The study is designed to evaluate the safety, immunogenicity, and efficacy of the intramuscular administration of a CS6 based vaccine (CssBA) against ETEC co-administered with double mutant labile toxin (dmLT) in preventing moderate-severe diarrhea (MSD) following challenge with ETEC strain B7A in healthy adults. Approximately 72 adult participants, divided into 4 cohorts of 18, will be randomized 1:1 to receive vaccine (45 micrograms CssBA with 0.5 micrograms dmLT) or placebo (normal saline) on an outpatient basis. All participants will receive 3 intramuscular (IM) doses of vaccine or placebo at 3-week intervals (days 1, 22 and 43). Following vaccination, participants will be followed as outpatients for safety using a memory aid from the time of each vaccination through 7 days post each vaccination. Approximately 28 days (plus or minus 1 day) after receipt of the 3rd dose of study agent, participants meeting challenge criteria will be admitted to an inpatient unit and be administered an oral dose of 1 x 10\^10 cfu (colony-forming unit) of ETEC strain B7A. Five days after challenge, participants will be treated with ciprofloxacin, except in cases of known allergy or intolerance. Participants will be discharged from the inpatient unit when they have completed their 3-day antibiotic course and are able to care for themselves. After discharge from the inpatient unit, participants will return for clinic visits and have a phone visit to provide any updates on medication, medical history and AE/SAEs. The primary objectives are: 1) Estimate CssBA+dmLT efficacy in preventing moderate-severe diarrhea (MSD) following challenge with ETEC strain B7A in healthy adults. 2) Evaluate the safety of intramuscular injection of CssBA+dmLT.
The study is designed to evaluate the safety, immunogenicity, and efficacy of the intramuscular administration of a CS6 based vaccine (CssBA) against ETEC co-administered with double mutant labile toxin (dmLT) in preventing moderate-severe diarrhea (MSD) following challenge with ETEC strain B7A in healthy adults. Approximately 72 adult participants, divided into 4 cohorts of 18, will be randomized 1:1 to receive vaccine (45 micrograms CssBA with 0.5 micrograms dmLT) or placebo (normal saline) on an outpatient basis. All participants will receive 3 intramuscular (IM) doses of vaccine or placebo at 3-week intervals (days 1, 22 and 43). Following vaccination, participants will be followed as outpatients for safety using a memory aid from the time of each vaccination through 7 days post each vaccination. Approximately 28 days (plus or minus 1 day) after receipt of the 3rd dose of study agent, participants meeting challenge criteria will be admitted to an inpatient unit and be administered an oral dose of 1 x 10\^10 cfu (colony-forming unit) of ETEC strain B7A. After receipt of challenge agent, the participant will fast for 90 minutes. Participants will be monitored daily for diarrhea and other signs/symptoms of enteric illness. All stool will be collected and graded, and loose stools (grade 3-5) will be weighed. Five days after challenge (or earlier if clinically indicated), participants will be treated with ciprofloxacin, except in cases of known allergy or intolerance in which case trimethoprim-sulfamethoxazole will be used. Participants will be discharged from the inpatient unit when they have completed their 3-day antibiotic course and are able to care for themselves, including maintaining hydration status. Follow-up outpatient visits for 5 days and 4 weeks after discharge will monitor safety and immunologic parameters, and a phone visit will be conducted 6 months after last dose of study agent. The primary objectives are: 1) Estimate CssBA+dmLT efficacy in preventing moderate-severe diarrhea (MSD) following challenge with ETEC strain B7A in healthy adults. 2) Evaluate the safety of intramuscular injection of CssBA+dmLT. The secondary objectives are: 1)Determine illness severity following ETEC B7A challenge in participants who received CssBA+dmLT vs placebo using an evidence-based disease severity score (1). 2)Evaluate ETEC CS6- and LT-specific serum IgG and IgA responses following vaccination and challenge. 3)Evaluate ETEC CS6- and LT-specific IgG and IgA in Antibodies from Lymphocyte Supernatant (ALS) following vaccination and 4) Determine the prevalence and duration of fecal shedding of B7A following challenge.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
PREVENTION
Masking
DOUBLE
Enrollment
72
A pathogenic strain of ETEC that can cause illness ranging from mild watery diarrhea to severe symptoms. The primary complication associated with an infection from this strain is dehydration.
A CS6 based vaccine against ETEC (Enterotoxigenic Escherichia coli) in preventing moderate-severe diarrhea obtained via purification from a host E. coli expression strain, BL21(DE3), harboring a pET24a (+) plasmid containing the CssBA gene expressing the his-tagged CssBA protein.
An E. coli double mutant heat labile toxin. This genetically attenuated strain is expressed from a plasmid (pLC403) in the E. coli expression strain JM83.
Placebo
University of Maryland, School of Medicine, Center for Vaccine Development and Global Health
Baltimore, Maryland, United States
Cincinnati Children's Hospital Medical Center Vaccine Research Center
Cincinnati, Ohio, United States
Number and percentage of CssBA+dmLT injected participants experiencing local solicited AEs
Time frame: Through 7 days after vaccination
Number and percentage of CssBA+dmLT injected participants experiencing MAAEs
Time frame: Through 6 months after last vaccination
Number and percentage of CssBA+dmLT injected participants experiencing SAEs
Time frame: Through 6 months after last vaccination
Number and percentage of CssBA+dmLT injected participants experiencing systemic solicited AEs
Time frame: Through 7 days after vaccination
Number and percentage of CssBA+dmLT injected participants experiencing unsolicited AEs
Time frame: Through Day 71
Number and percentage of participants experiencing moderate-severe diarrhea (MSD) with Enterotoxigenic Escherichia coli (ETEC)
MSD is defined as experiencing \>/=4 loose/liquid stools or \>/= 400 g of loose/liquid stools in any 24-hour period during inpatient stay.
Time frame: Day 70-79
Geometric Mean Titer (GMT) summarizing the maximum observed antigen-specific CS6 IgG antibody titers by Antibodies from Lymphocyte Supernatant (ALS)
Time frame: Day 8 - Day 99
GMT of summarizing maximum observed antigen-specific dmLT IgG antibody titer by ALS
Time frame: Day 8 -Day 99
GMT summarizing maximum observed antigen-specific dmLT IgA antibody titer by ALS
Time frame: Day 8 -Day 99
GMT summarizing the maximum observed antigen-specific CS6 IgA antibody titers by ALS
Time frame: Day 8 - Day 99
Mean severity of ETEC B7A-associated diarrhea
ETEC B7A disease severity score calculated from three components that are evaluated daily during the ETEC Challenge. ETEC B7A disease severity scores will only be calculated for participants who receive a dose of ETEC B7A.
Time frame: Day 70 - Day 79
Median number of days with a positive stool culture for B7A following challenge
Time frame: Day 70 - Day 79
Number and percentage of participants with >/= 4-fold rise from baseline in antigen-specific CS6 antibody titer to IgA in serum
Time frame: Through Day 99
Number and percentage of participants with >/= 4-fold rise from baseline in antigen-specific CS6 antibody titer to IgG in serum
Time frame: Through Day 99
Number and percentage of participants with >/= 4-fold rise from baseline in antigen-specific dmLT antibody titer to IgA in serum
Time frame: Through Day 99
Number and percentage of participants with >/= 4-fold rise from baseline in antigen-specific dmLT antibody titer to IgG in serum
Time frame: Through Day 99
Number and percentage of participants with a positive stool culture for B7A
Time frame: Day 71 - Day 79
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