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Enterotoxigenic Escherichia C...

Enterotoxigenic Escherichia Coli (ETEC) ETVAX Vaccine Trial in Bangladesh

Last Updated: 2018-09-12

Study Results

Results available

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE1/PHASE2

Total Enrollment

475 participants

Study Classification

INTERVENTIONAL

Study Start Date

2015-10-31

Study Completion Date

2017-07-29

Brief Summary

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The purpose of this study is to determine if the ETEC vaccine ETVAX with and without dmLT adjuvant is safe and immunogenic in adults, children, toddlers and infants in Bangladesh.

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Detailed Description

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This Phase I/II trial will serve to assess whether ETVAX is safe and provides mucosal as well as systemic immune responses against the key protective antigens when tested in different age-groups in Bangladesh. This study provides an opportunity to test the safety profile of a mucosal adjuvant, double-mutant LT (dmLT), in adults and children, as well as provide the opportunity to potentially assess the ability of dmLT to further enhance the mucosal and systemic antibody responses to key antigens in the ETVAX vaccine among age groups in developing country sites, like Bangladesh, that have proved refractory to oral immunization with enteric vaccines. In addition, this study also allows for the evaluation of the potential dose-sparing effect of dmLT when combined with a lower dose of vaccine. Finally, this clinical trial is considered an essential study along the critical path of the overall clinical development plan before determining whether the vaccine can be tested for protective efficacy in children in developing countries.

Conditions

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Escherichia Coli Diarrhea

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

PREVENTION

Blinding Strategy

QUADRUPLE

Participants Caregivers Investigators Outcome Assessors

Study Groups

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Adult: ETVAX (Full)

Adult arm (18-45 year olds) receiving the full dose of ETVAX vaccine (10\^11 inactivated E. coli bacteria) added to bicarbonate buffer solution administered orally on Day 0 and 14

Group Type EXPERIMENTAL

ETVAX

Intervention Type BIOLOGICAL

Varying dosages of liquid ETVAX vaccine (Batch BX1003574). A full dose consisted of:

* Hybrid protein between the B-subunit of the E. coli heat-labile enterotoxin and the B-subunit of the cholera toxin (LCTBA): 1 mg
* E. coli ETEX 21 formalin inactivated: 1.3 mg colonization factor 1 (CFA/I)
* E. coli ETEX 22 formalin inactivated: 6.4 mg coli surface antigen 3 (CS3)
* E. coli ETEX 23 formalin inactivated: 1.1 mg coli surface antigen 5 (CS5)
* E. coli ETEX 24 phenol inactivated: 0.5 mg coli surface antigen 6 (CS6)

The vaccine was given together with sodium bicarbonate effervescent granules (Recip), which was dissolved in water and mixed with the vaccine suspension prior to oral administration. The buffer was used to prevent degradation of LCTBA hybrid protein by the gastric acid.

Bicarbonate Buffer

Intervention Type OTHER

Sodium bicarbonate buffer dissolved in 150 ml of potable water

Adult: ETVAX (Full) + 10 ug dmLT

Adult arm (18-45 year olds) receiving the full dose of ETVAX vaccine (10\^11 inactivated E. coli bacteria) with 10 ug dmLT added to bicarbonate buffer solution administered orally on Day 0 and 14

Group Type EXPERIMENTAL

ETVAX

Intervention Type BIOLOGICAL

dmLT

Intervention Type BIOLOGICAL

Varying dosages of dmLT, a derivative of wild-type enterotoxigenic Escherichia coli LT that has been genetically modified by replacing the arginine at amino acid position 192 with glycine and the leucine at amino acid position 211 with alanine. These two amino acid substitutions take place in proteolytic cleavage sites which are critical for activation of the secreted toxin molecules.

Bicarbonate Buffer

Intervention Type OTHER

Sodium bicarbonate buffer dissolved in 150 ml of potable water

Adult: Placebo

Adult arm (18-45 year olds) receiving a placebo on days 0 and 14

Group Type PLACEBO_COMPARATOR

Bicarbonate Buffer

Intervention Type OTHER

Sodium bicarbonate buffer dissolved in 150 ml of potable water

24-59 months: ETVAX (1/4)

24-59 month old children receiving a quarter adult dose (2.5 x 10\^10 inactivated E. coli bacteria) of ETVAX vaccine in bicarbonate buffer solution administered orally on Day 0 and 14

Group Type EXPERIMENTAL

ETVAX

Intervention Type BIOLOGICAL

Bicarbonate Buffer

Intervention Type OTHER

Sodium bicarbonate buffer dissolved in 150 ml of potable water

24-59 months: ETVAX (1/2)

24-59 month old children receiving a half adult dose of ETVAX vaccine (5 x 10\^10 inactivated E. coli bacteria) in bicarbonate buffer solution administered orally on Day 0 and 14

Group Type EXPERIMENTAL

ETVAX

Intervention Type BIOLOGICAL

Bicarbonate Buffer

Intervention Type OTHER

Sodium bicarbonate buffer dissolved in 150 ml of potable water

24-59 months: ETVAX (full)

24-59 month old children receiving a full adult dose of ETVAX vaccine (10\^11 inactivated E. coli bacteria) in bicarbonate buffer solution administered orally on Day 0 and 14

Group Type EXPERIMENTAL

ETVAX

Intervention Type BIOLOGICAL

Bicarbonate Buffer

Intervention Type OTHER

Sodium bicarbonate buffer dissolved in 150 ml of potable water

24-59 months: ETVAX (1/2) + 2.5 ug dmLT

24-59 month old children receiving a half adult dose of ETVAX vaccine (5 x 10\^10 inactivated E. coli bacteria) plus 2.5 ug dmLT in bicarbonate buffer solution administered orally on Day 0 and 14

Group Type EXPERIMENTAL

ETVAX

Intervention Type BIOLOGICAL

dmLT

Intervention Type BIOLOGICAL

Bicarbonate Buffer

Intervention Type OTHER

Sodium bicarbonate buffer dissolved in 150 ml of potable water

24-59 months: ETVAX (1/2) + 5 ug dmLT

24-59 month old children receiving a half adult dose of ETVAX vaccine (5 x 10\^10 inactivated E. coli bacteria) plus 5 ug dmLT in bicarbonate buffer solution administered orally on Day 0 and 14

Group Type EXPERIMENTAL

ETVAX

Intervention Type BIOLOGICAL

dmLT

Intervention Type BIOLOGICAL

Bicarbonate Buffer

Intervention Type OTHER

Sodium bicarbonate buffer dissolved in 150 ml of potable water

24-59 months: ETVAX (1/2) + 10 ug dmLT

24-59 month old children receiving a half adult dose of ETVAX vaccine (5 x 10\^10 inactivated E. coli bacteria) plus 10 ug dmLT in bicarbonate buffer solution administered orally on Day 0 and 14

Group Type EXPERIMENTAL

ETVAX

Intervention Type BIOLOGICAL

dmLT

Intervention Type BIOLOGICAL

Bicarbonate Buffer

Intervention Type OTHER

Sodium bicarbonate buffer dissolved in 150 ml of potable water

24-59 months: Placebo

24-59 month old children receiving a placebo of bicarbonate buffer solution administered orally on Day 0 and 14

Group Type PLACEBO_COMPARATOR

Bicarbonate Buffer

Intervention Type OTHER

Sodium bicarbonate buffer dissolved in 150 ml of potable water

12-23 months: ETVAX (1/4)

12-23 month old children receiving a quarter adult dose of ETVAX vaccine (2.5 x 10\^10 inactivated E. coli bacteria) in bicarbonate buffer solution administered orally on Day 0 and 14

Group Type EXPERIMENTAL

ETVAX

Intervention Type BIOLOGICAL

Bicarbonate Buffer

Intervention Type OTHER

Sodium bicarbonate buffer dissolved in 150 ml of potable water

12-23 months: ETVAX (1/2)

12-23 month old children receiving a half adult dose of ETVAX vaccine (5 x 10\^10 inactivated E. coli bacteria) in bicarbonate buffer solution administered orally on Day 0 and 14

Group Type EXPERIMENTAL

ETVAX

Intervention Type BIOLOGICAL

Bicarbonate Buffer

Intervention Type OTHER

Sodium bicarbonate buffer dissolved in 150 ml of potable water

12-23 months: ETVAX (1/2) + 2.5 ug dmLT

12-23 month old children receiving a half adult dose of ETVAX vaccine (5 x 10\^10 inactivated E. coli bacteria) plus 2.5 ug dmLT in bicarbonate buffer solution administered orally on Day 0 and 14

Group Type EXPERIMENTAL

ETVAX

Intervention Type BIOLOGICAL

dmLT

Intervention Type BIOLOGICAL

Bicarbonate Buffer

Intervention Type OTHER

Sodium bicarbonate buffer dissolved in 150 ml of potable water

12-23 months: ETVAX (1/2) + 5 ug dmLT

12-23 month old children receiving a half adult dose of ETVAX vaccine (5 x 10\^10 inactivated E. coli bacteria) plus 5 ug dmLT in bicarbonate buffer solution administered orally on Day 0 and 14

Group Type EXPERIMENTAL

ETVAX

Intervention Type BIOLOGICAL

dmLT

Intervention Type BIOLOGICAL

Bicarbonate Buffer

Intervention Type OTHER

Sodium bicarbonate buffer dissolved in 150 ml of potable water

12-23 months: Placebo

12-23 month old children receiving a placebo of bicarbonate buffer solution administered orally on Day 0 and 14

Group Type PLACEBO_COMPARATOR

Bicarbonate Buffer

Intervention Type OTHER

Sodium bicarbonate buffer dissolved in 150 ml of potable water

6-11 months: ETVAX (1/8)

6-11 month old children receiving an eighth of an adult dose of ETVAX vaccine in bicarbonate buffer solution administered orally on Day 0 and 14

Group Type EXPERIMENTAL

ETVAX

Intervention Type BIOLOGICAL

Bicarbonate Buffer

Intervention Type OTHER

Sodium bicarbonate buffer dissolved in 150 ml of potable water

6-11 months: ETVAX (1/4)

6-11 month old children receiving a quarter of an adult dose of ETVAX vaccine (2.5 x 10\^10 inactivated E. coli bacteria) in bicarbonate buffer solution administered orally on Day 0 and 14

Group Type EXPERIMENTAL

ETVAX

Intervention Type BIOLOGICAL

Bicarbonate Buffer

Intervention Type OTHER

Sodium bicarbonate buffer dissolved in 150 ml of potable water

6-11 months: ETVAX (1/2)

6-11 month old children receiving a half of an adult dose of ETVAX vaccine (5 x 10\^10 inactivated E. coli bacteria) in bicarbonate buffer solution administered orally on Day 0 and 14

Group Type EXPERIMENTAL

ETVAX

Intervention Type BIOLOGICAL

Bicarbonate Buffer

Intervention Type OTHER

Sodium bicarbonate buffer dissolved in 150 ml of potable water

6-11 months: ETVAX (1/4) + 2.5 ug dmLT

6-11 month old children receiving a quarter of an adult dose of ETVAX vaccine (2.5 x 10\^10 inactivated E. coli bacteria) plus 2.5 ug dmLT in bicarbonate buffer solution administered orally on Day 0 and 14

Group Type EXPERIMENTAL

ETVAX

Intervention Type BIOLOGICAL

dmLT

Intervention Type BIOLOGICAL

Bicarbonate Buffer

Intervention Type OTHER

Sodium bicarbonate buffer dissolved in 150 ml of potable water

6-11 month olds: ETVAX (1/4) + 5 ug dmLT

6-11 month old children receiving a quarter of an adult dose of ETVAX vaccine (2.5 x 10\^10 inactivated E. coli bacteria) plus 5 ug dmLT in bicarbonate buffer solution administered orally on Day 0 and 14

Group Type EXPERIMENTAL

ETVAX

Intervention Type BIOLOGICAL

dmLT

Intervention Type BIOLOGICAL

Bicarbonate Buffer

Intervention Type OTHER

Sodium bicarbonate buffer dissolved in 150 ml of potable water

6-11 month olds: Placebo

6-11 month old children receiving a placebo of bicarbonate buffer solution administered orally on Day 0 and 14

Group Type PLACEBO_COMPARATOR

Bicarbonate Buffer

Intervention Type OTHER

Sodium bicarbonate buffer dissolved in 150 ml of potable water

Interventions

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ETVAX

Intervention Type BIOLOGICAL

dmLT

Intervention Type BIOLOGICAL

Bicarbonate Buffer

Sodium bicarbonate buffer dissolved in 150 ml of potable water

Intervention Type OTHER

Other Intervention Names

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double mutant heat labile toxin, LT(R192G/L211A)

Eligibility Criteria

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Inclusion Criteria

1. Healthy male or female adults 18-45 years old, inclusive
2. General good health as determined by the screening evaluation no greater than 7days before enrollment and vaccination
3. Properly informed about the study, able to understand it and sign or thumb print the informed consent form
4. Available for the entire period of the study and reachable by study staff throughout the entire follow-up period
5. Females of childbearing potential who are willing to take a urine pregnancy test at screening and before the second vaccination. Pregnancy tests must be negative before each vaccination. Females of childbearing potential must agree to use an efficacious hormonal or barrier method of birth control during the study. Abstinence is also acceptable.
6. Informed Consent (signature or thumb print provided, with witness signature)

1. Healthy male or female infants/toddlers/children ages:

* Part B: \>24 and ≤59 months old at the time of enrollment
* Part C: ≥12 and \<24 months old at the time of enrollment
* Part D: ≥6 and \<12 months at the time of enrollment
2. General good health as determined by the screening evaluation no greater than 7 days before enrollment and vaccination
3. Parent properly informed about the study, able to understand it and sign or thumb print the informed consent form
4. Parent and child available for the entire study period of the study and reachable by study staff throughout the entire follow-up period
5. Informed Consent (signature or thumb of parent, with signature of witness, provided)

Exclusion Criteria

1. Presence of any significant known systemic disorder (cardiovascular, pulmonary, hepatic, renal, gastrointestinal, endocrine, immunological, dermatological, neurological, cancer or autoimmune disease) as determined by medical history and/or physical examination which would endanger the participant's health or is likely to result in non-conformance to the protocol.
2. History of congenital abdominal disorders, intussusception, abdominal surgery or any other congenital disorder or presence of a significant medical condition that in the opinion of the Investigator precludes participation in the study. Known or suspected impairment of immunological function based on medical history and physical examination. Clinical evidence of active gastrointestinal illness and acute disease at the time of enrollment
3. Screening positive with hepatitis B antigen and/or hepatitis C antibodies
4. Participation in research involving another investigational product (defined as receipt of investigational product) during the 30 days before planned date of first vaccination or concurrently participating in another clinical study at any time during the study period, in which the participant has been or will be exposed to an investigational or a non-investigational product
5. Clinically significant abnormalities in screening hematology or serum chemistry, as determined by the Study Physician
6. History of febrile illness within 48 hours prior to vaccination and fever at the time of immunization (fever is defined as a temperature ≥ 37.5 C (99.5 F) on axillary, oral, or tympanic measurement)
7. Prior receipt of any cholera (e.g., Dukoral, Shanchol) or ETEC vaccine
8. Prior receipt of a blood transfusion or blood products, including immunoglobulins
9. Evidence of current illicit drug use or drug dependence
10. Current use of iron or zinc supplements within the past 7 days; current use of antacids (H2 blockers, omeprazole, over-the-counter (OTC) agents) or immunosuppressive drug
11. Any condition which, in the opinion of the investigator, might jeopardize the safety of study participants or interfere with the evaluation of the study objectives
12. Receipt of antimicrobial drugs for any reason within 14 days before vaccination
13. History of diarrhea during the 7 days before vaccination (see protocol definition of diarrhea)
14. Culture positive for ETEC, Shigella, V. Cholerae or Salmonella within 7 days before vaccination.
15. Acute disease at the time of enrollment or 3 days prior to enrollment
16. History of chronic administration (defined as more than 14 days) of immunosuppressant medications, including corticosteroids.

1. Presence of any significant known systemic disorder (cardiovascular, pulmonary, hepatic, renal, gastrointestinal, endocrine, immunological, dermatological, neurological, cancer or autoimmune disease) as determined by medical history and/or physical examination which would endanger the participant's health or is likely to result in non-conformance to the protocol.
2. History of congenital abdominal disorders, intussusception, abdominal surgery or any other congenital disorder or presence of a significant medical condition that in the opinion of the Investigator precludes participation in the study. Known or suspected impairment of immunological function based on medical history and physical examination. Clinical evidence of active gastrointestinal illness and acute disease at the time of enrollment
3. Screening positive with hepatitis B antigen and/or hepatitis C antibodies
4. Participation in research involving another investigational product (defined as receipt of investigational product) during the 30 days before planned date of first vaccination or concurrently participating in another clinical study at any time during the study period, in which the participant has been or will be exposed to an investigational or a non-investigational product
5. Clinically significant abnormalities in screening hematology or serum chemistry, as determined by the Study Physician
6. History of febrile illness within 48 hours prior to vaccination and fever at the time of immunization (fever is defined as a temperature ≥ 37.5 C (99.5 F) on axillary, oral, or tympanic measurement)
7. Prior receipt of any cholera (e.g., Dukoral, Shanchol) or ETEC vaccine
8. Prior receipt of a blood transfusion or blood products, including immunoglobulins
9. Current use of iron or zinc supplements within the past 7 days; current use of antacids (H2 blockers, omeprazole, OTC agents) or immunosuppressive drug
10. Any condition which, in the opinion of the investigator, might jeopardize the safety of study participants or interfere with the evaluation of the study objectives
11. Receipt of antimicrobial drugs for any reason within 14 days before vaccination
12. History of diarrhea during the 7 days before vaccination (see Protocol definition of diarrhea))
13. Culture positive for ETEC, Shigella, V. cholerae, Salmonella or Rotavirus (the latter for all children \<5 years of age) within 7 days of vaccination
14. Acute disease at the time of enrollment or 3 days prior to enrollment
15. Known or suspected impairment of immunological function based on medical history and physical examination
16. Participant's parents/guardians not able, available or willing to accept active weekly follow-up by the study staff
17. History of chronic administration (defined as more than 14 days) of immunosuppressant medications, including corticosteroids. Infants on inhaled or topical steroids may be permitted to participate in the study
18. Any medical condition in the child/infant that, in the judgment of the investigator, would interfere with or serves as a contraindication to protocol adherence or a participant's parents' ability to give informed consent
19. Medically significant malnutrition, defined as moderate malnutrition (wt-for-ht z-score between -3.0 and -2.0) and severe malnutrition (wt-for-ht z-score \<-3.0 or edema)

Minimum Eligible Age

6 Months

Maximum Eligible Age

45 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

Yes