Enterotoxigenic Escherichia Coli (ETEC) ETVAX Vaccine Trial in Bangladesh

PATH475 enrolled

Overview

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.

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

PREVENTION

Masking

QUADRUPLE

Enrollment

475

Conditions

Escherichia Coli Diarrhea

Interventions

ETVAXBIOLOGICAL

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.

dmLTBIOLOGICAL

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.

Eligibility

Sex: ALLMin age: 6 MonthsMax age: 45 YearsHealthy volunteers:

Medical Language ↔ Plain English

Adults 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) 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. Children, Toddlers and Infants Inclusion Criteria 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. 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)

Locations (1)

International Centre for Diarrheal Disease, Bangladesh (icddr,b)

Dhaka, Bangladesh

Outcomes

Primary Outcomes

Number and Percentage of Participants Experiencing Solicited Events by Symptom and Maximum Severity

Adverse events (AEs) were assessed post-vaccination using participant/parent/guardian interview (including memory aids), targeted physical examinations, vital signs and clinical laboratory tests and reactogenicity assessments which were completed following each vaccination. The solicited AEs of nausea (adults only), abdominal pain/stomach ache (adults and children 24-59 months only), fever, vomiting and diarrhea were evaluated daily for 7 days post vaccination.

Time frame: 7 days after each vaccination (Day 7 and Day 21)

Number and Percentage of Participants Experiencing Unsolicited Adverse Events Related to Vaccine

Adverse events (AEs) were assessed post-vaccination using participant/parent/guardian interview (including memory aids), targeted physical examinations, vital signs and clinical laboratory tests and reactogenicity assessments which were completed following each vaccination. Unsolicited AEs were assessed through Day 42 and serious adverse events (SAEs) were assessed over the entire duration of the study.

Time frame: 6 months ± 14 days after the first dose

Secondary Outcomes

Number and Percentage of Subjects With ≥Two-fold Increase in Antibody Lymphocyte Supernatant (ALS) Immunoglobulin A (IgA) Response After Either Vaccine Dose, by Antigen

Between baseline and post-immunization (measured 7 days after the first dose and 5 days after the second). Antigen in ETVAX were: E. coli, CFA/I, strain ETEX 21 formalin inactivated, E. coli, CS3, strain ETEX 22 formalin inactivated, E. coli, CS5, strain ETEX 23 formalin inactivated, E. coli, CS6, strain ETEX 24 phenol inactivated, B-subunit of the E. coli heat-labile enterotoxin

Time frame: 19 days

Number and Percentage of Subjects With ≥Four-fold Increase in Antibody Lymphocyte Supernatant (ALS) Immunoglobulin A (IgA) Response After Either Vaccine Dose, by Antigen

Data from ClinicalTrials.gov

This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.

Sodium bicarbonate buffer dissolved in 150 ml of potable water

Geometric Mean Titer (GMT) of Antibody Lymphocyte Supernatant (ALS) Immunoglobulin A (IgA) Response After Either Vaccine Dose, by Antigen

Time frame: 19 days

Geometric Mean Fold Change of Antibody Lymphocyte Supernatant (ALS) Immunoglobulin A (IgA) Response After Either Vaccine Dose, by Antigen

Time frame: 19 days

Number and Percentage of 6-11 Month Old Subjects With ≥Two-fold Increase in Fecal Secretory Immunoglobulin A (SIgA) Response, by Antigen

Fecal secretion was measured on Day 7, Day 19, and Day 28; number in table is subjects experiencing a two-fold rise at any of these time points. Antigen in ETVAX were: E. coli, CFA/I, strain ETEX 21 formalin inactivated, E. coli, CS3, strain ETEX 22 formalin inactivated, E. coli, CS5, strain ETEX 23 formalin inactivated, E. coli, CS6, strain ETEX 24 phenol inactivated, B-subunit of the E. coli heat-labile enterotoxin

Time frame: 28 days

Number and Percentage of 6-11 Month Old Subjects With ≥Four-fold Increase in Fecal Secretory Immunoglobulin A (SIgA) Response, by Antigen

Fecal secretion was measured on Day 7, Day 19, and Day 28; number in table is subjects experiencing a four-fold rise at any of these time points. Antigens in ETVAX were: E. coli, CFA/I, strain ETEX 21 formalin inactivated, E. coli, CS3, strain ETEX 22 formalin inactivated, E. coli, CS5, strain ETEX 23 formalin inactivated, E. coli, CS6, strain ETEX 24 phenol inactivated, B-subunit of the E. coli heat-labile enterotoxin

Time frame: 28 days

Geometric Mean Titer (GMT) of Fecal Secretory Immunoglobulin A (SIgA) Response 6-11 Month Old Subjects, by Antigen

Fecal secretion was measured on Day 7, Day 19, and Day 28; number in table is based on the maximum value for each subject. Antigen in ETVAX were: E. coli, CFA/I, strain ETEX 21 formalin inactivated, E. coli, CS3, strain ETEX 22 formalin inactivated, E. coli, CS5, strain ETEX 23 formalin inactivated, E. coli, CS6, strain ETEX 24 phenol inactivated, B-subunit of the E. coli heat-labile enterotoxin

Time frame: 28 days

Geometric Mean Fold Change of Fecal Secretory Immunoglobulin A (SIgA) Response Among 6-11 Month Old Subjects, by Antigen

Time frame: 28 days

Number and Percentage of Subjects With ≥Two-fold Increase in Plasma Immunoglobulin A (IgA) Response After Either Vaccine Dose, for Antigens in ETVAX

Time frame: 19 days

Number and Percentage of Subjects With ≥Four-fold Increase in Plasma Immunoglobulin A (IgA) Response After Either Vaccine Dose, for Antigens in ETVAX

Time frame: 19 days

Geometric Mean Titer (GMT) of Plasma Immunoglobulin A (IgA) Response After Either Vaccine Dose, for Antigens in ETVAX

Time frame: 19 days

Geometric Mean Fold Change in Plasma Immunoglobulin A (IgA) Response After Either Vaccine Dose, for Antigens in ETVAX

Time frame: 19 days

Number and Percentage of Adult Subjects With ≥Two-fold and ≥Four-fold Increase in Plasma Immunoglobulin A (IgA) Response After Either Vaccine Dose, for O78 Antigen

Between baseline and post-immunization (measured 7 days after the first dose and 5 days after the second).

Time frame: 19 days

Geometric Mean Titer (GMT) for Plasma Immunoglobulin A (IgA) Response After Either Vaccine Dose, for O78 Antigen, Among Adults

Between baseline and post-immunization (measured 7 days after the first dose and 5 days after the second).

Time frame: 19 days

Geometric Mean Fold Change in Plasma Immunoglobulin A (IgA) Response After Either Vaccine Dose, for O78 Antigen, Among Adults

Between baseline and post-immunization (measured 7 days after the first dose and 5 days after the second).

Time frame: 19 days

Number and Percentage of Subjects With ≥Two-fold and ≥Four-fold Increase in Plasma Immunoglobulin G (IgG) Response to E. Coli Heat-labile Enterotoxin (LTB) After Either Vaccine Dose

Between baseline and post-immunization (measured 7 days after the first dose and 5 days after the second). B-subunit of the E. coli heat-labile enterotoxin (LTB) was one of the antigens in the ETVAX vaccine.

Time frame: 19 days

Geometric Mean Titer (GMT) of Plasma Immunoglobulin G (IgG) Response to E. Coli Heat-labile Enterotoxin (LTB) After Either Vaccine Dose

Measured 7 days after the first dose and 5 days after the second). B-subunit of the E. coli heat-labile enterotoxin (LTB) was one of the antigens in the ETVAX vaccine.

Time frame: 19 days

Geometric Mean Fold Change of Plasma Immunoglobulin G (IgG) Response to E. Coli Heat-labile Enterotoxin (LTB) After Either Vaccine Dose

Between baseline and after vaccination (measured 7 days after the first dose and 5 days after the second). B-subunit of the E. coli heat-labile enterotoxin (LTB) was one of the antigens in the ETVAX vaccine.

Time frame: 19 days

Number of Antigen Responses in Antibody Lymphocyte Supernatant (ALS) Immunoglobulin A (IgA) Experienced by Subjects

Time frame: 19 days

Number of Antigen Responses in Plasma Immunoglobulin A (IgA) Experienced by Subjects

Time frame: 19 days

Number and Percentage of 6-11 Month Old Subjects With ≥Two-fold Increase in Fecal Secretory Immunoglobulin A (SIgA) Response on Day 7, by Antigen

Fecal secretion was measured on Day 0 and Day 7 (7 days after administration of first dose of vaccine). Antigens in ETVAX were: E. coli, CFA/I, strain ETEX 21 formalin inactivated, E. coli, CS3, strain ETEX 22 formalin inactivated, E. coli, CS5, strain ETEX 23 formalin inactivated, E. coli, CS6, strain ETEX 24 phenol inactivated, B-subunit of the E. coli heat-labile enterotoxin

Time frame: 7 days

Number and Percentage of 6-11 Month Old Subjects With ≥Four-fold Increase in Fecal Secretory Immunoglobulin A (SIgA) Response on Day 7, by Antigen

Time frame: 7 days

Geometric Mean Titer (GMT) of Fecal Secretory Immunoglobulin A (SIgA) Response 6-11 Month Old Subjects on Day 7, by Antigen

Fecal secretion was measured on Day 7 (7 days after administration of first dose of vaccine). Antigen in ETVAX were: E. coli, CFA/I, strain ETEX 21 formalin inactivated, E. coli, CS3, strain ETEX 22 formalin inactivated, E. coli, CS5, strain ETEX 23 formalin inactivated, E. coli, CS6, strain ETEX 24 phenol inactivated, B-subunit of the E. coli heat-labile enterotoxin

Time frame: 7 days

Geometric Mean Fold Change of Fecal Secretory Immunoglobulin A (SIgA) Response Among 6-11 Month Old Subjects on Day 7, by Antigen

Fecal secretion was measured on Day 0 and Day 7 (7 days after administration of first dose of vaccine). Antigen in ETVAX were: E. coli, CFA/I, strain ETEX 21 formalin inactivated, E. coli, CS3, strain ETEX 22 formalin inactivated, E. coli, CS5, strain ETEX 23 formalin inactivated, E. coli, CS6, strain ETEX 24 phenol inactivated, B-subunit of the E. coli heat-labile enterotoxin

Time frame: 7 days

Number and Percentage of 6-11 Month Old Subjects With ≥Two-fold Increase in Fecal Secretory Immunoglobulin A (SIgA) Response on Day 19, by Antigen

Fecal secretion was measured on Day 0 and Day 19 (5 days after administration of second dose of vaccine). Antigen in ETVAX were: E. coli, CFA/I, strain ETEX 21 formalin inactivated, E. coli, CS3, strain ETEX 22 formalin inactivated, E. coli, CS5, strain ETEX 23 formalin inactivated, E. coli, CS6, strain ETEX 24 phenol inactivated, B-subunit of the E. coli heat-labile enterotoxin

Time frame: Day 19

Number and Percentage of 6-11 Month Old Subjects With ≥Four-fold Increase in Fecal Secretory Immunoglobulin A (SIgA) Response on Day 19, by Antigen

Fecal secretion was measured on Day 0 and Day 19 (5 days after administration of second dose of vaccine). Antigens in ETVAX were: E. coli, CFA/I, strain ETEX 21 formalin inactivated, E. coli, CS3, strain ETEX 22 formalin inactivated, E. coli, CS5, strain ETEX 23 formalin inactivated, E. coli, CS6, strain ETEX 24 phenol inactivated, B-subunit of the E. coli heat-labile enterotoxin

Time frame: 19 days

Geometric Mean Titer (GMT) of Fecal Secretory Immunoglobulin A (SIgA) Response 6-11 Month Old Subjects on Day 19, by Antigen

Fecal secretion was measured on Day 19 (5 days after administration of second dose of vaccine). Antigen in ETVAX were: E. coli, CFA/I, strain ETEX 21 formalin inactivated, E. coli, CS3, strain ETEX 22 formalin inactivated, E. coli, CS5, strain ETEX 23 formalin inactivated, E. coli, CS6, strain ETEX 24 phenol inactivated, B-subunit of the E. coli heat-labile enterotoxin

Time frame: 19 days

Geometric Mean Fold Change of Fecal Secretory Immunoglobulin A (SIgA) Response Among 6-11 Month Old Subjects on Day 19, by Antigen

Time frame: 19 days

Number and Percentage of 6-11 Month Old Subjects With ≥Two-fold Increase in Fecal Secretory Immunoglobulin A (SIgA) Response on Day 28, by Antigen

Fecal secretion was measured on Day 0 and Day 28 (2 weeks after administration of second dose of vaccine). Antigen in ETVAX were: E. coli, CFA/I, strain ETEX 21 formalin inactivated, E. coli, CS3, strain ETEX 22 formalin inactivated, E. coli, CS5, strain ETEX 23 formalin inactivated, E. coli, CS6, strain ETEX 24 phenol inactivated, B-subunit of the E. coli heat-labile enterotoxin

Time frame: 28 days

Number and Percentage of 6-11 Month Old Subjects With ≥Four-fold Increase in Fecal Secretory Immunoglobulin A (SIgA) Response on Day 28, by Antigen

Fecal secretion was measured on Day 0 and Day 28 (2 weeks after administration of second dose of vaccine). Antigens in ETVAX were: E. coli, CFA/I, strain ETEX 21 formalin inactivated, E. coli, CS3, strain ETEX 22 formalin inactivated, E. coli, CS5, strain ETEX 23 formalin inactivated, E. coli, CS6, strain ETEX 24 phenol inactivated, B-subunit of the E. coli heat-labile enterotoxin

Time frame: 28 days

Geometric Mean Titer (GMT) of Fecal Secretory Immunoglobulin A (SIgA) Response 6-11 Month Old Subjects on Day 28, by Antigen

Fecal secretion was measured on Day 28 (2 weeks after administration of second dose of vaccine). Antigen in ETVAX were: E. coli, CFA/I, strain ETEX 21 formalin inactivated, E. coli, CS3, strain ETEX 22 formalin inactivated, E. coli, CS5, strain ETEX 23 formalin inactivated, E. coli, CS6, strain ETEX 24 phenol inactivated, B-subunit of the E. coli heat-labile enterotoxin

Time frame: 28 days

Geometric Mean Fold Change of Fecal Secretory Immunoglobulin A (SIgA) Response Among 6-11 Month Old Subjects on Day 28, by Antigen

Time frame: 28 days