Clinical trial NCT01813071: Safety Study of Live Attenuated Oral Shigella (WRSS1) Vaccine in Bangladeshi Adults and Children
Official title: A Randomized, Double-Blinded, Placebo-controlled, Dose-Escalation, Age-Descending Study to Assess the Safety and Tolerability of Live Attenuated, Oral Shigella WRSS1 (Walter Reed S. Sonnei) Vaccine in Bangladeshi Adults and Children
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Diarrhea
Keywords: Enterobacteriaceae Infections
Gram-Negative Bacterial Infections
Bacterial Infections
Gastroenteritis
Gastrointestinal Diseases
Digestive System Diseases
Intestinal Diseases
Shigellosis
Lead sponsor: PATH
Sponsor class: OTHER
Collaborators: name: International Centre for Diarrhoeal Disease Research, Bangladesh
First posted: 2013-03-18
Enrollment: 103
Sex: ALL
Minimum age (years): 5
Maximum age (years): 39
Standard ages: CHILD
ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: This is a research study about an experimental (investigational) oral Shigella sonnei - Walter Reed S. sonnei (WRSS1). WRSS1 is a live 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 39 healthy adults, ages 18-39, and 48 healthy children, ages 5-9, will participate in this study. Once the vaccine is proven safe and tolerable in adults, then it will be tested in the children. This study will require volunteers to stay in the research facility for several nights for the first dose; they will not be required to stay overnight for the second and third doses. Participants will be assigned to receive 1 of 3 vaccine dose levels 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.

Detailed description: This is a single site, double-blind, randomized, placebo-controlled, dose-escalation, age-descending study that will start testing the vaccine in healthy adults and move subsequently into school-age children. The study is designed as 2 parts, each part comprising 3 cohorts. The cohort receiving the lowest dose in Parts A and B will receive only one administration of vaccine or placebo; the subsequent two higher dose cohorts in Parts A and B will receive three administrations of vaccine or placebo. In each cohort, the first dose and immediate safety evaluation will be conducted at the International Centre for Diarrhoeal Disease Research (icddr,b) Inpatient Unit, where the participants will be admitted for observation for 72 hours. Follow-up visits for participants in A1 and B1 will take place on an outpatient basis at the Mirpur, Bangladesh (Mirpur) Field Office. Second and third vaccinations within A2, A3, B2, and B3 cohorts and all follow-up visits will take place on an outpatient basis at the Mirpur Field Office. Before enrolling participants in subsequent cohorts to receive a higher vaccine dose, or to move to the lower age group, the safety data from the previous cohort(s) (through Study Day 7) will be evaluated and reviewed by the Internal Protocol Safety Team (IPST) comprised of the study physician, the Medical Monitor from GVK Biosciences (GVK), the principal investigator, and the Medical Monitor from PATH Vaccine Solutions (PVS). Upon completion of the last adult cohort, the Data Safety Monitoring Board (DSMB -an advisory body to the Ethical Review Committee) will convene to review the cumulative safety data and IPST recommendation, and determine whether to proceed to Part B (children). Adverse events (AE)s will be graded according to standardized criteria. The immunogenicity outcome measures of interest include serum immunoglobulin G (IgG) and immunoglobulin A (IgA) antibodies by Antibodies in Lymphocyte Supernatant (ALS) assay against S. sonnei2a lipopolysaccharide (LPS), shedding profile of WRSS1, and vaccine-specific mucosal IgA responses.

The proposed study builds upon successful preliminary observations with this vaccine in the US, Israel and Thailand. While secondary objectives include studying the immunogenicity of the WRSS1 vaccine, the primary goal of the current trial is to establish a clear safety profile for the WRSS1 vaccine in adults and children 5-9 years old.The primary objective of the study is to evaluate the safety and tolerability of the vaccine; the secondary objective is to evaluate vaccine immunogenicity.

Eligibility criteria: Inclusion Criteria:

* Healthy male or female adults from 18-39 years old, inclusive
* General good health as determined by the screening evaluation no greater than 30 days before admission
* Properly informed about the study, able to understand it and sign the informed consent form
* Normal bowel habits (\< 3 grade 1 or 2 stools each day; ≥ 1 grade 1 or 2 stools every 2 days)
* Free of obvious health problems as established by medical history and clinical examination before entering into the study.
* Available for the entire period of the study and reachable by study staff throughout the entire follow-up period
* Females of childbearing potential who are willing to take a serum pregnancy test at screening and urine pregnancy tests before each vaccination. Pregnancy tests must be negative before each vaccination. Females of childbearing potential must agree to use an efficacious hormonal or barrier method of birth control during the study. Abstinence is also acceptable.
* Signed Informed Consent

Exclusion Criteria:

* Presence of a significant medical or psychiatric condition that in the opinion of the Investigator precludes participation in the study
* Known infection with Hepatitis C or Human Immunodeficiency Virus (HIV)
* History of congenital abdominal disorders, intussusception, abdominal surgery or any other congenital disorder.
* Participation in research involving another investigational product (defined as receipt of investigational product) 30 days before planned date of first vaccination or concurrently participating in another clinical study, at any time during the study period, in which the participant has been or will be exposed to an investigational or a non-investigational product
* Clinically significant abnormalities on physical examination
* Clinically significant abnormalities in screening hematology, serum chemistry, or urinalysis as determined by the PI or the PI in consultation with the Study Physician
* History of febrile illness within 48 hours prior to vaccination
* Known or suspected impairment of immunological function based on medical history and physical examination
* Prior receipt of any Shigella vaccine
* Fever at the time of immunization. Fever is defined as a temperature ≥ 37.5 degrees Celsius (99.5 degrees Fahrenheit) on axillary, oral, or tympanic measurement
* Clinical evidence of active gastrointestinal illness
* Prior receipt of a blood transfusion or blood products, including immunoglobulins
* Presence of any significant systemic disorder (cardiovascular, pulmonary, hepatic, renal, gastrointestinal, endocrine, immunological, dermatological, neurological, cancer or autoimmune disease) as determined by medical history and/or physical examination which would endanger the participant's health or is likely to result in non-conformance to the protocol.
* History of any neurologic disorders or seizures.
* Acute disease at the time of enrolment
* Evidence of current excessive alcohol consumption
* Evidence of current illicit drug use or drug dependence
* Current use of iron or zinc supplements within the past 7 days; current use of antacids (Histamine H2-receptor antagonists (H2 blockers), Omeprazole, over the counter (OTC) agents) or immunosuppressive drug
* Allergy to quinolone, sulfa, and penicillin classes of antibiotics
* History of any of the following conditions within the past 10 years:

  1. Arthritis (two or more episodes of joint pain and swelling)
  2. Gastrointestinal disease (diagnosed by a doctor as having irritable bowel disease, Crohn's disease, ulcerative colitis (biopsy confirmed), celiac disease, stomach or intestinal ulcers
  3. Dyspepsia (indigestion or heartburn requiring medication more than once per week)
  4. History of gallbladder disease
  5. History of chronic heart disease
* Any conditions which, in the opinion of the investigator, might jeopardize the safety of study participants or interfere with the evaluation of the study objectives
* Receipt of antimicrobial drugs for any reason or a fever ≥ 38 degrees Celsius within 7 days before vaccination
* History of diarrhea during the 7 days before vaccination.
* Has any household member(s) who is immunocompromised or under the age of 2 years old.

Primary outcomes:
measure: Number and Percentage of Participants With Serious Adverse Events (SAEs)
timeFrame: Day -1(admission day) through 6 months (Day 224 +/- 14 days) after the third vaccination for Cohorts A2,A3, B2, B3, B4, and after the first vaccination (Day 168 +/- 14 days) for Cohorts A1 and B1.
measure: Number and Percentage of Participants With Any Non-serious Unsolicited Adverse Events
timeFrame: Day -1(admission day) through 6 months (Day 224 +/- 14 days) after the third vaccination for Cohorts A2,A3, B2, B3, B4, and after the first vaccination (Day 168 +/- 14 days) for Cohorts A1 and B1.
measure: Number and Percentage of Participants With Solicited Systemic and Intestinal Reactions
timeFrame: Day 0 through Day 7 after any vaccination
measure: Number and Percentage of Participants With Any Unsolicited AEs and SAEs Judged as Having a Reasonable Possibility That the Study Product Caused the Event
timeFrame: SAEs at any time and AEs after any vaccination until Day 168 (Cohort A1, B1) and Day 224 (all other Cohorts).
Secondary outcomes:
measure: Number and Percentage of Participants With a 4-fold Rise From Baseline in Immunoglobulin A (IgA) Antibodies in Antibody Titers in Lymphocyte Supernatant (ALS)
timeFrame: Day 7
measure: Number and Percentage of Participants With a 4-fold Rise From Baseline in IgA Antibodies in ALS
timeFrame: Day 35
measure: Number and Percentage of Participants With a 4-fold Rise From Baseline in IgA Antibodies in ALS
timeFrame: Day 63
measure: Number and Percentage of Participants With a 4-fold Rise From Baseline in IgA Antibodies in ALS
timeFrame: At any time (Day 7 to Day 63)
measure: Number and Percentage of Participants With a 4-fold Rise From Baseline in Immunoglobulin G (IgG ) IgG Antibodies in ALS
timeFrame: Day 7
measure: Number and Percentage of Participants With a 4-fold Rise From Baseline in IgG Antibodies in ALS
timeFrame: Day 35
measure: Number and Percentage of Participants With a 4-fold Rise From Baseline in IgG Antibodies in ALS: Invaplex
timeFrame: Day 63
measure: Number and Percentage of Participants With a 4-fold Rise From Baseline in IgG Antibodies in ALS: Lipopolysaccharide (LPS)
timeFrame: Day 63
measure: Number and Percentage of Participants With a 4-fold Rise From Baseline in IgG Antibodies in ALS
timeFrame: At any time (Day 7 to Day 63)
measure: Number and Percentage of Child Participants With a 4-fold Rise From Baseline in IgM Antibodies in ALS
timeFrame: Day 7
measure: Number and Percentage of Child Participants With a 4-fold Rise From Baseline in IgM Antibodies in ALS: Invaplex
timeFrame: Day 35
measure: Number and Percentage of Child Participants With a 4-fold Rise From Baseline in IgM Antibodies in ALS: LPS
timeFrame: Day 35
measure: Number and Percentage of Child Participants With a 4-fold Rise From Baseline in IgM Antibodies in ALS: Invaplex
timeFrame: Day 63
measure: Number and Percentage of Child Participants With a 4-fold Rise From Baseline in IgM Antibodies in ALS : LPS
timeFrame: Day 63
measure: Number and Percentage of Child Participants With a 4-fold Rise From Baseline in IgM Antibodies in ALS
timeFrame: At any time (Day 7 to Day 63)
measure: Number and Percentage of Participants With a 4-fold Rise From Baseline in IgA Antibodies in Serum
timeFrame: Day 7
measure: Number and Percentage of Participants With a 4-fold Rise From Baseline in IgA Antibodies in Serum
timeFrame: Day 28
measure: Number and Percentage of Participants With a 4-fold Rise From Baseline in IgA Antibodies in Serum
timeFrame: Day 35
measure: Number and Percentage of Participants With a 4-fold Rise From Baseline in IgA Antibodies in Serum
timeFrame: Day 56
measure: Number and Percentage of Participants With a 4-fold Rise From Baseline in IgA Antibodies in Serum
timeFrame: Day 63
measure: Number and Percentage of Participants With a 4-fold Rise From Baseline in IgA Antibodies in Serum
timeFrame: Day 84
measure: Number and Percentage of Participants With a 4-fold Rise From Baseline in IgA Antibodies in Serum
timeFrame: At any time (Day 7 to Day 84)
measure: Number and Percentage of Participants With a 4-fold Rise From Baseline in IgG Antibodies in Serum
timeFrame: Day 7
measure: Number and Percentage of Participants With a 4-fold Rise From Baseline in IgG Antibodies in Serum
timeFrame: Day 28
measure: Number and Percentage of Participants With a 4-fold Rise From Baseline in IgG Antibodies in Serum
timeFrame: Day 35
measure: Number and Percentage of Participants With a 4-fold Rise From Baseline in IgG Antibodies in Serum
timeFrame: Day 56
measure: Number and Percentage of Participants With a 4-fold Rise From Baseline in IgG Antibodies in Serum
timeFrame: Day 63
measure: Number and Percentage of Participants With a 4-fold Rise From Baseline in IgG Antibodies in Serum
timeFrame: Day 84
measure: Number and Percentage of Participants With a 4-fold Rise From Baseline in IgG Antibodies in Serum
timeFrame: At any time (Day 7 to Day 84)
measure: Number and Percentage of Child Participants With a 4-fold Rise From Baseline in (Immunoglobulin M) IgM Antibodies in Serum
timeFrame: Day 7
measure: Number and Percentage of Child Participants With a 4-fold Rise From Baseline in IgM Antibodies in Serum
timeFrame: Day 28
measure: Number and Percentage of Child Participants With a 4-fold Rise From Baseline in IgM Antibodies in Serum
timeFrame: Day 35
measure: Number and Percentage of Child Participants With a 4-fold Rise From Baseline in IgM Antibodies in Serum
timeFrame: Day 56
measure: Number and Percentage of Child Participants With a 4-fold Rise From Baseline in IgM Antibodies in Serum
timeFrame: Day 63
measure: Number and Percentage of Child Participants With a 4-fold Rise From Baseline in IgM Antibodies in Serum
timeFrame: Day 84
measure: Number and Percentage of Child Participants With a 4-fold Rise From Baseline in IgM Antibodies in Serum
timeFrame: At any time (Day 7 to Day 84)
measure: Number and Percentage of Adult Participants With a 2-fold Rise From Baseline in IgA and IgG Antibodies in ASC
timeFrame: Day 7
measure: Number and Percentage of Adult Participants With a 2-fold Rise From Baseline in IgA and IgG Antibodies in ASC
timeFrame: Day 35
measure: Number and Percentage of Adult Participants With a 2-fold Rise From Baseline in IgA and IgG Antibodies in ASC
timeFrame: Day 63
measure: Number and Percentage of Adult Participants With a 2-fold Rise From Baseline in IgA and IgG Antibodies in ASC
timeFrame: At any time (Day 7 to Day 63)
measure: Number and Percentage of Participants With a 4-fold Rise From Baseline in IgA Antibodies in Stool
timeFrame: Day 7
measure: Number and Percentage of Participants With a 4-fold Rise From Baseline in IgA Antibodies in Stool
timeFrame: Day 28
measure: Number and Percentage of Participants With a 4-fold Rise From Baseline in IgA Antibodies in Stool
timeFrame: Day 35
measure: Number and Percentage of Participants With a 4-fold Rise From Baseline in IgA Antibodies in Stool
timeFrame: Day 56
measure: Number and Percentage of Participants With a 4-fold Rise From Baseline in IgA Antibodies in Stool
timeFrame: Day 63
measure: Number and Percentage of Participants With a 4-fold Rise From Baseline in IgA Antibodies in Stool
timeFrame: Day 84
measure: Number and Percentage of Participants With a 4-fold Rise From Baseline in IgA Antibodies in Stool
timeFrame: At any time (Day 7 to Day 84)
measure: Number and Percentage of Participants With a 4-fold Rise From Baseline in Ratio of Specific IgA to Total IgA Antibodies in Stool
timeFrame: Day 7
measure: Number and Percentage of Participants With a 4-fold Rise From Baseline in Ratio of Specific IgA to Total IgA Antibodies in Stool
timeFrame: Day 28
measure: Number and Percentage of Participants With a 4-fold Rise From Baseline in Ratio of Specific IgA to Total IgA Antibodies in Stool
timeFrame: Day 35
measure: Number and Percentage of Participants With a 4-fold Rise From Baseline in Ratio of Specific IgA to Total IgA Antibodies in Stool
timeFrame: Day 56
measure: Number and Percentage of Participants With a 4-fold Rise From Baseline in Ratio of Specific IgA to Total IgA Antibodies in Stool
timeFrame: Day 63
measure: Number and Percentage of Participants With a 4-fold Rise From Baseline in Ratio of Specific IgA to Total IgA Antibodies in Stool
timeFrame: Day 84
measure: Number and Percentage of Participants With a 4-fold Rise From Baseline in Ratio of Specific IgA to Total IgA Antibodies in Stool
timeFrame: At any time (Day 7 to Day 84)
measure: Number and Percentage of Adult Participants With WRSS1 Shedding at Any Time After Vaccination
timeFrame: At any time (Day 0 to Day 84)
Other outcomes:
Locations:
city: Dhaka
country: Bangladesh
facility: Icddr,B
Study officials:
affiliation: International Centre for Diarrhoeal Disease Research, Bangladesh
name: Rubhana Raqib, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Sarker P, Mily A, Ara A, Haque F, Maier N, Wierzba TF, Walker RI, Venkatesan MM, Raqib R. Functional Antibodies and Innate Immune Responses to WRSS1, a Live Oral Shigella sonnei Vaccine Candidate, in Bangladeshi Adults and Children. J Infect Dis. 2021 Dec 20;224(12 Suppl 2):S829-S839. doi: 10.1093/infdis/jiab395.