Phase 3 Study of 10-valent Pneumococcal Conjugate Vaccine (PNEUMOSIL) in Healthy Infants

Study Overview
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Brief Summary
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This study will examine the consistency of 3 batches of the Pneumosil vaccine by looking at the immune response in infants. In addition, the study will compare the immunogenicity of the Pneumosil vaccine to another WHO-prequalified vaccine, Synflorix.

Detailed Description
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This is a randomized, active-controlled, double-blind, Phase 3 study in 2,250 healthy infants (6 to 8 weeks of age). Subjects will receive 3 doses of either PNEUMOSIL (3 groups receiving vaccine from different lots) or Synflorix (1 group) at 6, 10, and 14 weeks of age. The first 675 randomized subjects will receive a booster dose of either PNEUMOSIL or Synflorix at 9 months of age that matches the treatment assignment for the priming phase. Standard EPI vaccinations in The Gambia will be given concomitantly with all 4 doses of the study vaccines. Out of the 675 booster subjects, subjects who consented for further evaluation will participate for the assessment of immune persistence 12 (+1) months after the booster vaccination The primary objectives are to demonstrate that the three lots of the Pneumosil vaccine is consistent by evaluating the immune responses, and to demonstrate that the immune responses generated by Pneumosil are non-inferior to those generated by Synflorix. The safety and tolerability of Pneumosil will also be evaluated.

Official Title
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A Phase 3, Randomized, Double-Blind Study of the Safety, Tolerability, Lot-to-Lot Consistency, Immunogenicity & Non-Interference With Concomitant Vaccinations of Serum Institute of PNEUMOSIL in Healthy Infants in The Gambia

Conditions
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Pneumonia, Pneumococcal

Intervention / Treatment
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* Biological: Pneumosil
* Biological: Synflorix


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: They are healthy infants based on medical history and clinical assessment. They are 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. 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 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 of suddenly without apparent cause. History of meningitis, seizures or any neurological disorder.

Ages Eligible for Study
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Minimum Age: 6 Weeks
Maximum Age: 8 Weeks

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 Lot 1<br>Pneumosil Lot 1 | Biological: Pneumosil<br>* 10-Valent Pneumococcal Conjugate Vaccine<br>|
| Experimental: Pneumosil Lot 2<br>Pneumosil Lot 2 | Biological: Pneumosil<br>* 10-Valent Pneumococcal Conjugate Vaccine<br>|
| Experimental: Pneumosil Lot 3<br>Pneumosil Lot 3 | Biological: Pneumosil<br>* 10-Valent Pneumococcal Conjugate Vaccine<br>|
| Active Comparator: Synflorix<br>Synflorix | Biological: Synflorix<br>* Pneumococcal conjugate vaccine (Non-Typeable Haemophilus influenzae (NTHi) protein D, diphtheria or tetanus toxoid conjugates) adsorbed<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serotype-specific Geometric Mean Concentration of IgG Antibody | Serotype-specific concentrations of immunoglobulin G (IgG) antibody measured by ELISA | 4 weeks after the third dose | 
| Number and Percentage of Subjects With Serotype-specific IgG Antibody Responses ≥ 0.35 μg/mL | Number and Percentage of subjects with serotype-specific IgG Antibody Responses ≥ 0.35 μg/mL | 4 weeks after the third dose | 
| Serotype-specific Geometric Mean Concentration of IgG Antibody | Serotype-specific immunoglobulin G (IgG) geometric mean concentration (GMC) 4 weeks after the primary series of PNEUMOSIL/Synflorix co-administered with pentavalent, RV and polio vaccines. | 4 weeks after the third dose | 
| Number and Percentage of Subjects With EPI Vaccine Immune Responses (Diphtheria, Tetanus, Hepatitis B, Hib, Polio and Rotavirus) | Subjects with 1) anti-diphtheria toxoid (DT) and anti-tetanus toxoid (DT) IgG concentration ≥ 0.1 IU/mL; 2) anti-Hepatitis B surface antigen (HBsAg) IgG concentration ≥ 10 mIU/mL; 3) anti-Hib (polyribosylribitol phosphate [PRP]) IgG concentration ≥ 0.15 µg/mL; 4) anti-poliovirus types 1, 2 and 3 neutralizing antibody titers ≥ 1:8; 5) anti-rotavirus IgA concentration ≥ 20 U/mL. | 4 weeks after the third dose | 
| Anti-pertussis Toxoid GMCs for the Pertussis Antigen | Anti-pertussis toxoid GMCs for the pertussis antigen | 4 weeks after the third dose | 
| Anti Fimbriae 2/3 IgG GMCs for the Pertussis Antigen | Anti fimbriae 2/3 IgG GMCs for the pertussis antigen | 4 weeks after the third dose | 
| Number and Percentage of Solicited Local and Systemic Reactogenicity by Severity- Vaccination 1 | In the primary reactogenicity cohort, local and systemic reactogenicity of the study vaccine was evaluated through day 6 for severity by toxicity grading scale (0 [none], 1 [mild], 2 [moderate], 3 [severe], 4 [life threatening]. | 7 days (including day of vaccination) | 
| Number and Percentage of Solicited Local and Systemic Reactogenicity by Severity- Vaccination 2 | In the primary reactogenicity cohort, local and systemic reactogenicity of the study vaccine was evaluated through day 6 for severity by toxicity grading scale (0 [none], 1 [mild], 2 [moderate], 3 [severe], 4 [life threatening]. | 7 days (including day of vaccination) | 
| Number and Percentage of Solicited Local and Systemic Reactogenicity by Severity- Vaccination 3 | In the primary reactogenicity cohort, local and systemic reactogenicity of the study vaccine was evaluated through day 6 for severity by toxicity grading scale (0 [none], 1 [mild], 2 [moderate], 3 [severe], 4 [life threatening]. | 7 days (including day of vaccination) | 
| Number and Percentage of Solicited Local and Systemic Reactogenicity by Severity- Booster | In the primary reactogenicity cohort, local and systemic reactogenicity of the study vaccine was evaluated through day 6 for severity by toxicity grading scale (0 [none], 1 [mild], 2 [moderate], 3 [severe], 4 [life threatening]. | 7 days (including day of vaccination) | 
| Number and Percentage of All AEs Including SAEs Occurring in Greater Than 1% Subjects by Severity and Relatedness | All subjects were followed up for AEs till 4 weeks post vaccination dose 3 and subjects in the booster cohort were followed up for AEs till 4 weeks post booster vaccination | 4 weeks post last vaccination | 
| Number and Percentage of All SAEs by Severity and Relatedness | All subjects were followed up for SAEs till 4 weeks post vaccination dose 3 and subjects in the booster cohort were followed up for SAEs till 4 weeks post booster vaccination | 4 weeks post last vaccination | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number and Percentage of Subjects With 6A and 19A Serotype-specific Concentrations of Immunoglobulin G Antibody | Subjects with 6A and 19A serotype-specific concentrations of immunoglobulin G (IgG) antibody measured by ELISA | 4 weeks after the third dose | 
| 6A and 19A Serotype Specific Geometric Mean Concentration of IgG Antibody | 6A and 19A Serotype Specific Immune Responses in terms of IgG GMCs measured by ELISA | 4 weeks after the third dose | 
| Number and Percentage of Subjects With Functional Antibody Responses | Serotype-specific functional antibody titer measured by OPA | 4 weeks after the third dose | 
| Serotype-specific OPA Geometric Mean Titer | Serotype-specific functional antibody titer measured by OPA and expressed as OPA GMT in a subset | 4 weeks after the third dose | 
| Comparison of Serotype-specific Geometric Mean Concentration of IgG Antibody Response 4 Weeks After a 3-dose Primary Series to 4 Weeks After a Booster Dose | Comparison of Serotype-specific booster responses (antibody concentrations) measured by ELISA from 4 weeks after a 3-dose primary series to 4 weeks after a booster dose | 4 weeks post booster vaccination | 
| Serotype-specific Geometric Mean Concentration of IgG Antibody Response and Treatment-Group GMC Ratios 4 Weeks After a Booster Dose | Comparison of Serotype-specific booster responses (antibody concentrations) to PNEUMOSIL in comparison to Synflorix 4 weeks after a booster dose | 4 weeks post booster vaccination | 
| Comparison of Functional Response (OPA) From 4 Weeks After a 3-dose Primary Series to 4 Weeks After a Booster Dose | Comparison of Serotype-specific booster responses (functional response-OPA) from 4 weeks after a 3-dose primary series to 4 weeks after a booster dose | 4 weeks post booster vaccination | 
| Serotype-specific OPA GMT and Treatment-Group GMT Ratios 4 Weeks After a Booster Dose | Comparison of Serotype-specific booster responses (functional response) to PNEUMOSIL in comparison to Synflorix 4 weeks after a booster dose | 4 weeks post booster vaccination | 
| Number and Percentage of Subjects With EPI Vaccine Immune Responses (Measles, Rubella and Yellow Fever) | Anti-measles IgG, anti-rubella IgG and anti-yellow fever neutralizing antibody titer | 4 weeks post booster vaccination |