Shigella WRSS1 Vaccine Trial in Bangladesh

PATH16 enrolled

Overview

This is a research study of an experimental (investigational) live attenuated Shigella sonnei vaccine (WRSS1) to find a dose of the vaccine that is safe, tolerable, and develops an immune response. Shigella causes bloody and watery diarrhea, and infants and children living in developing countries experience the greatest consequences of this disease.

The WRSS1 vaccine in will be given to healthy toddlers (12-24 months old). The first vaccination was given to toddlers in the inpatient unit and the second and third doses will be administered on an outpatient basis. A safety evaluation was performed after the first dose before enrolling subjects in subsequent cohorts to receive a higher vaccine dose. After the study was initiated, its funder, the Bill and Melinda Gates Foundation (BMGF) made significant changes to the PATH Enteric Vaccine Initiative (EVI) portfolio and decided not to support the three higher-dose cohorts (Cohort 1, 2, and 3) planned as part of this study.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

PREVENTION

Masking

QUADRUPLE

Enrollment

Conditions

Diarrhea

Interventions

Shigella sonnei Strain WRSS1 VaccineBIOLOGICAL

Live attenuated, oral Shigella WRSS1 vaccine

PlaceboBIOLOGICAL

Sterile saline solution

Eligibility

Sex: ALLMin age: 12 MonthsMax age: 24 MonthsHealthy volunteers:

Medical Language ↔ Plain English

Inclusion Criteria: 1. Male or female children aged between 12 to 24 month of age at the time of vaccination 2. General good health as determined by the screening evaluation no greater than 30 days before admission 3. Father, mother or other legally acceptable representative (guardian) properly informed about the study, able to understand it and sign the informed consent form 4. Normal bowel habits (\< 3 grade 1 or 2 stools each day; ≥ 1 grade 1 or 2 stools every 2 days) 5. Free of obvious health problems as established by medical history and clinical examination before entering into the study. 6. Parent or guardian available for the entire period of the study and reachable by study staff throughout the entire follow-up period. 7. Signed Informed Consent from the Parent or legal guardian Exclusion Criteria: 1. Presence of a significant medical that in the opinion of the Investigator precludes participation in the study 2. Known infection with human immunodeficiency virus (HIV) 3. Presence in the serum of hepatitis A virus (HAV) or hepatitis C virus (HCV) antibody. 4. History of congenital abdominal disorders, intussusception, abdominal surgery or any other congenital disorder. 5. 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 child has been or will be exposed to an investigational or a non-investigational product 6. Clinically significant abnormalities on physical examination 7. Clinically significant abnormalities in screening hematology, serum chemistry as determined by the PI or the PI in consultation with the Study Physician 8. History of febrile illness within 48 hours prior to vaccination 9. Known or suspected impairment of immunological function based on medical history and physical examination 10. Prior receipt of any Shigella vaccine 11. Fever at the time of immunization. Fever is defined as a temperature ≥ 37.5C (99.5F) on axillary, oral, or tympanic measurement 12. History of known shigellosis, chronic diarrhea/dysentery in the past 2 months 13. Current use of iron or zinc supplements within the past 7 days; current use of antacids (H2 blockers, omeprazol, OTC agents) or immunosuppressive drug 14. Allergy to quinolone, sulfa, and penicillin classes of antibiotics 15. Clinical evidence of active gastrointestinal illness 16. Prior receipt of a blood transfusion or blood products, including immunoglobulins 17. 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. 18. History of any neurologic disorders or seizures. 19. Acute disease at the time of enrolment 20. Medically significant malnutrition, defined as moderate malnutrition (wt-for-age z-score between -3.0 and -2.0) and severe malnutrition (wt-for-age z-score \<-3.0 or edema) 21. 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 22. Receipt of antimicrobial drugs for any reason or a fever ≥ 38C within 7 days before vaccination 23. History of diarrhea during the 7 days before vaccination. 24. Has any household member(s) who is immunocompromised or under the age of 1 year old. 25. Culture or polymerase chain reaction (PCR) positive for any Shigella strain

Locations (1)

Mirpur Field Office

Mirpur, Bangladesh

Outcomes

Primary Outcomes

Maximum Severity of Reactogenicity by Vaccination

All toddlers were monitored for evidence of immediate reactions, assessed for systemic reactogenicity (fever, irritability, decreased appetite, and decreased activity) and gastrointestinal (GI) symptoms (abdominal pain, nausea, vomiting, loose stool, diarrhea, dysentery, bloating, excess flatulence, constipation) during the 72 hours following each vaccine dose.

Time frame: 72 hours after each vaccination (Day 3, Day 31, Day 59)

Number of Participants With Adverse Events Occurring Within 28 Days After Any Vaccination by Maximum Severity

All toddlers were monitored for the occurrence of any adverse event (AE) or serious adverse event (SAE). Toddlers visited the clinic for safety assessments approximately one month after each vaccination. Grades are based on maximum severity per participant.

Time frame: Up to 28 days after any vaccination (up to Day 84)

Secondary Outcomes

Geometric Mean Titer (GMT) of Immunoglobulin A (IgA) Antibodies in Antibody Lymphocyte Supernatant (ALS): Invaplex Antigens

The mucosal immune response to WRSS1 was evaluated by assessing specific IgA antibody responses to S. sonnei Invaplex using the 'antibodies in lymphocyte supernatant' (ALS) assay on culture supernatants of cultured peripheral blood mononuclear cells from different study days (Days 0, 7, 35, and 63) to determine Invaplex-specific IgA response from circulating lymphocytes. Invaplex is a mixture of purified S. sonnei lipopolysaccharide (LPS) and purified protein antigens IpaB and IpaC.

Time frame: Days 0, 7, 35, and 63

Geometric Mean Titer (GMT) of Immunoglobulin A (IgA) Antibodies in Lymphocyte Supernatant (ALS): Lipopolysaccharide (LPS) Antigen

The mucosal immune response to WRSS1 was evaluated by assessing specific IgA antibody responses to S. sonnei lipopolysaccharide (LPS) using the 'antibodies in lymphocyte supernatant' (ALS) assay on culture supernatants from cultured peripheral blood mononuclear cells from different study days (Days 0, 7, 35, and 63) to determine LPS-specific IgA response from circulating lymphocytes.

Data from ClinicalTrials.gov

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Time frame: Days 0, 7, 35, and 63

Geometric Mean Titer (GMT) of Immunoglobulin G (IgG) Antibodies in Antibody Lymphocyte Supernatant (ALS): Invaplex Antigen

The mucosal immune response to WRSS1 was evaluated by assessing specific IgG antibody responses to S. sonnei Invaplex using the 'antibodies in lymphocyte supernatant' (ALS) assay on culture supernatants of cultured peripheral blood mononuclear cells from different study days (Days 0, 7, 35, and 63) to determine Invaplex-specific IgG response from circulating lymphocytes. Invaplex is a mixture of purified S. sonnei lipopolysaccharide (LPS) and purified protein antigens IpaB and IpaC.

Time frame: Days 0, 7, 35, and 63

Geometric Mean Titer (GMT) of Immunoglobulin G (IgG) Antibodies in Antibody Lymphocyte Supernatant (ALS): Lipopolysaccharide (LPS)

The mucosal immune response to WRSS1 was evaluated by assessing specific IgG antibody responses to S. sonnei LPS using the 'antibodies in lymphocyte supernatant' (ALS) assay on culture supernatants of cultured peripheral blood mononuclear cells from different study days (Days 0, 7, 35, and 63) to determine LPS-specific IgG response from circulating lymphocytes.

Time frame: Days 0, 7, 35, and 63

Geometric Mean Titer (GMT) of Immunoglobulin M (IgM) Antibodies in Antibody Lymphocyte Supernatant (ALS): Invaplex Antigen

The mucosal immune response to WRSS1 was evaluated by assessing specific IgM antibody responses to S. sonnei Invaplex using the 'antibodies in lymphocyte supernatant' (ALS) assay on culture supernatants of cultured peripheral blood mononuclear cells from different study days (Days 0, 7, 35, and 63) to determine Invaplex-specific IgM response from circulating lymphocytes. Invaplex is a mixture of purified S. sonnei lipopolysaccharide (LPS) and purified protein antigens IpaB and IpaC.

Time frame: Days 0, 7, 35, and 63

Geometric Mean Titer (GMT) of Immunoglobulin M (IgM) Antibodies in Antibody Lymphocyte Supernatant (ALS): Lipopolysaccharide (LPS) Antigen

The mucosal immune response to WRSS1 was evaluated by assessing specific IgM antibody responses to S. sonnei LPS using the 'antibodies in lymphocyte supernatant' (ALS) assay on culture supernatants of cultured peripheral blood mononuclear cells from different study days (Days 0, 7, 35, and 63) to determine LPS-specific IgM response from circulating lymphocytes.

Time frame: Days 0, 7, 35, and 63

Geometric Mean Fold Change From Baseline in Immunoglobulin A (IgA) Antibodies in Antibody Lymphocyte Supernatant (ALS): Invaplex Antigens

Time frame: Baseline (Day 0, pre-vaccination) and Days 7, 35, and 63

Geometric Mean Fold Change From Baseline in Immunoglobulin A (IgA) Antibodies in Antibody Lymphocyte Supernatant (ALS): Lipopolysaccharide (LPS) Antigen

Time frame: Baseline (Day 0, pre-vaccination) and Days 7, 35, and 63

Geometric Mean Fold Change From Baseline in Immunoglobulin G (IgG) Antibodies in Antibody Lymphocyte Supernatant (ALS): Invaplex Antigen

Time frame: Baseline (Day 0, pre-vaccination) and Days 7, 35, and 63

Geometric Mean Fold Change From Baseline in Immunoglobulin G (IgG) Antibodies in Antibody Lymphocyte Supernatant (ALS): Lipopolysaccharide (LPS)

Time frame: Baseline (Day 0, pre-vaccination) and Days 7, 35, and 63

Geometric Mean Fold Change From Baseline in Immunoglobulin M (IgM) Antibodies in Antibody Lymphocyte Supernatant (ALS): Invaplex Antigen

Time frame: Baseline (Day 0, pre-vaccination) and Days 7, 35, and 63

Geometric Mean Fold Change From Baseline in Immunoglobulin M (IgM) Antibodies in Antibody Lymphocyte Supernatant (ALS): Lipopolysaccharide (LPS) Antigen

Time frame: Baseline (Day 0, pre-vaccination) and Days 7, 35, and 63

Count of Participants With 4-fold Rise From Baseline in Immunoglobulin A (IgA) Antibodies in Antibody Lymphocyte Supernatant (ALS): Invaplex Antigen

Time frame: Days 7, 35, and 63

Count of Participants With 4-fold Rise From Baseline in Immunoglobulin G (IgG) Antibodies in Antibody Lymphocyte Supernatant (ALS): Invaplex Antigen

Time frame: Days 7, 35, and 63

Count of Participants With 4-fold Rise From Baseline in Immunoglobulin M (IgM) Antibodies in Antibody Lymphocyte Supernatant (ALS): Invaplex Antigen

Time frame: Days 7, 35, and 63

Count of Participants With 4-fold Rise From Baseline in Immunoglobulin A (IgA) Antibodies in Antibody Lymphocyte Supernatant (ALS): Lipopolysaccharide (LPS) Antigen

Time frame: Days 7, 35, and 63

Count of Participants With 4-fold Rise From Baseline in Immunoglobulin G (IgG) Antibodies in Antibody Lymphocyte Supernatant (ALS): Lipopolysaccharide (LPS) Antigen

Time frame: Days 7, 35, and 63

Count of Participants With 4-fold Rise From Baseline in Immunoglobulin M (IgM) Antibodies in Antibody Lymphocyte Supernatant (ALS): Lipopolysaccharide (LPS) Antigen

Time frame: Days 7, 35, and 63

Geometric Mean Titer (GMT) of Immunoglobulin A (IgA) Antibodies in Serum: Invaplex Antigens

The systemic immune response to WRSS1 was evaluated by assessing the IgA antibody response to S. sonnei Invaplex in serum/plasma samples at Days 0, 7, 35 and 63. Invaplex is a mixture of purified S. sonnei LPS and purified protein antigens IpaB and IpaC. Serotype-specific LPS from the Walter Reed Army Institute was used to coat the enzyme-linked immunosorbent assay (ELISA) plates.

Time frame: Days 0, 7, 35, and 63

Geometric Mean Titer (GMT) of Immunoglobulin A (IgA) Antibodies in Serum: Lipopolysaccharide (LPS) Antigen

The systemic immune response to WRSS1 was evaluated by assessing the IgA antibody response to S. sonnei 2a LPS in serum/plasma samples at Days 0, 7, 35 and 63. Serotype-specific lipopolysaccharide (LPS) from the Walter Reed Army Institute was used to coat the ELISA plates.

Time frame: Days 0, 7, 35, and 63

Geometric Mean Titer (GMT) of Immunoglobulin G (IgG) Antibodies in Serum: Invaplex Antigen

The systemic immune response to WRSS1 was evaluated by assessing the IgG antibody response to S. sonnei Invaplex in serum/plasma samples at Days 0, 7, 35 and 63. Invaplex is a mixture of purified S. sonnei LPS and purified protein antigens IpaB and IpaC. Serotype-specific LPS from the Walter Reed Army Institute was used to coat the ELISA plates.

Time frame: Days 0, 7, 35, and 63

Geometric Mean Titer (GMT) of Immunoglobulin G (IgG) Antibodies in Serum: Lipopolysaccharide (LPS)

The systemic immune response to WRSS1 was evaluated by assessing the IgG antibody response to S. sonnei 2a LPS in serum/plasma samples at Days 0, 7, 35 and 63. Serotype-specific LPS from the Walter Reed Army Institute was used to coat the ELISA plates.

Time frame: Days 0, 7, 35, and 63

Geometric Mean Titer (GMT) of Immunoglobulin M (IgM) Antibodies in Serum: Invaplex Antigen

The systemic immune response to WRSS1 was evaluated by assessing the IgM antibody response to S. sonnei Invaplex in serum/plasma samples at Days 0, 7, 35 and 63. Invaplex is a mixture of purified S. sonnei LPS and purified protein antigens IpaB and IpaC. Serotype-specific LPS from the Walter Reed Army Institute was used to coat the ELISA plates.

Time frame: Days 0, 7, 35, and 63

Geometric Mean Titer (GMT) of Immunoglobulin M (IgM) Antibodies in Serum: Lipopolysaccharide (LPS) Antigen

The systemic immune response to WRSS1 was evaluated by assessing the IgM antibody response to S. sonnei 2a LPS in serum/plasma samples at Days 0, 7, 35 and 63. Serotype-specific LPS from the Walter Reed Army Institute was used to coat the ELISA plates.

Time frame: Days 0, 7, 35, and 63

Geometric Mean Fold Change From Baseline in Immunoglobulin A (IgA) Antibodies in Serum: Invaplex Antigens

Time frame: Baseline (Day 0, pre-vaccination) and Days 7, 35, and 63

Geometric Mean Fold Change From Baseline in Immunoglobulin A (IgA) Antibodies in Serum: Lipopolysaccharide (LPS) Antigen

Time frame: Baseline (Day 0, pre-vaccination) and Days 7, 35, and 63

Geometric Mean Fold Change From Baseline in Immunoglobulin G (IgG) Antibodies in Serum: Invaplex Antigen

Time frame: Baseline (Day 0, pre-vaccination) and Days 7, 35, and 63

Geometric Mean Fold Change From Baseline in Immunoglobulin G (IgG) Antibodies in Serum: Lipopolysaccharide (LPS)

Time frame: Baseline (Day 0, pre-vaccination) and Days 7, 35, and 63

Geometric Mean Fold Change From Baseline in Immunoglobulin M (IgM) Antibodies in Serum : Invaplex Antigen

Time frame: Baseline (Day 0, pre-vaccination) and Days 7, 35, and 63

Geometric Mean Fold Change From Baseline in Immunoglobulin M (IgM) Antibodies in Serum: Lipopolysaccharide (LPS) Antigen

Time frame: Baseline (Day 0, pre-vaccination) and Days 7, 35, and 63

Count of Participants With 4-fold Rise in Immunoglobulin A (IgA) Antibodies in Serum From Baseline: Invaplex Antigen

Time frame: Days 7, 35, and 63

Count of Participants With 4-fold Rise in Immunoglobulin G (IgG) Antibodies in Serum From Baseline: Invaplex Antigen

Time frame: Days 7, 35, and 63

Count of Participants With 4-fold Rise in Immunoglobulin M (IgM) Antibodies in Serum From Baseline: Invaplex Antigen

Time frame: Days 7, 35, and 63

Count of Participants With 4-fold Rise in Immunoglobulin A (IgA) Antibodies in Serum From Baseline: Lipopolysaccharide (LPS) Antigen

Time frame: Days 7, 35, and 63

Count of Participants With 4-fold Rise in Immunoglobulin G (IgG) Antibodies in Serum From Baseline: Lipopolysaccharide (LPS) Antigen

Time frame: Days 7, 35, and 63

Count of Participants With 4-fold Rise in Immunoglobulin M (IgM) Antibodies in Serum From Baseline: Lipopolysaccharide (LPS) Antigen

Time frame: Days 7, 35, and 63

Geometric Mean Titer (GMT) of Immunoglobulin A (IgA) Antibodies in Stool: Invaplex Antigen

The mucosal immune response to the WRSS1 was evaluated by assessing fecal IgA antibody responses to S. sonnei Invaplex in ELISA assays at Days 0, 7, 28, 35, 56, 63, and 84. Invaplex is a mixture of purified S. sonnei LPS and purified protein antigens IpaB and IpaC.

Time frame: Days 0, 7, 28, 35, 56, 63, and 84

Geometric Mean Titer (GMT) of Immunoglobulin A (IgA) Antibodies in Stool: Lipopolysaccharide (LPS) Antigen

The mucosal immune response to the WRSS1 was evaluated by assessing fecal IgA antibody responses to S. sonnei LPS in ELISA assays at Days 0, 7, 28, 35, 56, 63, and 84.

Time frame: Days 0, 7, 28, 35, 56, 63, and 84

Geometric Mean Fold Change From Baseline in Immunoglobulin A (IgA) Antibodies in Stool: Invaplex Antigens

Time frame: Baseline (Day 0, pre-vaccination) and Days 7, 28, 35, 56, 63, and 84

Geometric Mean Fold Change From Baseline in Immunoglobulin A (IgA) Antibodies in Stool: Lipopolysaccharide (LPS) Antigen

Time frame: Baseline (Day 0, pre-vaccination) and Days 7, 28, 35, 56, 63, and 84

Count of Participants With 4-fold Rise From Baseline in Immunoglobulin A (IgA) Antibodies in Stool: Invaplex Antigen

Time frame: Days 7, 28, 35, 56, 63, and 84

Count of Participants With 4-fold Rise From Baseline in Immunoglobulin A (IgA) Antibodies in Stool: Lipopolysaccharide (LPS) Antigen

Time frame: Days 7, 28, 35, 56, 63, and 84