Persistence of Immunogenicity Following Reduced PCV Dosing Schedules in South African Children

Study Overview
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Brief Summary
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This study will evaluate the persistence of immunogenicity following a reduced dosing schedule of 10- or 13-valent Pneumococcal Conjugate Vaccine (PCV10, PCV13). This is the follow-up of a randomized controlled trial in which children received a single priming dose of PCV10 or PCV13 (at 6 or 14 weeks of age) followed by booster dose at 9 months of age (1+1 schedule), compared to a 2+1 PCV schedule (6, 14 weeks of age and 9 months of age).

Detailed Description
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Between 2017 and 2019, we conducted an open-labelled, randomized controlled trial to evaluate for non-inferiority in the post-booster serotype-specific geometric mean concentrations (GMC's) in children randomized to receive either PCV10 or PCV13 as a 1+1 schedule (with the first dose occurring either at 6 or 14 weeks of age) compared to infants who received a two dose primary series (6 and 14 weeks of age). All six study groups received a booster dose at 40 weeks of age, and serotype-specific IgG and opsonophagocytic activity was measured one-month post booster. Subjects were planned to be followed-up until 18 months of age as part of the initial study. In the present study, we propose to extent the follow-up of the cohort to include annual visit at 3, 4 and 5 years of age, to evaluate the sustainability of the humoral immune response of the different PCV dosing schedules.

Official Title
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Evaluation of Persistence of Immunogenicity Following an Open-labelled, Randomized Controlled Trial Evaluating Non-inferiority of 1+1 Compared to 2+1 Dosing Schedules of 10-valent and 13-valent Pneumococcal Conjugate Vaccine in South Africa

Conditions
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Pneumonia, Meningitis

Intervention / Treatment
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* Biological: PCV10
* Biological: PCV13


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Children between and including the ages of 36 - 38 months of age at the time of first blood sampling; Subjects who previously participated in the PCV1+1 study and received the full study vaccination regime as per protocol; The parent or legal guardian of the child must be able and willing to provide written informed consent for all 3 visits and comply with all study requirements; The parent or legal guardian of the child must indicate the intention to remain in the study area for the duration of the trial - or be willing to bring the child for all visits. Exclusion Criteria: Receipt of any additional pneumococcal vaccine since the end of participation in the PCV1+1 study; Any known or suspected immunodeficiency condition which could affect immune response to vaccination, including living with HIV; Receipt of any immunoglobulins and/or blood products less than 6 months prior to blood sampling; Parent/legal guardian unable or unwilling to attend scheduled study visits.

Ages Eligible for Study
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Minimum Age: 3 Years
Maximum Age: 5 Years

Sexes Eligible for Study
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All

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| PCV10 1+1, 6 weeks & 9 months<br>Follow-up of children who were previously randomized to PCV10 (Synflorix 0.5ml injection) administered at 6 weeks and 9 months of age. | Biological: PCV10<br>* 0.5 ml injection<br>* Other names: Synflorix;|
| PCV13 1+1, 6 weeks & 9 months<br>Follow-up of children who were previously randomized to PCV13 (Prevnar 13, 0.5ml injection) administered at 6 weeks and 9 months of age. | Biological: PCV13<br>* 0.5 ml injection<br>* Other names: Prevnar13;|
| PCV10 1+1, 14 weeks & 9 months<br>Follow-up of children who were previously randomized to PCV10 (Synflorix 0.5ml injection) administered at 14 weeks and 9 months of age. | Biological: PCV10<br>* 0.5 ml injection<br>* Other names: Synflorix;|
| PCV13 1+1, 14 weeks & 9 months<br>Follow-up of children who were previously randomized to PCV13 (Prevnar 13, 0.5ml injection) administered at 14 weeks and 9 months of age. | Biological: PCV13<br>* 0.5 ml injection<br>* Other names: Prevnar13;|
| PCV10 2+1, 6&14 weeks & 9 months<br>Follow-up of children who were previously randomized to PCV10 (Synflorix 0.5ml injection) administered at 6 weeks, 14 weeks and 9 months of age. | Biological: PCV10<br>* 0.5 ml injection<br>* Other names: Synflorix;|
| PCV13 2+1, 6&14 weeks & 9 months<br>Follow-up of children who were previously randomized to PCV13 (Prevnar 13, 0.5ml injection) administered at 6 weeks, 14 weeks and 9 months of age. | Biological: PCV13<br>* 0.5 ml injection<br>* Other names: Prevnar13;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serotype specific geometric mean antibody concentrations (GMC) | To evaluate persistence of vaccine-serotype specific GMCs at 3, 4 and 5 years of age between children receiving differing 1+1 dosing schedules compared to the 2+1 dosing schedule of the same vaccine formulation (i.e. PCV10 or PCV13). | 3, 4 and 5 years of age | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Modified threshold of protection | To evaluate persistence of vaccine-serotype specific serum IgG antibody concentration above the WHO-defined putative threshold for protection (≥0.35 µg/mL) and the modified serotype-specific correlate of protection against IPD as proposed by Andrews et al.(17) at 3, 4 and 5 years of between children with differing 1+1 dosing schedules compared to the 2+1 dosing schedule of the same vaccine formulation | 3, 4 and 5 years of age | 
| Comparison between 6-week and 14-week primary dose | To evaluate persistence of vaccine-serotype specific serum IgG antibody concentration above the WHO-defined putative threshold for protection (≥0.35 µg/mL), the modified serotype-specific correlate of protection against IPD as proposed by Andrews et al. (17) and GMC's at 3, 4 and 5 years in children receiving the 1+1 dosing schedule at either 6 weeks of age compared to those who received it at 14 weeks of age, stratified for the individual vaccine formulation (PCV10 and PCV13). | 3, 4 and 5 years of age |