Live Attenuated ETEC Vaccine ACE527 With and Without dmLT Adjuvant in Adults
Condition: Diarrhea
MeSH terms: Diarrhea
Study type: Interventional
Phase: Phase 1/Phase 2

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.
    

Intervention name(s): ACE527; dmLT; CeraVacx placebo; H10407 challenge strain
Intervention type(s): Biological; Biological; Biological; Biological
Intervention description(s): 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.; 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.; 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.; 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.
Other intervention name(s): LT(R192G/L211A); ST+, LT+, CFA/I toxin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment