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.
This is a Phase 1 double-blinded, placebo-controlled, dose-escalation 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, who meet all the eligibility criteria and reside in Bangladesh. Study duration is approximately 2.5 years, with each participant duration for up to 9 months depending on the route of dmLT administered. The study population will be recruited from Mirpur, a community of Dhaka, Bangladesh, known as having a high rate of diarrheal, respiratory, and enteric disease. This clinical trial is designed to assess the safety, reactogenicity, tolerability, and immunogenicity of a range of dosages of dmLT administered by three different routes: oral, sublingual, or intradermal. The oral and sublingual routes of administration will evaluate dosages of 5, 25, and 50 micrograms of dmLT; the intradermal route of administration will evaluate dosages of 0.3, 1.0, and 2.0 micrograms of dmLT. Participants will receive a total of three sequential doses of dmLT; the oral and sublingual routes will be at days 1, 15, and 29 and the intradermal route will be at days 1, 22, and 43. 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. The secondary objectives of this study are: 1) to assess the long-term safety, from first vaccination through 6 months following the last dose of vaccine, 2) to evaluate the serum anti-dmLT IgG and IgA response, 3) to evaluate the IgG and IgA anti-dmLT Antibody Secreting Cell (ASC) response, 4) to evaluate the IgG and IgA anti-dmLT Antibodies in Lymphocyte Supernatant (ALS) response, 5) to evaluate the total fecal IgA and fecal anti-dmLT IgA response, and 6) to evaluate the total salivary IgA and the saliva-derived anti-dmLT IgA response.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
PREVENTION
Masking
DOUBLE
Enrollment
75
Placebo
Placebo
Placebo
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.
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.
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.
University of Maryland, School of Medicine, Center for Vaccine Development and Global Health
Baltimore, Maryland, United States
International Center for Diarrheal Disease Research Bangladesh - Infectious Diseases Division - Mucosal Immunology and Vaccinology Unit
Dhaka, Bangladesh
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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: Day 1 through Day 57 (Day 71 for Intradermal cohorts)
Number of Vaccine-related Serious Adverse Events From Post Dose 1 Through 6 Months After Last Dose
Serious Adverse Events (SAE) were defined as an adverse event which resulted in death, was life threatening, resulted in an inpatient hospitalization, prolongation of an existing hospitalization, led to persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, or led to a congenital anomaly/birth defect. Important medical events that may not result in death, be life-threatening, or require hospitalizations were considered serious when, based upon appropriate medical judgment, they jeopardize the participant and may require medical or surgical intervention to prevent one of the outcomes listed in this definition.
Time frame: 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
Blood was collected for the IgA and IgG assay which was conducted with dmLT as the antigen. Each sample was tested per the laboratory's standard operating procedure. The percentage of participants with a \>= 4-fold rise in dmLT-specific serum IgA and IgG titers over baseline was calculated for each study arm from the available results at any time post-first study vaccination. Study halted on Day 43 due to COVID-19 pandemic and the intradermal group did not receive the final dose.
Time frame: Day 8 through Day 114
Percentage of Participants With a >= 4-fold Rise in dmLT-specific Serum IgG Titers Over Baseline Measured by ELISA
Blood was collected for the IgG and IgA assay which was conducted with dmLT as the antigen. Each sample was tested per the laboratory's standard operating procedure. The percentage of participants with a \>= 4-fold rise in dmLT-specific serum IgG and IgA titers over baseline was calculated for each study arm from the available results at any time post-first study vaccination. Study halted on Day 43 due to COVID-19 pandemic and the intradermal group did not receive the final dose.
Time frame: Day 8 through Day 114
Percentage of Participants With >= 8 dmLT-specific IgA ASC / 10^6 PBMC as Measured by ELISpot
PBMCs were collected for the IgA and IgG assay which was conducted with dmLT as the antigen. Each sample was tested per the laboratory's standard operating procedure. The percentage of participants with \>= 8 dmLT-specific IgA and IgG ASC / 10\^6 PBMC was calculated for each study arm from the available results at any time post-first study vaccination. Study halted on Day 43 due to COVID-19 pandemic and the intradermal group did not receive the final dose.
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Time frame: Day 1 through Day 36
Percentage of Participants With >= 8 dmLT-specific IgG ASC / 10^6 PBMC as Measured by ELISpot
PBMCs were collected for the IgA and IgG assay which was conducted with dmLT as the antigen. Each sample was tested per the laboratory's standard operating procedure. The percentage of participants with \>= 8 dmLT-specific IgA and IgG ASC / 10\^6 PBMC was calculated for each study arm from the available results at any time post-first study vaccination. Study halted on Day 43 due to COVID-19 pandemic and the intradermal group did not receive the final dose.
Time frame: Day 1 through Day 36
Percentage of Participants With >= 2-fold Rise in ALS Anti-dmLT-specific IgA Titers Over Baseline Measured by ELISA
Blood was collected for the IgA and IgG assay which was conducted with dmLT as the antigen. Each sample was tested per the laboratory's standard operating procedure. The percentage of participants with a \>= 2-fold rise in ALS anti-dmLT-specific IgG and IgA titers over baseline was calculated for each study arm from the available results at any time post-first study vaccination. Study halted on Day 43 due to COVID-19 pandemic and the intradermal group did not receive the final dose.
Time frame: Day 1 through Day 36
Percentage of Participants With >= 2-fold Rise in ALS Anti-dmLT-specific IgG Titers Over Baseline Measured by ELISA
Blood was collected for the IgA and IgG assay which was conducted with dmLT as the antigen. Each sample was tested per the laboratory's standard operating procedure. The percentage of participants with a \>= 2-fold rise in ALS anti-dmLT-specific IgG and IgA titers over baseline was calculated for each study arm from the available results at any time post-first study vaccination. Study halted on Day 43 due to COVID-19 pandemic and the intradermal group did not receive the final dose.
Time frame: Day 1 through Day 36
Percentage of Participants With >= 4-fold Rise Over Baseline in dmLT-specific Fecal IgA Titers Measured by ELISA
Stool was collected for the IgA assay which was conducted with dmLT as the antigen. Each sample was tested per the laboratory's standard operating procedure. The percentage of participants with a \>= 4-fold rise over baseline in dmLT-specific fecal IgA titers was calculated for each study arm from the available results at any time post-first study vaccination. Study halted on Day 43 due to COVID-19 pandemic and the intradermal group did not receive the final dose.
Time frame: Day 1 through Day 57
Percentage of Participants With >= 4-fold Rise Over Baseline in dmLT-specific Salivary IgA Titers Measured by ELISA
Saliva was collected for the IgA assay which was conducted with dmLT as the antigen. Each sample was tested per the laboratory's standard operating procedure. The percentage of participants with a \>= 4-fold rise over baseline in dmLT-specific salivary IgA titers was calculated for each study arm from the available results at any time post-first study vaccination. Study halted on Day 43 due to COVID-19 pandemic and the intradermal group did not receive the final dose.
Time frame: Day 1 through Day 57