Efficacy Study of IM Administered CssBA+dmLT Against Moderate-severe Diarrhea in Human Infection Model With ETEC Strain B7A in Healthy Adults

NCT06692907 | Completed Phase 2 FDA Drug

• 2 other identifiers: 23-00065UM1AI148684-04
• Study Type: interventional
• Target: 72
• Locations: 1 country
• Sites: 2

Brief Summary

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.

Conditions

Escherichia Infection

Keywords

B7A; Controlled; Diarrhea; Double-Blind; ETEC; Health Adult; IM Administered; Infection Model; Phase 2B; Vaccine

Outcome Measures

Primary Outcomes (6)

• Number and percentage of CssBA+dmLT injected participants experiencing local solicited AEs

  Through 7 days after vaccination

• Number and percentage of CssBA+dmLT injected participants experiencing MAAEs

  Through 6 months after last vaccination

• Number and percentage of CssBA+dmLT injected participants experiencing SAEs

  Through 6 months after last vaccination

• Number and percentage of CssBA+dmLT injected participants experiencing systemic solicited AEs

  Through 7 days after vaccination

• Number and percentage of CssBA+dmLT injected participants experiencing unsolicited AEs

  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.

  Day 70-79

Secondary Outcomes (11)

• Geometric Mean Titer (GMT) summarizing the maximum observed antigen-specific CS6 IgG antibody titers by Antibodies from Lymphocyte Supernatant (ALS)

  Day 8 - Day 99

• GMT of summarizing maximum observed antigen-specific dmLT IgG antibody titer by ALS

  Day 8 -Day 99

• GMT summarizing maximum observed antigen-specific dmLT IgA antibody titer by ALS

  Day 8 -Day 99

• GMT summarizing the maximum observed antigen-specific CS6 IgA antibody titers by ALS

  Day 8 - Day 99

• Mean severity of ETEC B7A-associated diarrhea

  Day 70 - Day 79

Study Arms (4)

Cohort 1A

EXPERIMENTAL

Participants will receive 45 mcg CssBA with 0.5 mcg dmLT vaccine intramuscular injection on Days 1, 22 and 43, outpatient. Participants who meet challenge criteria will orally receive 1x10\^10 cfu of ETEC strain B7A, inpatient, approximately 28 days after the third dose of study agent. N= 18.

Other: B7A (ETEC challenge strain); Biological: CssBA; Biological: dmLT

Cohort 1B

PLACEBO COMPARATOR

Participants will receive 0.6 mL of 0.9% normal saline intramuscular injection on Days 1, 22 and 43, outpatient. Participants who meet challenge criteria will orally receive 1x10\^10 cfu of ETEC strain B7A, inpatient, approximately 28 days after the third dose of study agent . N= 18.

Other: B7A (ETEC challenge strain); Other: Placebo

Cohort 2A

EXPERIMENTAL

Participants will receive 45 mcg CssBA with 0.5 mcg dmLT vaccine intramuscular injection on Days 1, 22 and 43, outpatient. Participants who meet the challenge criteria will orally receive 1x10\^10 cfu of ETEC strain B7A, inpatient, approximately 28 days after the third dose of study agent. N= 18.

Other: B7A (ETEC challenge strain); Biological: CssBA; Biological: dmLT

Cohort 2B

PLACEBO COMPARATOR

Participants will receive 0.6 mL of 0.9% normal saline intramuscular injection on Days 1, 22 and 43, outpatient. Participants who meet the challenge criteria will orally receive 1x10\^10 cfu of ETEC strain B7A, inpatient, approximately 28 days after the third dose of study agent. N= 18.

Other: B7A (ETEC challenge strain); Other: Placebo

Interventions

CssBA BIOLOGICAL

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.

Cohort 1A; Cohort 2A

B7A (ETEC challenge strain) OTHER

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.

Cohort 1A; Cohort 1B; Cohort 2A; Cohort 2B

dmLT BIOLOGICAL

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.

Cohort 1A; Cohort 2A

Placebo OTHER

Placebo

Cohort 1B; Cohort 2B

Eligibility Criteria

• Age: 18 Years - 49 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Non-pregnant, non-breast-feeding adults, age 18 to 49 years (inclusive) at the time of enrollment.
• Willing and able to sign and date informed consent document prior to study procedures.
• Stated willingness to be available for all study visits and comply with all trial procedures throughout the duration of the trial, including adherence to Lifestyle Considerations.
• Participants of childbearing potential must have a negative pregnancy test at study enrollment.
• For participants of childbearing potential\*: agree to use highly effective contraception with heterosexual intercourse for at least 1 month prior to the first vaccination through at least two months after receipt of the challenge agent or last dose of study product if not challenged. True abstinence is also acceptable.
• Childbearing potential in a participant assigned female at birth is defined as not sterilized via tubal ligation, bilateral oophorectomy, salpingectomy, hysterectomy, or successful Essure(R) placement (permanent, non-surgical, non-hormonal sterilization) with documented radiological confirmation test at least 90 days after the procedure, and still menstruating or \<1 year of the last menses if menopausal.
• Acceptable forms of highly effective contraception for participants assigned female at birth include same sex relationships, abstinence from sexual intercourse with a male partner, monogamous relationship with vasectomized partner who has been vasectomized for 180 days or more prior to the participant enrollment, barrier methods such as condoms or diaphragms with spermicide, effective intrauterine devices, NuvaRing(R), and licensed hormonal methods such as implants, injectables, or oral contraceptives ("the pill"). Periodic abstinence \[e.g., calendar, ovulation, symptothermal, post-ovulation methods\] and withdrawal are not acceptable methods of contraception.
• Body mass index (BMI) 19 to less than 40 kg/m\^2 at screening.
• Oral temperature is less than 100.4 degrees Fahrenheit (38 degrees Celsius) at the time of enrollment.
• Heart rate (HR) 60 to 100 beats per minute, inclusive. If participant baseline HR is between 50 and 60 beats per minute and the Principal or sub-Investigator licensed to make medical diagnosis determines that this is not clinically significant (e.g., if they are known to be high intensity athletes, have no clinical symptoms associated with the bradycardia, and have no signs or symptoms of other diseases causing bradycardia), this will NOT be considered a grade 1 adverse event and the participant still will be eligible.
• Blood pressure (BP):systolic BP \>/= 90 to \</= 140 mm Hg; diastolic BP \>/=55 to \</=90 mmHg.
• Must agree to refrain from donating blood or plasma (outside of this trial) from the first dose of study product until at least 30 days after completion of inpatient portion of the trial or last day of study product if not challenged.

You may not qualify if:

• Abnormal stool pattern (fewer than 3 stools per week or more than 3 stools per day) on a regular basis; loose or liquid stools on other than an occasional basis.
• History of microbiologically confirmed ETEC or cholera infection in the last 3 years.
• Symptoms consistent with MSD concurrent with travel to countries where ETEC infection is endemic (refer to MOP section for a list of endemic countries) within 3 years prior to enrollment.
• Vaccination for, ingestion of or occupational handling of ETEC, cholera, or E. coli heat labile toxin within 3 years prior to enrollment.
• Any condition that, in the judgment of the investigator, precludes participation because it could affect participant safety or endpoint evaluation.
• Unable to understand spoken and written English.
• Venous access deemed inadequate for phlebotomy/cannulation needs of the study.
• Have any disease or medical condition that, in the opinion of the Principal or sub-Investigator licensed to make medical diagnosis, is a contraindication to study participation. These include:
• History within the past 12 months of inflammatory bowel disease (IBD) (including ulcerative colitis, Crohn's disease, indeterminate colitis, or celiac disease), irritable bowel syndrome (IBS), or any active uncontrolled gastrointestinal disorders or diseases as assessed by the investigator.
• Within the past 12 months have symptoms or evidence of active gastritis or severe gastroesophageal reflux disease not well controlled on medication, gastric surgery, or gastric acid hyper-secretory disorders (e.g., Zollinger-Ellison syndrome), gastrointestinal obstruction, ileus, gastric retention, bowel perforation, toxic colitis, persistent infectious gastroenteritis, persistent or chronic diarrhea of unknown etiology, Clostridium difficile infection.
• Known active neoplastic disease (non-melanoma, treated, skin cancers are permitted), a history of any hematologic malignancy, or have used anticancer chemotherapy/radiation therapy (cytotoxic) within 3 years prior to study enrollment.
• Positive serology results for HIV Ag/Ab combo, HBsAg, or HCV Ab.
• Serum IgA \<40 mg/dL
• History of immunodeficiency due to congenital or hereditary causes, underlying illness, or treatment
• Within the past 3 years have participated in an ETEC challenge study or reports having received vaccination for ETEC.

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead

Study Sites (2)

University of Maryland, School of Medicine, Center for Vaccine Development and Global Health

Baltimore, Maryland, 21201-1509, United States

Location

Cincinnati Children's Hospital Medical Center Vaccine Research Center

Cincinnati, Ohio, 45229-3039, United States

Location

MeSH Terms

Conditions

Diarrhea

Condition Hierarchy (Ancestors)

Signs and Symptoms, Digestive; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Masking Details: Study staff including Outcomes Assessor, Study Statistician, Study Regulatory, QC coordinators and lab staff.
• Purpose: PREVENTION
• Intervention Model: SEQUENTIAL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 14, 2024
• First Posted: November 18, 2024
• Study Start: March 31, 2025
• Primary Completion: April 1, 2026
• Study Completion: April 1, 2026
• Last Updated: April 17, 2026

Record last verified: 2025-07

Locations

US (2)