, 8, 29 and 50 | 
| Geometric Mean Titer of Antibody Lymphocyte Supernatant Anti-CS6 Immunoglobulin A Antibodies | Lymphocyte supernatant was assayed for IgA antibody titers against CS6 using ELISA. | Days 1, 8, 29, and 50 | 
| Geometric Mean Titer of Antibody Lymphocyte Supernatant Anti-LT Immunoglobulin G Antibodies | Lymphocyte supernatant was assayed for IgG antibody titers against labile toxin using ELISA. | Days 1, 8, 29, and 50 | 
| Geometric Mean Titer of Antibody Lymphocyte Supernatant Anti-LT Immunoglobulin A Antibodies | Lymphocyte supernatant was assayed for IgA antibody titers against labile toxin using ELISA. | Days 1, 8, 29, and 50 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ETEC, Escherichia coli, enteric