Enterotoxigenic Escherichia Coli (ETEC) ETVAX Vaccine Trial in Bangladesh

A Randomized, Double-blind, Placebo-controlled, Dose-Escalation Study Evaluating the Safety, Tolerability, and Immunogenicity of an Oral Inactivated ETEC Vaccine (ETVAX) Alone and Together With dmLT Adjuvant in Descending Age Groups in Bangladesh

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.

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)