Phase 1 Trial for Safety, Tolerability, and Immunogenicity of a Live, Attenuated, Oral Shigella/ETEC Combination Vaccine to Healthy Adults
Condition: Diarrheal Disease, Infectious; Gastrointestinal Disease; Reactive Arthritis
MeSH terms: Communicable Diseases; Infections; Arthritis, Reactive; Gastrointestinal Diseases; Digestive System Diseases; Dysentery
Study type: Interventional
Phase: Phase 1

Summary: 
      This is a Phase 1 dose escalating study to assess the safety, tolerability, and
      immunogenicity of ShigETEC, a live, attenuated Shigella/ETEC combination vaccine given orally
      to healthy European adults 18 to 45 years of age.

      The major aim is the development of an efficacious and safe vaccine that prevents diarrhea
      caused by Shigella and ETEC in travelers, military personal visiting endemic countries and
      children of the developing world.

      This Phase 1 safety and immunogenicity study used a double-blind, placebo-control design and
      was conducted in two stages, a single ascending and a multiple ascending stage.
    

Detailed description: 
      ShigETEC vaccine is intended to stimulate an immune response in which protective antibodies
      are generated that prevent infection if a vaccinee is subsequently exposed to Shigella and
      ETEC.

      Main objective of the study:

      In Stage 1 is to determine Maximum Tolerated Single Dose of ShigETEC vaccine. Determine
      optimal immunogenicity of single dose in dose escalation.

      In Stage 2 is to determine safety of multiple dose regimens of ShigETEC Determine number of
      doses for maximum immune response to Shigella and ETEC.

      In both stages to determine the duration of shedding.

      Stage 1 is conducted in an inpatient hospital setting at a single site through Day 6. A total
      of 48 subjects (2 vaccine recipients to each placebo recipient) are to be enrolled
      sequentially in 4 different ascending dose groups (12 subjects per group) to receive a single
      oral dose of the ShigETEC vaccine starting at a dose in the first group of 1 x 10^9 Colony
      Forming Units (CFU) of vaccine or a placebo. Each group will have baseline serum and stool
      samples collected at the time of admission, but in any case, before vaccination. Following
      12-16 hours, they would receive oral immunization followed by evaluation of acute safety and
      tolerability for 6 days. Provided that no stopping rules are met through 6 days of follow-up
      for the entire group then the next group would be enrolled until all 4 groups were enrolled
      and evaluated through 6 days of assessment. Subjects in each group would be discharged to
      outpatient follow-up 6 days after dosing (7 days in hospital) if they were asymptomatic for
      shigellosis-like illness. Any subject with symptomatic illness would be treated with an
      appropriate course of antibiotic at the time of discharge. Daily stools will be tested for
      the presence of the ShigETEC vaccine until at least 2 sequential specimens are negative. If
      shedding persists through 14 days then the participant would be treated with antibiotics
      regardless of any symptomatology. All subjects would then be followed through 60 days
      following immunization to collect adverse events and blood samples.

      Stage 2 of the study is an outpatient double-blind, placebo-controlled study. In this stage,
      a total of 36 subjects (2 vaccine recipients to each placebo recipient) will be enrolled in 3
      different groups (12 subjects per group). The optimal dose and schedule of ShigETEC will be
      determined by analysis of the safety, shedding, and immunogenicity of each of the
      immunization schedules and interval of 3 days between doses (e.g dosing on days 1, 4, 7 and
      10 for four doses.) Each group will be enrolled and followed for acute safety and
      tolerability from the first dose of vaccine through 6 days following the last dose of vaccine
      administered in their schedule and then for 60 days following the last dose of vaccine for
      other adverse events. Blood for serum immunogenicity studies will be obtained
      pre-immunization and at 6, 10, 28, and 60 days following the last immunization. Stool samples
      for evaluation of vaccine shedding will be collected as available (with a target of daily)
      through up to 14 days following the last dose of vaccine/placebo. Stool samples pre
      immunization and at or nearest to days 10 and 28 after the last vaccine dose for each group
      were evaluated for IgA titers to vaccine components. Collection of stool samples for
      determining vaccine shedding were terminated after two sequential negative samples after day
      6 following the last dose.
    

Intervention name(s): ShigETEC live, attenuated, oral vaccine; Placebo
Intervention type(s): Biological; Drug
Intervention description(s): Vaccine or placebo will be delivered orally as a single dose in Stage 1 and between 2 and 4 doses at 3-day intervals in Stage 2 of the Study.; Vaccine or placebo will be delivered orally as a single dose in Stage 1 and between 2 and 4 doses at 3-day intervals in Stage 2 of the Study.
Allocation: Randomized
Intervention model: Sequential Assignment
Masking: Double (Participant, Outcomes Assessor)
Primary purpose: Prevention
Keywords: Shigellosis