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

Diarrhea Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03404674
• Other study ID #: VAC-050
• Status: Completed
• Phase: Phase 1
• Start date: January 16, 2018
• Est. completion date: March 26, 2019

Study information

• Verified date: November 2020
• Source: PATH
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 50
• Est. completion date: March 26, 2019
• Est. primary completion date: March 26, 2019
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 45 Years

Eligibility

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

Related Conditions & MeSH terms

• Diarrhea

Intervention

Biological:
• CssBA
Recombinant enterotoxigenic Escherichia coli (ETEC) surface antigen 6 containing modified structural subunits A and B
• dmLT
Escherichia coli double mutant heat-labile toxin with mutations at amino acids 192 and 211

Locations

Country	Name	City	State
United States	Walter Reed Army Institute of Research Clinical Trial Center	Silver Spring	Maryland

Sponsors (3)

Lead Sponsor	Collaborator
PATH	Naval Medical Research Center, Walter Reed Army Institute of Research Clinical Trials Center

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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