Live Attenuated ETEC Vaccine ACE527 With and Without dmLT Adjuvant in Adults

NCT ID: NCT01739231

Last Updated: 2019-02-12

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 81 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2012-09-30
• Study Completion Date: 2014-01-31

Brief Summary

This is a research study about an experimental (investigational) oral ETEC vaccine (ACE527). ACE527 is a live attenuated vaccine that is being made to prevent disease from enterotoxigenic Escherichia coli (ETEC), which causes watery diarrhea, largely in children living in developing countries and in travelers to those countries. This research study is also testing an investigational adjuvant called dmLT. An adjuvant is something that is added to a vaccine to make it work better. The purpose of this study is two-fold. First, Part A aims to find out if the vaccine by itself or the vaccine combined with the adjuvant is safe, tolerable, and initiates an immune response. Second, Part B aims to find out if the vaccine by itself or the vaccine combined with the adjuvant prevents diarrheal disease when challenged with ETEC H10407. About 60 healthy adults, ages 18-50, will participate in Part A, and they will be required to stay in the research facility for several nights for the first dose, but will not be required to stay overnight for the second and third doses. Participants will be assigned to receive either the vaccine alone, the vaccine with adjuvant, or placebo by mouth. Study procedures include: stool samples, blood samples, and documentation of side effects. Participants will be involved in study related procedures for about 8 months.

Interested volunteers from Part A will along with volunteers who were never vaccinated in Part A will return to participate in Part B. These volunteers will be required to stay overnight in the research facility for several nights after challenge, after which they will be treated with antibiotics and sent home. Study procedures include stool samples, blood samples, and documentation of infection with ETEC H10407. If the vaccine with/without adjuvant is effective, the volunteers should not development diarrhea, but if the vaccine with/without adjuvant is not effective, the volunteers will have diarrhea for a few days.

Detailed Description

This study is a clinical trial in healthy adult volunteers to evaluate the safety, immunogenicity and efficacy of a live attenuated ETEC vaccine, ACE527, with and without a mucosal adjuvant, dmLT. This study was designed initially as a single site, Phase 1, double-blind, randomized, placebo-controlled, clinical trial in healthy adult volunteers to evaluate the safety and immunogenicity of a live attenuated ETEC vaccine, ACE527, with and without a mucosal adjuvant, dmLT (Part A). The addition of a challenge step provides a unique opportunity to evaluate the efficacy of the new lyophilized formulation of ACE527 vaccine, given in a two or three dose regimen, with and without dmLT, against wild type ETEC strain H10407 challenge (designated as Part B: Phase 2b Open Label Challenge Study). In addition, challenging the volunteers may allow for the identification of immune correlates of protection, taking advantage of newly available technologies (immune proteomics, transcriptomics, etc.)

ACE527 comprises three genetically attenuated and engineered strains of E. coli, with antigen profiles covering a wide range of ETEC surface colonization factor antigens (CFA/I, CFA/II [CS1, CS2, CS3] and CFA/IV [CS5, CS6]) and also expressing LT-B, the inactive subunit of LT (ETEC heat labile toxin). LT(R192G/L211A), or dmLT, is a derivative of wild-type enterotoxigenic Escherichia coli heat-labile enterotoxin 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.

Volunteers were enrolled in Part A into each of two separate Cohorts. Cohort 1 and 2 volunteers received 10^10 colony-forming units (cfu) total dose of ACE527, 10^10 cfu total dose of ACE527 with 25 µg dmLT, or placebo at 0, 1, and 2 months. Enrollment and dosing of Cohort 2 was dependent on an acceptable safety profile of the first dose of Cohort 1, based on evaluation of data up until Day 3 by the Safety Review Committee (SRC). The first immunization of each Cohort was administered in the Center for Immunization Research (CIR) Inpatient Unit, followed by 72 hours of direct post-immunization observation. The SRC met after the first dose of cohort to determine continuation of volunteer dosing on an outpatient basis, and enrollment of Cohort 2. The SRC met again after the first dose of Cohort 2 after concluding that the first dose appeared safe and well tolerated, subsequent doses would be administered on an outpatient basis. Safety was assessed by solicited symptoms/subject memory aid and laboratory evaluations. Adverse events (AE)s were graded according to standardized criteria. The immunogenicity outcome measures of interest include serum immunoglobulin G (IgG) and immunoglobulin A (IgA) antibodies by enzyme-linked immunosorbent assay (ELISA) against all vaccine antigens, cytokine assays, B and T cell memory responses, shedding profile of ACE527, and vaccine specific mucosal IgA responses.

Part B challenge cohorts were recruited among those participating in Part A; plus additional unvaccinated control volunteers sufficient to enroll up to a total of 60 recruited, as needed. Volunteers in the Phase 2b study were enrolled and challenged in 2-4 cohorts due to the CIR Inpatient Unit capacity of 30 beds. A minimum of 8-10 controls were challenged with each cohort of vaccinees to ensure comparability of attack rates across challenge cohorts. Volunteers were admitted as inpatients and challenged, with approximately 2 x 10^7 cfu of the fully virulent ETEC strain, H10407, followed by 5 days of direct observation. A Data Review Committee (DRC) will be convened to review the clinical data for all challenged volunteers and verify all outcomes per protocol definitions before any vaccine efficacy assessments were made.

Conditions

Diarrhea

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

ACE527 alone

In Part A of the study, subjects were split into two cohorts whereby enrollment of the second cohort depended on the safety profile of the first cohort. In Part A, subjects received three oral doses of ACE527 at 0, 1, and 2 months. For Part B of the study, eligible subjects who expressed interest of the study were administered H10407 challenge strain 5-7 months after the three-dose vaccination series.

Group Type: EXPERIMENTAL

ACE527

Intervention Type: BIOLOGICAL

3x10^9 cfu ACE527 vaccine strain. Comprised of three genetically attenuated and engineered strains of E. coli, with antigen profiles covering a wide range of ETEC surface colonization factor antigens (CFA/I, CFA/II [CS1, CS2, CS3] and CFA/IV [CS5, CS6]) and also expressing LTB, the inactive subunit of LT (ETEC heat labile toxin). The constituent strains of ACE527 were:

• ACAM2025: a live, attenuated, CFA/I, LTB positive strain
• ACAM2022: a live, attenuated, CS5, CS6, LTB positive strain, and
• ACAM2027: a live, attenuated, CS1, CS2, CS3, LTB positive strain.

H10407 challenge strain

Intervention Type: BIOLOGICAL

Approximately 2 x 10\^7 cfu of the fully virulent ETEC strain. Previously administered to 91 volunteers at this challenge dose by the CIR clinical team over the previous 4 years in conjunction with other Phase 1/2b trials.

ACE527 plus dmLT

In Part A of the study, subjects were split into two cohorts whereby enrollment of the second cohort depended on the safety profile of the first cohort. In Part A, subjects received three oral doses of ACE527 with mucosal adjuvant (dmLT) at 0, 1, and 2 months. For Part B of the study, eligible subjects who expressed interest of the study were administered H10407 challenge strain 5-7 months after the three-dose vaccination series.

Group Type: EXPERIMENTAL

ACE527

Intervention Type: BIOLOGICAL

3x10^9 cfu ACE527 vaccine strain. Comprised of three genetically attenuated and engineered strains of E. coli, with antigen profiles covering a wide range of ETEC surface colonization factor antigens (CFA/I, CFA/II [CS1, CS2, CS3] and CFA/IV [CS5, CS6]) and also expressing LTB, the inactive subunit of LT (ETEC heat labile toxin). The constituent strains of ACE527 were:

• ACAM2025: a live, attenuated, CFA/I, LTB positive strain
• ACAM2022: a live, attenuated, CS5, CS6, LTB positive strain, and
• ACAM2027: a live, attenuated, CS1, CS2, CS3, LTB positive strain.

dmLT

Intervention Type: BIOLOGICAL

A derivative of wild-type enterotoxigenic Escherichia coli heat-labile enterotoxin 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 (13). These two amino acid substitutions take place in proteolytic cleavage sites which are critical for activation of the secreted toxin molecules.

H10407 challenge strain

Intervention Type: BIOLOGICAL

Approximately 2 x 10\^7 cfu of the fully virulent ETEC strain. Previously administered to 91 volunteers at this challenge dose by the CIR clinical team over the previous 4 years in conjunction with other Phase 1/2b trials.

Control: Part A and B

In Part A of the study, subjects were split into two cohorts whereby enrollment of the second cohort depended on the safety profile of the first cohort. In Part A, subjects received three oral doses of CeraVacx placebo at 0, 1, and 2 months. For Part B of the study, eligible subjects who expressed interest of the study were administered H10407 challenge strain 5-7 months after the three-dose vaccination series.

Group Type: ACTIVE_COMPARATOR

CeraVacx placebo

Intervention Type: BIOLOGICAL

CeraVacx® is used to neutralize gastric acidity upon ingestion of vaccine. It was also used as the placebo in this study. CeraVacx® was prepared from the commercial product (Cera Products, Inc.); 9.5 grams were added to sterile water for each dose and mixed. Each dose contained 7 grams of rice syrup, 2 grams of sodium bicarbonate, and 0.5 grams of trisodium citrate.

H10407 challenge strain

Intervention Type: BIOLOGICAL

Approximately 2 x 10\^7 cfu of the fully virulent ETEC strain. Previously administered to 91 volunteers at this challenge dose by the CIR clinical team over the previous 4 years in conjunction with other Phase 1/2b trials.

Control: Part B only

Eligible participants were screened and administered H10407 challenge strain concurrently with other arms in Part B of the study. Their results for Part B are combined with that of the Control Arm in Part A, which received three oral doses of CeraVacx placebo.

Group Type: ACTIVE_COMPARATOR

H10407 challenge strain

Intervention Type: BIOLOGICAL

Approximately 2 x 10\^7 cfu of the fully virulent ETEC strain. Previously administered to 91 volunteers at this challenge dose by the CIR clinical team over the previous 4 years in conjunction with other Phase 1/2b trials.

Interventions

ACE527

3x10^9 cfu ACE527 vaccine strain. Comprised of three genetically attenuated and engineered strains of E. coli, with antigen profiles covering a wide range of ETEC surface colonization factor antigens (CFA/I, CFA/II [CS1, CS2, CS3] and CFA/IV [CS5, CS6]) and also expressing LTB, the inactive subunit of LT (ETEC heat labile toxin). The constituent strains of ACE527 were:

• ACAM2025: a live, attenuated, CFA/I, LTB positive strain
• ACAM2022: a live, attenuated, CS5, CS6, LTB positive strain, and
• ACAM2027: a live, attenuated, CS1, CS2, CS3, LTB positive strain.

Intervention Type: BIOLOGICAL

dmLT

A derivative of wild-type enterotoxigenic Escherichia coli heat-labile enterotoxin 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 (13). These two amino acid substitutions take place in proteolytic cleavage sites which are critical for activation of the secreted toxin molecules.

Intervention Type: BIOLOGICAL

CeraVacx placebo

CeraVacx® is used to neutralize gastric acidity upon ingestion of vaccine. It was also used as the placebo in this study. CeraVacx® was prepared from the commercial product (Cera Products, Inc.); 9.5 grams were added to sterile water for each dose and mixed. Each dose contained 7 grams of rice syrup, 2 grams of sodium bicarbonate, and 0.5 grams of trisodium citrate.

Intervention Type: BIOLOGICAL

H10407 challenge strain

Approximately 2 x 10\^7 cfu of the fully virulent ETEC strain. Previously administered to 91 volunteers at this challenge dose by the CIR clinical team over the previous 4 years in conjunction with other Phase 1/2b trials.

Intervention Type: BIOLOGICAL

Other Intervention Names

LT(R192G/L211A); ST+, LT+, CFA/I toxin

Eligibility Criteria

Inclusion Criteria

1. Male and female healthy adults between 18 and 50 years of age at the time of enrollment.

2. General good health, without clinically significant medical history, physical examination findings or clinical laboratory abnormalities per clinical judgment of PI.

3. Negative pregnancy test at screening and before the first (V0), second (V28), and third vaccinations (V56) for female volunteers of childbearing potential. Females of childbearing potential must agree to use an efficacious hormonal or barrier method of birth control during the study. Abstinence is acceptable. Female volunteers unable to bear children must have this documented (e.g. tubal ligation or hysterectomy) or must have negative pregnancy tests.

4. Willingness to participate in the study after all aspects of the protocol have been explained and written informed consent obtained.

5. Completion of a training session and demonstrated comprehension of the protocol procedures and knowledge of ETEC associated illness by passing a written examination (70% pass score).

6. Availability for the study duration, including all planned follow-up visits.

7. Received at least 2 doses of ACE527 vaccine alone or in combination with 25 ug dmLT 4-6 months prior to challenge (Part B only)

Exclusion Criteria

1. Presence of a significant medical or psychiatric condition which in the opinion of the investigator precludes participation in the study. Some medical conditions which are adequately treated and stable would not preclude entry into the study. These conditions might include stable asthma controlled with inhalers or mild hypertension stably controlled with a single agent.

2. Significant abnormalities in screening hematology, or serum chemistry as determined by PI or PI in consultation with the Medical Officer and sponsor.

3. Presence in the serum of HIV antibody, HBsAg, or HCV antibody.

4. Evidence of IgA deficiency (serum IgA < 7 mg/dl or limit of detection of assay).

5. Evidence of current excessive alcohol consumption or drug dependence.

6. Volunteers whose Body Mass Index (BMI) is less than 19.0 or greater than 34.0 (kg/m2)

7. Recent vaccination or receipt of an investigational product (within 30 days before vaccination).

8. Intention to donate blood or blood products within one month following the completion of study participation (note: The Red Cross will not allow blood donations for 1 year following participation in an investigational research study).

9. Any other criteria which, in the investigator's opinion, would compromise the ability of the volunteer to participate in the study, the safety of the study, or the results of the study

10. Working as a food handler, in child-care or as a healthcare worker with direct patient contact.

11. Have household contacts who are <2 years old or >80 years old or infirm or immunocompromised (for reasons including corticosteroid therapy, HIV infection, cancer chemotherapy, or other chronic debilitating disease).

12. Abnormal stool pattern (fewer than 3 per week or more than 3 per day).

13. Regular (≥ weekly) use of laxatives, antacids, or other agents to lower stomach acidity.

14. Use of any medication known to affect the immune function (e.g., corticosteroids and others) within 30 days preceding the first vaccination or planned use during the active study period.

15. Symptoms consistent with Traveler's Diarrhea concurrent with travel to countries where ETEC infection is endemic (most of the developing world) within two years prior to dosing, OR planned travel to endemic countries during the length of the study.

16. Vaccination for or ingestion of ETEC, cholera, or LT toxin within 3 years prior to dosing.

17. Use of antibiotics during the 7 days before dosing or proton pump inhibitors, H2 blockers or antacids within 48hours prior to dosing.

18. History of diarrhea in the 7 days prior to vaccination (outpatient diarrhea is defined as ≥ 3 unformed (grade 3 or greater) loose stools in 24 hours).

19. Known allergy to two of the three following antibiotics: Ciprofloxacin, amoxicillin, and/or trimethoprim/sulfamethoxazole

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 50 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

PATH

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Clayton D Harro, MD, ScM

Role: PRINCIPAL_INVESTIGATOR

Johns Hopkins Bloomberg School of Public Health

Locations

Center for Immunization Research (CIR) at Johns Hopkins School of Public Health (JHSPH)

Baltimore, Maryland, United States

Countries

United States

References

Harro C, Louis Bourgeois A, Sack D, Walker R, DeNearing B, Brubaker J, Maier N, Fix A, Dally L, Chakraborty S, Clements JD, Saunders I, Darsley MJ. Live attenuated enterotoxigenic Escherichia coli (ETEC) vaccine with dmLT adjuvant protects human volunteers against virulent experimental ETEC challenge. Vaccine. 2019 Mar 28;37(14):1978-1986. doi: 10.1016/j.vaccine.2019.02.025. Epub 2019 Feb 21.

Reference Type: DERIVED

PMID: 30797634 (View on PubMed)

Other Identifiers

VAC 006

Identifier Type: -

Identifier Source: org_study_id