Study of 10-valent Pneumococcal Conjugate Vaccine (Pneumosil) Administered in a 2+1 Schedule to Healthy Infants

Study Overview
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Brief Summary
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The primary objectives of this study are to evaluate the immunogenicity (antibody response) and safety and tolerability of a 2-dose primary series and booster dose (2+1 schedule) of Pneumosil co-administered with routine pediatric vaccines in healthy infants in The Gambia.

Detailed Description
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This study will provide data necessary to evaluate the safety and immunogenicity of Pneumosil when administered in an alternative schedule to the 3 dose primary schedule (3+0) evaluated in the Phase 3 pivotal trial (VAC-056; NCT03197376) - namely in a 2 dose primary and booster (2+1) schedule - and compare immunogenicity to that of both currently licensed second-generation pneumococcal conjugate vaccines (Synflorix and Prevenar 13) administered in the same 2+1 schedule. In this prospective, single center, randomized, active-controlled, observer-blind, Phase 3 descriptive study, 660 healthy Gambian pneumococcal conjugate vaccine (PCV)-naïve infants will be randomized 1:1:1 to receive 3 doses of either Pneumosil, Synflorix or Prevenar 13 at 6 weeks, 14 weeks and 9-10 months of age. Standard Expanded Program on Immunization (EPI) vaccinations in The Gambia will be given concomitantly with all 3 doses of study vaccine. The booster vaccination window was extended up to 18 months of age due to a pause in the study due to the coronavirus disease 2019 (COVID-19) pandemic. The study schedule for participants is as follows: Age 6 weeks: First primary vaccination dose administered Age 14 weeks: Second primary vaccination dose administered (8 weeks after first primary dose) Age 18 weeks: Blood sample for immunogenicity testing (4 weeks after second primary dose) Age 9-18 months: Blood sample for immunogenicity testing and booster vaccination dose administered Age 10-19 months: Blood sample for immunogenicity testing (4 weeks after booster dose)

Official Title
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A Phase 3, Randomized, Observer-Blind Study to Evaluate the Safety, Tolerability, Immunogenicity of Serum Institute of India's 10-Valent Pneumococcal Conjugate Vaccine (PNEUMOSIL®) Administered in a 2+1 Schedule to Healthy Infants in The Gambia

Conditions
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Pneumonia, Pneumococcal

Intervention / Treatment
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* Biological: Pneumosil
* Biological: Prevenar 13
* Biological: Synflorix


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy infants based on medical history and clinical assessment. Between 6 and 8 weeks (ie 42 to 56 days) old, inclusive. Subject's parent must provide voluntary written/thumb-printed informed consent and be willing to comply with study requirements and procedures. Subjects must have been born full-term, have a weight-to-height Z score of ≥ -2 at the time of enrollment (WHO child growth standard), and be ≥ 3.5 kg at randomization. Subject's parents must be available for the duration of trial participation Exclusion Criteria: Use of any investigational medicinal product prior to randomization. Previous vaccination against or infection with S. pneumoniae. History of anaphylactic shock or an allergic reaction to any prior vaccination. Any fever, illness (including malaria). Receipt of another study vaccine within 30 days of study start. Chronic administration of an immunosuppressant or administration of immunoglobulins History of blood disorder, primary immunodeficiency, or a sibling who has such a diagnosis or who died suddenly without apparent cause. History of meningitis, seizures or any neurological disorder. Exposure to human immunodeficiency virus (HIV) by history.

Ages Eligible for Study
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Minimum Age: 42 Days
Maximum Age: 56 Days

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pneumosil<br>Infants received two primary vaccinations with Pneumosil, the first at age 6 weeks and the second at age 14 weeks. A booster vaccination was given between 9 and 16 months of age. | Biological: Pneumosil<br>* One single dose contains 2 μg of polysaccharide for serotypes 1, 5, 6A, 7F, 9V, 14, 19A, 19F and 23F, and 4 μg for serotype 6B formulated with aluminium phosphate as an adjuvant in an appropriate buffer<br>* Other names: Serum Institute of India Pneumococcal conjugate vaccine (SIIPL-PCV );|
| Active Comparator: Synflorix<br>Infants received two primary vaccinations with Synflorix, the first at age 6 weeks and the second at age 14 weeks. A booster vaccination was given between 9 and 16 months of age. | Biological: Synflorix<br>* One single dose contains 1 μg of polysaccharide for serotypes 1, 5, 6B, 7F, 9V, 14, and 23F, and 3μg of serotypes 4, 18C, and 19F formulated with aluminum phosphate as an adjuvant.<br>* Other names: Pneumococcal polysaccharide conjugate vaccine (adsorbed);|
| Active Comparator: Prevenar 13<br>Infants received two primary vaccinations with Prevenar 13, the first at age 6 weeks and the second at age 14 weeks. A booster vaccination was given between 9 and 16 months of age. | Biological: Prevenar 13<br>* One single dose contains 2.2 µg of the following pneumococcal polysaccharides serotypes - 1, 3, 4, 5, 6A, 7F, 9V, 14, 18C, 19A, 19F, 23F - and 4.4 µg of pneumococcal polysaccharide serotype 6B, all conjugated to CRM197 and absorbed onto aluminum phosphate<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Geometric Mean Concentration (GMC) of Serotype-specific Immunoglobulin G (IgG) Antibodies Four Weeks Post-Booster | The IgG antibody concentration to each of the 10 serotypes contained in Pneumosil was measured by enzyme-linked immunosorbent assay (ELISA) in serum samples collected 4 weeks after the booster dose (Visit 6). The pneumococcal serotype-specific IgG ELISAs were performed using the World Health Organisation (WHO) reference assay at the WHO Pneumococcal Serology Reference Laboratory, at the Institute of Child Health, University College London, United Kingdom (UK), where the assay was validated. | 4 weeks post booster dose | 
| Number of Participants With Solicited Local and Systemic Adverse Events (AEs) Through Day 6 Following Any Vaccination | Solicited local reactions included tenderness, erythema/redness and induration/swelling at the study vaccine injection site. Solicited systemic reactions included cutaneous rash, fever (based on axillary temperature), irritability, drowsiness, and decreased appetite. The severity of all solicited AEs was graded from mild (Grade 1) to potentially life threatening (Grade 4), based on protocol-defined criteria that were derived from Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (Version 2.0, November 2014). | Day 0 to Day 6 after each vaccination | 
| Number of Participants With Unsolicited Treatment-emergent Adverse Events (TEAEs) | AEs include any intercurrent illness or injury during the study, clinically significant worsening of a preexisting condition, and any solicited AE that occurred or was ongoing 6 days after study vaccine administration. A TEAE is an event that was not present prior to administration of the study vaccine, or increased in intensity after administration of the study vaccine. Unsolicited AEs were graded using the scale below: Grade 1: Mild; asymptomatic or mild symptoms; intervention not indicated. Grade 2: Moderate; minimal, local, or noninvasive intervention indicated. Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling. Grade 4: Life-threatening consequences; urgent intervention indicated. Grade 5: Death related to AE. Related AEs are AEs where the Investigator determined a reasonable causal relationship between the vaccine administered and the AE based on medical judgement. | AEs were collected from first dose at age 6 weeks up to 9 months of age, and then from the date of the booster vaccination through 4 weeks post vaccination; approximately 8.5 months overall. | 
| Number of Participants With Serious Adverse Events (SAEs) | An SAE was a specific AE that: Resulted in death. Was life-threatening. Required inpatient hospitalization or prolongation of an existing hospitalization. Resulted in a persistent or significant disability or incapacity. Resulted in a congenital anomaly or birth defect | SAEs were collected from first dose at age 6 weeks up to 4 weeks post booster vaccination, approximately 15.5 months overall. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Geometric Mean Titers (GMT) of Serotype-specific Opsonophagocytic Activity (OPA) Four Weeks Post-Booster | The functional activity of the antibody response to the 10 serotypes contained in Pneumosil was determined in serum samples collected 4 weeks after the booster dose in a subset of 50 participants per group. This activity was determined using the 4-fold multiplexed opsonophagocytic assay (MOPA) developed at the University of Alabama at Birmingham, and performed at the WHO Pneumococcal Serology Reference Laboratory, at the Institute of Child Health, University College London, UK, where the assay was validated. A higher titer indicates increased antibody-mediated opsonophagocytosis. | 4 weeks post booster dose | 
| Percentage of Participants With Serotype-specific Serum IgG Antibody Concentrations ≥ 0.35 μg/mL Four Weeks Post-Booster | The seroresponse rate was defined as the percentage of infants with serotype-specific IgG antibody concentrations of at least 0.35 μg/mL, which is the reference concentration for assessment of vaccine efficacy against invasive pneumococcal diseases (IPDs). The IgG concentration to each of the 10 serotypes contained in Pneumosil was measured by ELISA in serum samples collected 4 weeks after the booster dose. | 4 weeks post booster dose | 
| Percentage of Participants With Serotype-specific Serum IgG Antibody Concentrations ≥ 1.0 μg/mL Four Weeks Post-Booster | Seroresponse rate was also defined as the percentage of infants with serotype-specific IgG antibody concentrations of at least 1.0 μg/mL. The IgG concentration to each of the 10 serotypes contained in Pneumosil was measured by ELISA in serum samples collected 4 weeks after the booster dose. | 4 weeks post booster dose | 
| Percentage of Participants With Serotype-specific Serum OPA Titers ≥ 8 Four Weeks Post-Booster | The OPA seroresponse rate was defined as the percentage of infants with an OPA titer of at least 8. Opsonophagocytic activity was measured using the 4-fold multiplexed opsonophagocytic assay (MOPA) from serum samples taken 4 weeks after the booster vaccination. | 4 weeks post booster dose | 
| Percentage of Participants With Serotype-specific Serum IgG Antibody Concentrations ≥ 0.35 μg/mL Four Weeks After Completion of Primary Vaccinations | The seroresponse rate was defined as the percentage of infants with serotype-specific IgG antibody concentrations of at least 0.35 μg/mL, which is the reference concentration for assessment of vaccine efficacy against invasive pneumococcal diseases (IPDs). The IgG concentration to each of the 10 serotypes contained in Pneumosil was measured by ELISA in serum samples collected 4 weeks after the second primary vaccination dose. | 4 weeks after completion of primary vaccinations (at age 18 weeks) | 
| Geometric Mean Concentration of Serotype-specific IgG Antibodies Four Weeks After Completion of Primary Vaccinations | The IgG antibody concentration to each of the 10 serotypes contained in Pneumosil was measured by ELISA in serum samples collected 4 weeks after the second primary vaccination dose. | 4 weeks after completion of primary vaccinations (at age 18 weeks) | 
| Percentage of Participants With Serotype-specific Serum OPA Titers ≥ 8 Four Weeks After Completion of Primary Vaccinations | The OPA seroresponse rate was defined as the percentage of infants with an OPA titer of at least 8. Opsonophagocytic activity was measured using the 4-fold multiplexed opsonophagocytic assay (MOPA). | 4 weeks after completion of primary vaccinations (at age 18 weeks) | 
| Geometric Mean Titers of Serotype-specific Serum OPA Four Weeks After Primary Vaccinations | Opsonophagocytic activity was measured using the 4-fold multiplexed opsonophagocytic assay (MOPA). | 4 weeks after completion of primary vaccinations (at age 18 weeks) | 
| Percentage of Participants With Serotype-specific Serum IgG Concentrations ≥ 0.35 μg/mL Prior to Booster | The seroresponse rate was defined as the percentage of infants with serotype-specific IgG concentrations of at least 0.35 μg/mL, which is the reference concentration for assessment of vaccine efficacy against invasive pneumococcal diseases (IPDs). The IgG concentration to each of the 10 serotypes contained in Pneumosil was measured by ELISA in serum samples collected immediately prior to the booster vaccination dose. | Prior to the booster dose at approximately 9 to 16 months of age | 
| Geometric Mean Concentration of Serotype-specific Serum IgG Antibodies Prior to Booster | The IgG antibody concentration to each of the 10 serotypes contained in Pneumosil was measured by ELISA in serum samples collected immediately prior to the booster vaccination dose. | Prior to the booster dose at approximately 9 to 16 months of age | 
| Percentage of Participants With Serotype-specific Serum OPA Titers ≥ 8 Prior to Booster | The OPA seroresponse rate was defined as the percentage of infants with an OPA titer of at least 8. Opsonophagocytic activity was measured using the 4-fold multiplexed opsonophagocytic assay (MOPA) from serum samples collected immediately prior to the booster vaccination dose. | Prior to the booster dose at approximately 9 to 16 months of age | 
| Geometric Mean Titer of Serotype-specific Serum OPA Prior to Booster | Opsonophagocytic activity was measured using the 4-fold multiplexed opsonophagocytic assay (MOPA) from serum samples collected immediately prior to the booster vaccination dose. | Prior to the booster dose at approximately 9 to 16 months of age | 
| Ratio of Serotype-specific Serum IgG GMC 4 Weeks Post-Booster to Serotype-specific IgG GMC 4 Weeks After Completion of Primary Vaccinations | Booster response was measured by the ratio of IgG GMCs measured at the post-booster visit to those measured 4 weeks after completion of primary vaccinations. | 4 weeks after completion of primary vaccinations (at age 18 weeks) and 4 weeks post booster | 
| Ratio of Serotype-specific Serum OPA GMT 4 Weeks Post-Booster to Serotype-specific OPA GMT 4 Weeks After Completion of Primary Vaccinations | OPA booster response was measured by the ratio of OPA GMTs measured at the post-booster visit to those measured 4 weeks after completion of primary vaccinations. | 4 weeks after completion of primary vaccinations (at age 18 weeks) and 4 weeks post booster |