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
Condition: Gastroenteritis Escherichia Coli; Immunisation
MeSH terms: Escherichia coli Infections; Gastroenteritis
Intervention: Placebo; Placebo; Placebo; Recombinant Double Mutant Heat-Labile Toxin LT(R192G/L211A) (dmLT) Oral enterotoxigenic Escherichia coli (ETEC) Vaccine; Recombinant Double Mutant Heat-Labile Toxin LT(R192G/L211A) (dmLT) Oral enterotoxigenic Escherichia coli (ETEC) Vaccine; Recombinant Double Mutant Heat-Labile Toxin LT(R192G/L211A) (dmLT) Oral enterotoxigenic Escherichia coli (ETEC) Vaccine
Intervention description: 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.
Intervention MeSH terms: Vaccines
Phase: Phase 1
Study type: Interventional
Primary purpose: Prevention
Allocation: Randomized
Intervention model: Sequential Assignment
Masking: Double (Participant, Investigator)
Enrollment: 75.0
Sex: All
Minimum age: 18 Years
Maximum age: 45 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: dmLT; E. coli; Enterotoxigenic Escherichia coli (ETEC); LTR192G/L211A

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.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Male or female age 18-45 years old, inclusive.

          2. Provides written informed consent before initiation of any study procedures.

          3. Healthy as judged by the site investigators and determined by medical history,
             medication history, and physical examination.

          4. Capable of understanding, consenting, and complying with all the study visits and
             procedures.

          5. Body Mass Index of no less than 18.5.

          6. Agrees not to participate in another clinical trial during the study period.

          7. Agrees to complete all study visits and procedures.

          8. Agrees not to donate blood to a blood bank for 12 months after receiving the last
             vaccine.

        Exclusion Criteria:

          1. 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."

          2. 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.

          3. 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.

          4. Any developmental abnormality of the palate.

          5. Participants diagnosed with autoimmune disorders, chronic inflammatory disorders or
             neurological disorders with a potential autoimmune correlation.

          6. 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.

          7. 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.

          8. 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.

          9. 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.

         10. Moderate or severe diarrheal illness* during the 6 weeks prior to enrollment.

             *Note: Moderate or severe diarrheal illness is defined by the passage of > / = 4
             unformed or loose stools (mix of liquid and solid components) in a 24 hour period

         11. History of chronic gastrointestinal illness*.

             *Note: this includes severe dyspepsia or gastroesophageal reflux disease,
             constipation, irritable bowel syndrome (IBS), hemorrhoids, diverticular disease,
             colitis, colon polyps, colon cancer, and inflammatory bowel disease. Mild or moderate
             heartburn or epigastric pain occurring no more than three times per week is permitted.

         12. Regular use (weekly or more often) of laxatives, anti-diarrheal, anti-constipation, or
             antacid therapy.

         13. History of major gastrointestinal surgery, excluding uncomplicated appendectomy or
             cholecystectomy.

         14. History of systemic antimicrobial treatment (i.e., topical treatments are not an
             exclusion) during the week prior to any administration of dmLT.

         15. Acute febrile illness (body temperature > / = 38 degrees Celsius) during the week
             prior to enrollment.

         16. Abnormal screening laboratories. Note: screening labs include white blood cell count
             (WBC), absolute neutrophil count (ANC), hemoglobin (Hg), platelet count, serum
             creatinine, serum albumin, alanine aminotransferase (ALT, also known as SGPT), and
             serologic testing for Hepatitis B virus surface antigen (HBsAg) and Hepatitis C virus
             (HCV) antibody. Abnormal vital signs.

         17. Isolation of specific bacteria* from screening stool cultures.

             *Note: bacteria include ETEC, Vibrio cholerae, and Shigella spp. Salmonella and
             Campylobacter will not be evaluated as part this criterion.

         18. Received an inactivated licensed vaccine within 2 weeks of enrollment or live licensed
             vaccine within 4 weeks of enrollment.

         19. Received a cholera (licensed or experimental) vaccine, E. coli vaccine, or Shigella
             vaccine in the last 3 years.

         20. History of receiving immune globulin or other blood product within the 3 months before
             enrollment in this study.

         21. Currently enrolled in another study, involving an experimental agent. Participants
             involved in observational studies or surveys remain eligible.

         22. Any condition that would, in the opinion of the Site Investigator, place the
             participant at an unacceptable risk of injury or render the participant unable to meet
             the requirements of the protocol.

         23. Known allergies to study compound or components of the study vaccine.

         24. Donating blood in the 8 weeks prior to study entry.