Clinical Trial: Safety and Immunogenicity of Two Live, Attenuated Oral Shigella Sonnei Vaccines: WRSs2 and WRSs3

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

Official Title: Safety and Immunogenicity of Two Live, Attenuated Oral Shigella Sonnei Vaccines: WRSs2 and WRSs3

Brief 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 Summary: 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-direct
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Current Primary Outcome:

  • Safety: Frequency, duration, and severity of the following solicited symptoms: diarrhea, nausea, vomiting, fever, and abdominal cramping, also frequency of dysentery, and dehydration, and occurrence of abnormal clinical laboratory values. [ Time Frame: Day 0-14 ]
  • Safety: Occurrence of vaccine-associated serious adverse events (SAEs) [ Time Frame: Day 0 to Day 180 ]


Original Primary Outcome:

  • Safety: Occurrence of vaccine-associated serious adverse events (SAEs) [ Time Frame: Day 0 to Day 56 ]
  • Safety: Frequency, duration, and severity of the following solicited AEs: diarrhea, nausea, vomiting, fever, and abdominal cramping, also frequency of dysentery, hypovolemia, and dehydration, and occurrence of abnormal clinical laboratory values. [ Time Frame: within 15 days post vaccination (Day 0-14) ]


Current Secondary Outcome:

  • Secondary infectious spread of different vaccine strains to participants. Secondary infections will be measured by assessing fecal shedding using product-specific PCR. [ Time Frame: Day 0 to 10, 14 and 28 ]
  • Fecal shedding of vaccine - duration of detectable fecal presence of WRSs2 and WRSs3 by polymerase chain reaction (PCR) and culture. [ Time Frame: Day 0 to 10, 14 and 28 ]
  • Systemic immunogenicity: i) Serum IgA, IgM and IgG response to Shigella antigens: S. sonnei Invaplex 50, LPS, IpaB, IpaC, and IpaD. [ Time Frame: Day -1, 7, 14, 28 and 56 ]
  • Cell Mediated Immunogenicity: Measure memory B-cell response to Shigella specific antigens. [ Time Frame: Day 0, 28 and 56 ]
  • Mucosal immunogenicity: ii) Fecal IgA response to Shigella antigens: S. sonnei LPS, IpaB, IpaC, IpaD, and S. sonnei Invaplex 50. [ Time Frame: Day -1, 0, 3, 7, 10, 14 and 28 ]
  • Mucosal immunogenicity: i) IgA-ASC and IgG ASC and ALS response to Shigella antigens: S. sonnei LPS, IpaB, IpaC, IpaD, and S. sonnei Invaplex 50. [ Time Frame: Day -1, 5, 7, 9 and 14 ]


Original Secondary Outcome:

  • Secondary infectious spread of different vaccine strains to participants. Secondary infections will be measured by assessing fecal shedding using product-specific PCR. [ Time Frame: Day 0 to Day 56 ]
  • Mucosal immunogenicity: i) IgA-ASC and IgG ASC and ALS response to Shigella antigens: S. sonnei LPS, IpaB, IpaC, IpaD, and S. sonnei Invaplex 50. [ Time Frame: Day 0 to Day 56 ]
  • Fecal shedding of vaccine - frequency and duration of detectable fecal presence of WRSs2 and WRSs3 by polymerase chain reaction (PCR) and culture. [ Time Frame: Day 0 to Day 56 ]
  • Cell Mediated Immunogenicity: Measure memory B-cell response to Shigella specific antigens. [ Time Frame: Day 0 to Day 56 ]
  • Mucosal immunogenicity: ii) Fecal IgA response to Shigella antigens: S. sonnei LPS, IpaB, IpaC, IpaD, and S. sonnei Invaplex 50. [ Time Frame: Day 0 to Day 56 ]
  • Systemic immunogenicity: i) Serum IgA and IgG response to Shigella antigens: S. sonnei Invaplex 50, LPS, IpaB, IpaC, and IpaD. [ Time Frame: Day 0 to Day 56 ]


Information By: National Institute of Allergy and Infectious Diseases (NIAID)

Dates:
Date Received: April 14, 2011
Date Started: January 2013
Date Completion:
Last Updated: October 1, 2015
Last Verified: April 2015