A Double-Blind Placebo-Control Dose Escalating Study to Evaluate the Safety and Immunogenicity of dmLT by Oral, Sublingual and Intradermal Vaccination in Adults Residing in an Endemic Area

NCT03548064 | Terminated Phase 1 Results FDA Drug

• 1 other identifier: 14-0031
• Study Type: interventional
• Target: 75
• Locations: 2 countries
• Sites: 2

Brief Summary

This is a trial to evaluate the safety and immunogenicity of double mutant heat-labile toxin LTR192G/L211A (dmLT) from Enterotoxigenic Escherichia coli (ETEC) by oral, sublingual, or intradermal vaccination in approximately 135 healthy adult volunteers, age 18-45 years. Study duration is approximately 2.5 years, with each participant duration for up to 9 months depending on the route of dmLT administered. There is no specific hypothesis being tested in this study. The primary objective of this study is to assess the reactogenicity, safety, and tolerability of dmLT when administered in three sequential doses, over a range of dosages by oral, sublingual, or intradermal routes.

Conditions

Gastroenteritis Escherichia Coli; Immunisation

Keywords

dmLT; E. coli; Enterotoxigenic Escherichia coli (ETEC); LTR192G/L211A

Outcome Measures

Primary Outcomes (8)

• Number of Participants in the Oral Arms With Solicited Local Reactogenicity Events Post Each Dose

  Solicited adverse events were collected post-vaccination and for 7 days after. Local events for the oral route include irritation of the oral cavity or tongue, diarrhea, nausea, vomiting, and abdominal discomfort.

  Day 1 through Day 8 (post dose 1), Day 15 through Day 22 (post dose 2), Day 29 through Day 36 (post dose 3)

• Number of Participants in the Sublingual Arms With Solicited Local Reactogenicity Events Post Each Dose

  Solicited adverse events were collected post-vaccination and for 7 days after. Local events for the sublingual route include irritation of the oral cavity or tongue, facial nerve disturbance, diarrhea, nausea, vomiting, or abdominal discomfort.

  Day 1 through Day 8 (post dose 1), Day 15 through Day 22 (post dose 2), Day 29 through Day 36 (post dose 3)

• Number of Participants in the Intradermal Arms With Solicited Local Reactogenicity Events Post Each Dose

  Solicited adverse events were collected post-vaccination and for 7 days after. Local events for the intradermal route include injection site pain, redness, swelling, bruising, itching, hypo/hyper pigmentation and induration, vesicles, or hardened mass. Study halted on Day 43 due to COVID-19 pandemic and the intradermal group did not receive the final dose.

  Day 1 through Day 8 (post dose 1), Day 22 through Day 29 (post dose 2)

• Number of Participants in the Oral and Sublingual Arms With Solicited Systemic Reactogenicity Events Post Each Dose

  Solicited adverse events were collected post-vaccination and for 7 days after. Systemic events for the oral and sublingual routes include fever, feverishness, fatigue, malaise, myalgia, or headache.

  Day 1 through Day 8 (post dose 1), Day 15 through Day 22 (post dose 2), Day 29 through Day 36 (post dose 3)

• Number of Participants in the Intradermal Arms With Solicited Systemic Reactogenicity Events Post Each Dose

  Solicited adverse events were collected post-vaccination and for 7 days after. Systemic events for the intradermal route include fever, feverishness, fatigue, malaise, myalgia, headache, diarrhea, nausea, vomiting, or abdominal discomfort. Study halted on Day 43 due to COVID-19 pandemic and the intradermal group did not receive the final dose.

  Day 1 through Day 8 (post dose 1), Day 22 through Day 29 (post dose 2)

• Number of Participants Who Withdrew From the Study

  Participants could voluntarily withdraw their consent for study participation for any reason at any time. Primary reason for withdrawal was recorded and early termination visits were attempted.

  Day 1 through Day 209 (Day 223 for Intradermal cohorts)

• Number of Participants Who Discontinued Study Vaccination

  Participants who received the first vaccination could choose to discontinue receipt of study vaccine for any reason and could choose to remain in the study (i.e., not withdraw from study). In addition, a participant could be discontinued from receipt of the second or third vaccination. Discontinuation from vaccination did not mean automatic withdrawal from the study, and participants were monitored for safety and immunogenicity if the participant consented.

  Day 1 through Day 29 (Day 43 for Intradermal cohorts)

• Number of Vaccine-related Unsolicited Adverse Events From First Dose Through 28 Days After Last Dose

  Adverse events were defined as any untoward medical occurrence in a participant administered a pharmaceutical product regardless of its causal relationship to the study treatment.

  Day 1 through Day 57 (Day 71 for Intradermal cohorts)

Secondary Outcomes (9)

• Number of Vaccine-related Serious Adverse Events From Post Dose 1 Through 6 Months After Last Dose

  Day 1 through Day 209 (Day 223 for Intradermal cohorts)

• Percentage of Participants With a >= 4-fold Rise in dmLT-specific Serum IgA Titers Over Baseline Measured by ELISA

  Day 8 through Day 114

• Percentage of Participants With a >= 4-fold Rise in dmLT-specific Serum IgG Titers Over Baseline Measured by ELISA

  Day 8 through Day 114

• Percentage of Participants With >= 8 dmLT-specific IgA ASC / 10^6 PBMC as Measured by ELISpot

  Day 1 through Day 36

• Percentage of Participants With >= 8 dmLT-specific IgG ASC / 10^6 PBMC as Measured by ELISpot

  Day 1 through Day 36

Study Arms (9)

Regimen A

EXPERIMENTAL

5 µg of dmLT oral on days 1, 15, 29, n=12; placebo oral on days 1, 15, 29, n=3

Other: Placebo; Biological: Recombinant Double Mutant Heat-Labile Toxin LT(R192G/L211A) (dmLT) Oral enterotoxigenic Escherichia coli (ETEC) Vaccine

Regimen B

EXPERIMENTAL

25 µg of dmLT oral on days 1, 15, 29, n=12; placebo oral on days 1, 15, 29, n=3

Other: Placebo; Biological: Recombinant Double Mutant Heat-Labile Toxin LT(R192G/L211A) (dmLT) Oral enterotoxigenic Escherichia coli (ETEC) Vaccine

Regimen C

EXPERIMENTAL

5 µg of dmLT sublingual on days 1, 15, 29, n=12; placebo sublingual on days 1, 15, 29, n=3

Other: Placebo; Biological: Recombinant Double Mutant Heat-Labile Toxin LT(R192G/L211A) (dmLT) Oral enterotoxigenic Escherichia coli (ETEC) Vaccine

Regimen D

EXPERIMENTAL

25 µg of dmLT sublingual on days 1, 15, 29, n=12; placebo sublingual on days 1, 15, 29, n=3

Other: Placebo; Biological: Recombinant Double Mutant Heat-Labile Toxin LT(R192G/L211A) (dmLT) Oral enterotoxigenic Escherichia coli (ETEC) Vaccine

Regimen E

EXPERIMENTAL

0.3 µg of dmLT intradermal on days 1, 22, 43, n=12; placebo intradermal on days 1, 22, 43, n=3

Other: Placebo; Biological: Recombinant Double Mutant Heat-Labile Toxin LT(R192G/L211A) (dmLT) Oral enterotoxigenic Escherichia coli (ETEC) Vaccine

Regimen F

EXPERIMENTAL

1.0 µg of dmLT intradermal on days 1, 22, 43, n=12; placebo intradermal on days 1, 22, 43, n=3

Other: Placebo; Biological: Recombinant Double Mutant Heat-Labile Toxin LT(R192G/L211A) (dmLT) Oral enterotoxigenic Escherichia coli (ETEC) Vaccine

Regimen G

EXPERIMENTAL

50 µg of dmLT oral on days 1, 15, 29, n=12; placebo oral on days 1, 15, 29, n=3

Other: Placebo; Biological: Recombinant Double Mutant Heat-Labile Toxin LT(R192G/L211A) (dmLT) Oral enterotoxigenic Escherichia coli (ETEC) Vaccine

Regimen H

EXPERIMENTAL

50 µg of dmLT sublingual on days 1, 15, 29, n=12; placebo sublingual on days 1, 15, 29, n=3

Other: Placebo; Biological: Recombinant Double Mutant Heat-Labile Toxin LT(R192G/L211A) (dmLT) Oral enterotoxigenic Escherichia coli (ETEC) Vaccine

Regimen I

EXPERIMENTAL

2.0 µg of dmLT intradermal on days 1, 22, 43, n=12; placebo intradermal on days 1, 22, 43, n=3

Other: Placebo; Biological: Recombinant Double Mutant Heat-Labile Toxin LT(R192G/L211A) (dmLT) Oral enterotoxigenic Escherichia coli (ETEC) Vaccine

Interventions

Placebo OTHER

Placebo

Regimen A; Regimen B; Regimen G

Recombinant Double Mutant Heat-Labile Toxin LT(R192G/L211A) (dmLT) Oral enterotoxigenic Escherichia coli (ETEC) Vaccine BIOLOGICAL

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. These two amino acid substitutions take place in proteolytic cleavage sites which are critical for activation of the secreted toxin molecules.

Regimen A; Regimen B; Regimen G

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Male or female age 18-45 years old, inclusive.
• Provides written informed consent before initiation of any study procedures.
• Healthy as judged by the site investigators and determined by medical history, medication history, and physical examination.
• Capable of understanding, consenting, and complying with all the study visits and procedures.
• Body Mass Index of no less than 18.5.
• Agrees not to participate in another clinical trial during the study period.
• Agrees to complete all study visits and procedures.
• Agrees not to donate blood to a blood bank for 12 months after receiving the last vaccine.

You may not qualify if:

• Women who are pregnant or lactating or have a positive urine pregnancy test at screening or on the day of vaccinations.
• Note: all women presenting for screening will have urine pregnancy testing. "Females of childbearing potential must agree to use an efficacious hormonal or barrier method of birth control from screening and through 28 days post last dose of vaccine. Abstinence is also acceptable."
• Presence or history of a chronic medical condition\* that would, in the opinion of the investigator, render vaccination unsafe or interfere with the evaluation of the vaccine.
• \*Note: this may include, but is not limited to: significant renal disease, unstable or progressive neurological disorders, diabetes, heart disease, asthma, lung disease, liver disease, organ transplant recipients and cancer.
• Presence of a significant dermatologic condition\*, or tattoo(s), scarring or significant skin damage at the vaccination site that would impede evaluation of local reactogenicity.
• \*Note: this may include severe eczema, psoriasis or history of keloid formation. Participants with history of squamous cell or basal cell skin cancer that has been surgically excised and considered cured may be enrolled in the study if the skin cancer site is healed and is not at proposed vaccine administration site.
• Any developmental abnormality of the palate.
• Participants diagnosed with autoimmune disorders, chronic inflammatory disorders or neurological disorders with a potential autoimmune correlation.
• Use of long-term (\> / = 2 weeks) oral steroids, intranasal or topical prednisone (or equivalent), parenteral steroids, or high-dose inhaled steroids (\> 800 microgram/day of beclomethasone dipropionate or equivalent) within the preceding 6 months.
• Has major psychiatric illness\* during last 12 months that in the investigator's opinion would preclude participation.
• \*Note: Participants taking antipsychotic or antimanic drugs should not be enrolled. These include: aripiprazole, clozapine, ziprasidone, haloperidol, molindone, lamotrigine, gabapentin, topiramate, loxapine, thioridazine, thiothixene, pimozide, fluphenazine, risperidone, mesoridazine, quetiapine, trifluoperazine, chlorprothixene, chlorpromazine, perphenazine, olanzapine, carbamazepine, divalproex sodium, lithium carbonate, or lithium citrate. Participants taking a single antidepressant drug and are stable without de-compensating symptoms in the preceding 3 months can be enrolled in the study.
• Use of prescription or over-the-counter (OTC) anti-inflammatory medications\* 48 hours prior to receiving the investigational product.
• \*Note: This includes naproxen, aspirin, ibuprofen, and other non-steroidal anti-inflammatory drugs.
• Gastrointestinal symptoms\* in the past 24 hours or abdominal pain lasting for more than 2 weeks in the past 6 months.
• \*Note: this may include, but is not limited to: abdominal pain or cramps, loss of appetite, nausea, general ill-feeling or vomiting.

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

International Center for Diarrheal Disease Research Bangladesh - Infectious Diseases Division - Mucosal Immunology and Vaccinology Unit

Dhaka, 1212, Bangladesh

Location

Related Publications (1)

• Bhuiyan TR, Khanam F, Basher SR, Dash P, Chowdhury MI, Haque S, Harun NB, Akter A, Karmakar PC, Hakim A, Amin S, Kamruzzaman M, Parvin N, Ahmed T, Butts J, Pasetti MF, Wahid R, Sztein MB, Maier N, White JA, Tomashek KM, Bourgeois AL, Baqar S, Kotloff KL, Qadri F, Chen WH. Safety and immunogenicity of a recombinant double-mutant heat-labile toxin derived from enterotoxigenic Escherichia coli in healthy Bangladeshi adults delivered by three different routes. Front Bacteriol. 2025;4:10.3389/fbrio.2025.1567791. doi: 10.3389/fbrio.2025.1567791. Epub 2025 Jul 15.

  PMID: 41306922 DERIVED

MeSH Terms

Conditions

Escherichia coli Infections

Interventions

Vaccines

Condition Hierarchy (Ancestors)

Enterobacteriaceae Infections; Gram-Negative Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections

Intervention Hierarchy (Ancestors)

Biological Products; Complex Mixtures

Results Point of Contact

• Title: Wilbur H. Chen, MD, MS
• Organization: University of Maryland

wchen@som.umaryland.edu

410-706-1188

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: PREVENTION
• Intervention Model: SEQUENTIAL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 24, 2018
• First Posted: June 6, 2018
• Study Start: March 10, 2019
• Primary Completion: December 31, 2020
• Study Completion: December 31, 2020
• Last Updated: May 21, 2025
• Results First Posted: January 18, 2022

Record last verified: 2017-12-14

Locations

BA (1); US (1)