Safety and Immunogenicity of Two Live, Attenuated Oral Shigella Sonnei Vaccines: WRSs2 and WRSs3
Condition: Shigella Infection
MeSH terms: Dysentery, Bacillary
Study type: Interventional
Phase: Phase 1

Summary: 
      Phase 1, randomized, double-blind, placebo controlled, dose-escalation, inpatient study of
      single doses of S. sonnei. Health adult subjects, ranging in age from 18 to 45 years of age
      (inclusive) will be screened. Enroll serial groups up to 90 subjects. The primary objective
      is to evaluate safety and tolerance of WRSs2 by monitoring presence, frequency and severity
      of clinical signs and symptoms. A secondary objective is to evaluate the immune response in
      blood and stool following ingestion of WRSs2 and WRSs3.
    

Detailed description: 
      This is a Phase 1, randomized, double-blind, placebo controlled, dose-escalation, inpatient
      study. Subjects will receive a single oral dose of WRSs2, WRSs3 or placebo. Five doses of
      each vaccine, ranging from 1x10^3 to 1x10^7 colony forming units (cfu) will be evaluated in
      this study. For each dose, a cohort of 18 subjects (n=18) will be randomized into 3 groups to
      receive WRSs2 (n=8), WRSs3 (n=8) and placebo (n=2). The three groups will receive
      approximately the same inoculum dose. Ingestion of the vaccine will be preceded by ingestion
      of a sodium bicarbonate buffer. Subjects will be enrolled in serial groups at escalating
      doses to enable the identification of the dose that minimizes reactogenicity while inducing a
      robust immune response while allowing for a head-to-head comparison of the 2 vaccine
      candidates. Dose escalation will proceed by approximately 1 log10 cfu levels based on the
      observations from the preceding group (up to a maximum dose of 1x10^7 cfu). During the 10-13
      day inpatient monitoring period, subjects will be evaluated at least twice daily. This
      assessment will include asking about any symptoms they may be experiencing, with targeted
      questions for reactogenic symptoms twice each day. Additional assessments will include daily
      measurement of vital signs, daily-history directed physical examinations and the collection,
      and grading (for consistency) of each stool along and weighing of all loose or watery stools.
      Stool specimens or rectal swabs (if unable to produce a stool) will also be evaluated for
      grossly visible and occult blood and will be cultured for the presence of the vaccine strain.
      All volunteers will receive antibiotic therapy 8 days after inoculation (unless meeting
      criteria for early treatment). Subjects will be discharged after initiating antibiotic
      treatment and passing 2 consecutive stools (at least 6 hours apart) negative for S. sonnei
      using standard stool culture and identification techniques. Following evaluation and
      history-directed physical examination, subjects will be discharged, with follow-up on study
      days 14+/-1, 28+/-2 and 56+/-4 to provide additional specimens for safety checks or
      immunology monitoring. Subjects will be given an ice-pack and cooler for collection of a
      stool sample at home which is to be brought to the clinic on the day of the follow-up visit.
      An interim safety report will compile findings from the preceding group with the PI's
      interpretation and plan to go forward. The Data Safety Monitoring board (DSMB)/Safety
      Monitoring Committee (SMC) or its equivalent must concur with the plan before proceeding. The
      decision to advance to the next highest dose level will be based solely on the safety profile
      at the tested dose level and will be made independently for each vaccine candidate. The next
      inpatient group (at the next higher dose) will not be admitted until a minimum of 4 weeks
      have elapsed from the time of the preceding group's vaccination to ensure adequate time for
      safety monitoring. The primary objectives are: to evaluate the safety and clinical tolerance
      of WRSs2 and WRSs3 by monitoring the presence and severity of clinical signs and symptoms.
      The secondary objectives are: to evaluate the immune response in blood and stool following
      ingestion of WRSs2 and WRSs3; to assess frequency and duration of fecal shedding of WRSs2 and
      WRSs3 following ingestion; and to assess any secondary infectious spread of different vaccine
      strains (WRSs2 or WRSs3) to subjects.
    

Intervention name(s): Placebo; WRSs2; WRSs3
Intervention type(s): Other; Biological; Biological
Intervention description(s): Placebo comparator: 1 or 1.5 ml of sterile normal saline 0.9% added to 30 mL of 0.9% sterile normal saline, given orally.; WRSs2 is a live, attenuated Shigella sonnei vaccine product, given orally at five escalating doses from 1x10^3 colony-forming units (cfu) to 1x10^7 cfu.; WRSs3 is a live, attenuated Shigella sonnei vaccine product, given orally at five escalating doses from 1x10^3 colony-forming units (cfu) to 1x10^7 cfu.
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Prevention
Keywords: Shigella sonnei; shigellosis; vaccine; WRSs2; WRSs3