NCT01739231

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

Safety, Reactogenicity, Tolerability, Immunogenicity and Efficacy of Live Attenuated ETEC ACE527 Vaccine Administered Alone or With a Double Mutant E. Coli Heat Labile Toxin (dmLT) in Healthy Adult Volunteers

• Status: Completed
• Phase: Phase 1 / Phase 2
• Study type: Interventional
• Enrollment: 81 (actual)
• Sponsor: PATH · Academic / Other
• Sex: All
• Age: 18 Years – 50 Years
• Healthy volunteers: Accepted

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

Interventions

Type	Name	Description
BIOLOGICAL	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.
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.
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.
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.

Timeline

• Start date: 2012-09-01
• Primary completion: 2013-10-01
• Completion: 2014-01-01
• First posted: 2012-12-03
• Last updated: 2019-02-12
• Results posted: 2018-12-21

Locations

1 site across 1 country: United States