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

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

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.

Study Overview

• Status: Completed
• Conditions: Diarrhea
• Intervention / Treatment: Biological: CssBA; Biological: dmLT

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 50
• 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:

1. Healthy, adult, male or female, age 18 to 45 years (inclusive) at the time of enrollment.
2. Completion and review of comprehension test (achieved > 70% accuracy).
3. Signed informed consent document.
4. Available for the required follow-up period and scheduled clinic visits.
5. 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:

1. 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.
2. Clinically significant abnormalities on physical examination.
3. 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).
4. 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.
5. 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.
6. Positive blood test for Hepatitis B surface antigen (HBsAg), Hepatitis C virus (HCV), human immunodeficiency virus (HIV)-1/2.
7. Clinically significant abnormalities on basic laboratory screening.
8. 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
9. History of chronic skin disease (clinician judgement)
10. Acute skin infection/eruptions on the upper arms including fungal infections, severe acne or active contact dermatitis
11. Allergies that may increase the risk of AEs
12. Regular use (weekly or more often) of antidiarrheal, anti-constipation, or antacid therapy
13. 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
14. History of microbiologically confirmed ETEC or cholera infection in the last 3 years
15. 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)
16. 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
17. Vaccination for or ingestion of ETEC, cholera, or E. coli heat labile toxin within 3 years prior to dosing
18. Occupation involving handling of ETEC or V. cholerae currently, or in the past 3 years

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

6

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: PATH
• Collaborators: Naval Medical Research Center; Walter Reed Army Institute of Research Clinical Trials Center
• Investigators: Principal Investigator: Tida K Lee, MD, PhD, Naval Medical Research Center

Study record dates

Study Major Dates

• Study Start (Actual): January 16, 2018
• Primary Completion (Actual): March 26, 2019
• Study Completion (Actual): March 26, 2019

Study Registration Dates

• First Submitted: January 10, 2018
• First Submitted That Met QC Criteria: January 18, 2018
• First Posted (Actual): January 19, 2018

Study Record Updates

• Last Update Posted (Actual): January 6, 2021
• Last Update Submitted That Met QC Criteria: December 10, 2020
• Last Verified: November 1, 2020

More Information

Terms related to this study

• Keywords: Escherichia coli; ETEC; enteric
• Additional Relevant MeSH Terms: Infections; Signs and Symptoms, Digestive; Gram-Negative Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Enterobacteriaceae Infections; Diarrhea; Escherichia coli Infections
• Other Study ID Numbers: VAC-050

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No