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Safety Study of Inactivated Shigella Whole Cell Vaccine in Adults

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01509846
Recruitment Status : Completed
First Posted : January 13, 2012
Last Update Posted : February 5, 2013
Information provided by (Responsible Party):

Brief Summary:
This is a research study about an experimental (investigational) oral inactivated whole cell Shigella flexneri 2a killed vaccine (Sf2aWC). Sf2aWC is a killed vaccine that is being made to prevent disease from Shigella., which causes bloody, watery diarrhea. Infants and children living in developing countries experience the greatest consequences of this disease. The purpose of this study is to find a dose of the vaccine that is safe, tolerable, and develops an immune response. About 82 healthy adults, ages 18-45, will participate in this study. This study will require volunteers to stay in the research facility for several nights for the first dose. Participants in Cohorts 2, 3, and 4 will not be required to stay overnight for the second and third doses. Participants will be assigned to receive 1 of 4 vaccine doses by mouth. Study procedures include: stool samples, blood samples and documenting side effects. Participants will be involved in study related procedures for about 8 months.

Condition or disease Intervention/treatment Phase
Shigellosis Biological: Shigella flexneri 2a whole cell killed vaccine (Sf2aWC) Phase 1

Detailed Description:
Despite the public health burden of Shigella spp. on travelers, deployed soldiers and, most significantly, young children in the developing world, there is no licensed vaccine against Shigella. The rationale for using Shigella flexneri 2a whole cell killed vaccine (Sf2aWC), is that it is expected to be especially well tolerated by subjects. If Sf2aWC is safe and immunogenic, it may be combined with S. sonnei and S. flexneri 3a as the basis of a multivalent vaccine, because these three components should cover up to 80% of shigella infections in developing countries and over 90% in developed countries. This is a single site, Phase 1, double-blind, randomized, placebo-controlled, dose-escalation study in healthy adult subjects. Approximately 82 subjects will be enrolled into four separate cohorts and will be randomized to receive Sf2aWC or placebo. The placebo preparation will be bicarbonate buffer. Cohort 1 subjects will receive a single oral dose of Sf2aWC (2.6±0.8 x 10^8 vp/mL) or placebo. Dosing and 72 hours of supervised post-vaccination safety follow-up will be conducted in the CIR Inpatient Unit. Before enrolling subjects in subsequent cohorts, safety data from the previous Cohort(s) through Study Day 7 will be evaluated and reviewed by the Safety Review Committee (SRC). Cohorts 2, 3, and 4 participants will receive three doses of Sf2aWC vaccine or placebo at 0, 1 and 2 months. The first immunization will be administered in the CIR inpatient unit, followed by 72 hours of direct post-immunization observation. If after review by the SRC the first dose appears safe and well tolerated, subsequent doses will be administered on an outpatient basis. Safety will be assessed by solicited symptoms/subject memory aid and laboratory evaluations. Adverse events (AE)s will be graded according to standardized criteria. The immunogenicity outcome measures of interest include serum IgG and IgA antibodies by ELISA against S. flexneri 2a LPS and S. flexneri 2a invasive protein antigens (Ipa), cytokine assays, B and T cell memory responses, and vaccine-specific IgA responses. The proposed sample size of twenty per group in Cohorts 2, 3, and 4 would be sufficient to select the appropriate dose to move into the next study phase, providing that a difference in the immunogenicity between the two arms is 20% or greater. Participants will include 82 healthy adult male and female subjects, ages 18 to 45 inclusive. The primary objective of this study is to assess the safety and tolerability of Sf2aWC vaccine when administered in three oral doses over a range of dose levels in healthy adult subjects. The secondary objective is to assess the immunogenicity of the Sf2aWC vaccine over a range of doses in healthy adult subjects.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 82 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Phase 1 Study to Evaluate the Safety, Tolerability, and Immunogenicity of an Oral Inactivated Whole Cell Shigella Flexneri 2a Vaccine in Healthy Adult Subjects
Study Start Date : March 2011
Actual Primary Completion Date : December 2012
Actual Study Completion Date : December 2012

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Experimental: Cohort 4
Three oral doses of 2.6±0.8 x 10^11 vp/mL (20 participants) or placebo (5 participants).
Biological: Shigella flexneri 2a whole cell killed vaccine (Sf2aWC)
2.6±0.8 x 10^11 administered on Days 0, 28, and 56

Experimental: Cohort 3
Three oral doses of 2.6±0.8 x 10^10 vp/mL (20 participants) or placebo (5 participants).
Biological: Shigella flexneri 2a whole cell killed vaccine (Sf2aWC)
2.6±0.8 x 10^10 vp/mL administered on Days 0, 28, and 56

Experimental: Cohort 2
Three oral doses of 2.6±0.8 x 10^9 vp/mL (20 participants) or placebo (5 participants).
Biological: Shigella flexneri 2a whole cell killed vaccine (Sf2aWC)
2.6±0.8 x 10^9 vp/mL administered on Days 0, 28, and 56

Experimental: Cohort 1
One oral dose of 2.6±0.8 x 10^8 vp/mL (5 participants) or placebo (2 participants).
Biological: Shigella flexneri 2a whole cell killed vaccine (Sf2aWC)
2.6±0.8 x 10^8 vp/mL Sf2aWC administered on Day 0

Primary Outcome Measures :
  1. Safety [ Time Frame: 6 months after the 3rd vaccination ]
    Local and systemic reactogenicity will be assessed post-vaccination using targeted physical examinations, vital signs and clinical laboratory tests, and diary cards (to be completed following discharge daily through Day 7). The primary reactogenicity of fever, headache, malaise, and defined symptoms and signs for gastroenteritis and reactive arthritis will be evaluated daily through Day 7. For Cohorts 2, 3, and 4, doses 2 and 3 will be administered on an outpatient basis and daily diary cards will be utilized through Day 7 after each immunization.

Secondary Outcome Measures :
  1. Immunogenicity [ Time Frame: Baseline through 112 days post-vaccination ]
    ALS/ASC assays and measures of T cell response and B cell memory. B cell assays will be carried out with specimens obtained within 24 hours prior to vaccination and 7 days following each vaccination. Cytokine assays will be carried out with specimens obtained prior to initial vaccination and approximately 8, 24, 48, and 72 hours later. Cytokine assays will also be performed using specimens obtained from Cohorts 2, 3, and 4 subjects 2 days following the third vaccination. In Cohorts 2, 3, and 4, B cell memory will be assessed prior to first vaccination and on Day 112.

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 45 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes

Inclusion Criteria:

  • Healthy adults, male or female, age 18 to 45 years (inclusive) at the time of enrollment.
  • Completion and review of comprehension test (achieved >70% accuracy).
  • Signed informed consent form.
  • Available for the required follow-up period and scheduled clinic visits.
  • Negative urine pregnancy test before each vaccination for female subjects of childbearing potential. Females of childbearing potential must agree to use an efficacious hormonal or barrier method of birth control during the study. Abstinence is also acceptable.

Exclusion Criteria:

  • Presence of a significant medical or psychiatric condition that in the opinion of the investigator precludes participation in the study. Some medical conditions, that are adequately treated and stable, would not preclude entry into the study. These conditions might include stable asthma, hypertension or depression controlled with medication.
  • Clinically significant abnormalities on physical examination.
  • Clinically significant abnormalities in screening hematology, serum chemistry, or urinalysis as determined by PI or PI in consultation with Medical Monitor.
  • History of febrile illness within 48 hours prior to vaccination.
  • BMI <19 or >34.
  • Positive blood test for HBsAG, HCV, HIV-1, HLA-B27.
  • Women currently nursing.
  • History of reactive arthritis.
  • Evidence of current excessive alcohol consumption
  • Evidence of current drug use or drug dependence.
  • Regular use of anti-diarrheal, anti-constipation, or antacid therapy (excluding use associated with spicy meals).
  • Abnormal stool pattern (fewer than 3 stools per week or more than 3 stools per day) on a regular basis; loose or liquid stools on other than an occasional basis.
  • Personal or family history of an inflammatory arthritis.
  • History of allergy to soy products.
  • History of microbiologically confirmed Shigella infection within 3 years.
  • Prior receipt of experimental Shigella vaccine or live Shigella challenge within 3 years.
  • Symptoms of travelers' diarrhea associated with travel to countries where Shigella or other enteric infections are endemic (most of the developing world) within 1 year prior to dosing.
  • Occupation involving handling of Shigella bacteria currently, or in the past 3 years.
  • History of diarrhea during the 7 days before vaccination.
  • Use of antibiotics during the 7 days before vaccination.
  • Use of proton pump inhibitors, H2 blockers, or antacids within 48 hours prior to dosing.
  • Inability to comply with inpatient rules and regulations.
  • Use of immunosuppressive and/or immunomodulative drugs such as corticosteroids or chemotherapeutics that may influence antibody development.
  • Participation in research involving another investigational product (defined as receipt of investigational product or exposure to invasive investigational device) 30 days before planned date of first vaccination.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01509846

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United States, Maryland
Center for Immunization Research (CIR) at Johns Hopkins School of Public Health (JHSPH)
Baltimore, Maryland, United States, 21224
Johns Hopkins University CIR Isolation Unit
Baltimore, Maryland, United States, 21224
Sponsors and Collaborators
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Principal Investigator: Clayton D Harro, MD, ScM Johns Hopkins Bloomberg School of Public Health
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Responsible Party: PATH Identifier: NCT01509846    
Other Study ID Numbers: VAC 001
First Posted: January 13, 2012    Key Record Dates
Last Update Posted: February 5, 2013
Last Verified: January 2012
Keywords provided by PATH:
whole cell
Additional relevant MeSH terms:
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Dysentery, Bacillary
Enterobacteriaceae Infections
Gram-Negative Bacterial Infections
Bacterial Infections
Gastrointestinal Diseases
Digestive System Diseases
Intestinal Diseases
Immunologic Factors
Physiological Effects of Drugs