Reduced PCV Dosing Schedules in South African Infants

Study Overview
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Brief Summary
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This study will evaluate the immunogenicity of a reduced dosing schedule of Pneumococcal Conjugate vaccine (PCV) PCV10 and PCV13, in which children will receive a primary dose at either 6 or 14 weeks of age, followed by a booster dose at 9 months of age (1+1 schedule), and compare this immune response to those who receive a two dose primary series (at 6 and 14 weeks of age) and booster dose at 9-months (2+1 schedule).

Detailed Description
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Pneumonia is the leading global cause of childhood death outside of the neonatal period, and contributes to 19% of the 10 million childhood deaths occurring annually, the majority of which occurs in industrialising countries. Despite the successes in improving primary healthcare in South Africa since 1994, pneumonia nevertheless remains a leading cause of childhood death in South Africa, aggravated by the HIV/AIDS epidemic. Streptococcus pneumoniae is recognised as the leading bacterial cause of pneumonia in children as well as having been identified as a common cause of super-imposed bacterial infection in individuals with respiratory virus-associated pneumonia. In South Africa, the cost of procurement of PCV ($20 per dose) totals almost 50% of the total cost of all vaccines purchased for the national immunisation program. Similarly, PCV is the most expensive vaccine purchased by the Global Alliance for Vaccines and Immunisation (GAVI), which heavily funds vaccine procurement for low income countries. The sustainability of continued procurement of this vaccine at the current pricing in low-middle income countries remains uncertain. This will be a randomized, open-label study (laboratory personnel will however be blinded) in which subjects are randomized to one of two (primary dose at either 6 or 14 weeks of age) 1+1 dosing schedules of PCV10 or PCV13, or to a 2+1 schedule of these vaccines. A total of 600 subjects will be randomized in a 1:1:1:1:1:1 ratio to one of the six groups. The study will be undertaken at an experienced research site in Johannesburg, South Africa, where the 600 children born to HIV-uninfected women are expected to be enrolled over a 12- month period.

Official Title
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An Open-labeled, Randomized Controlled Trial Evaluating for Non-inferiority of 1+1 Compared to 2+1 Dosing Schedules of 10-valent and 13-valent Pneumococcal Conjugate Vaccine (PCV) in South African Children

Conditions
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Pneumonia, Meningitis

Intervention / Treatment
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* Biological: Pneumococcal conjugate vaccine (PCV10 ) 1+1, 6 weeks
* Biological: Pneumococcal conjugate vaccine (PCV10 ) 1+1, 14 weeks
* Biological: Pneumococcal conjugate vaccine (PCV10 ) 2+1
* Biological: Pneumococcal conjugate vaccine (PCV13 ) 1+1, 6 weeks
* Biological: Pneumococcal conjugate vaccine (PCV13 ) 1+1, 14 weeks
* Biological: Pneumococcal conjugate vaccine (PCV13 ) 2+1


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent by the parent/guardian of the child; Born to an HIV-uninfected women, based on testing undertaken as part of standard of care during the last trimester of pregnancy; Had not received any vaccine other than BCG and OPV (routinely given at birth) prior to enrolment; Birth weight >2499g AND weight of child >3.5 kg at time of proposed randomization; Aged 42-56 days of age at time of enrolment; Available for the duration of the study; Child is healthy based on medical history and physical examination of the study-staff. Exclusion Criteria: Any clinically significant major congenital abnormalities; Previous hospitalization for a respiratory illness following discharge from hospital after birth; Receipt of any other investigational drug/vaccine. Co-enrollment into non-investigational studies, including epidemiology studies, is allowed; Any previous PCV vaccination; Known allergy to any of the vaccine components; Febrile illness (axillary temperature ≥37.8°C) at time of enrolment. These participants are eligible if the temperature resolves for at least 48 hours and they remain within the study defined window periods; Planned relocation to outside of the study area during up until age of 2 years; Receipt of blood transfusion or any other blood products (including immunoglobulins) since birth. Receipt of such products during the course of the study, will require withdrawal of the child from the study; History of confirmed pneumococcal disease since birth; Any known or suspected immunodeficiency condition which could affect immune response to vaccination.

Ages Eligible for Study
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Minimum Age: 5 Weeks
Maximum Age: 18 Months

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1a (1+1, 6 weeks)<br>PCV10 (Synflorix 0.5ml injection) will be administered at 6 weeks and 9 months of age | Biological: Pneumococcal conjugate vaccine (PCV10 ) 1+1, 6 weeks<br>* PCV10 1+1, 6 weeks & 9 months<br>* Other names: Synflorix (PCV10);|
| Experimental: Group 1b (1+1, 6 weeks)<br>PCV13 (Prevenar 13, 0.5ml injection) will be administered at 6 weeks and 9 months of age | Biological: Pneumococcal conjugate vaccine (PCV13 ) 1+1, 6 weeks<br>* PCV13 1+1, 6 weeks & 9 months<br>* Other names: Prevenar 13;|
| Experimental: Group 2a (1+1, 14 weeks)<br>PCV10 (Synflorix 0.5ml injection) will be administered at 14 weeks and 9 months of age | Biological: Pneumococcal conjugate vaccine (PCV10 ) 1+1, 14 weeks<br>* PCV10 1+1, 14 weeks & 9 months<br>* Other names: Synflorix (PCV10);|
| Experimental: Group 2b (1+1, 14 weeks)<br>PCV13 (Prevenar 13, 0.5ml injection) will be administered at 14 weeks and 9 months of age | Biological: Pneumococcal conjugate vaccine (PCV13 ) 1+1, 14 weeks<br>* PCV13 1+1, 14 weeks & 9 months<br>* Other names: Prevenar 13;|
| Active Comparator: Group 3a (2+1)<br>PCV10 (Synflorix 0.5ml injection) will be administered at 6 weeks, 14 weeks and 9 months of age, as per EPI schedule in South Africa | Biological: Pneumococcal conjugate vaccine (PCV10 ) 2+1<br>* PCV10 2+1, 6&14 weeks & 9 months<br>* Other names: Synflorix (PCV10);|
| Active Comparator: Group 3b (2+1)<br>PCV13 (Prevenar 13, 0.5ml injection) will be administered at 6 weeks, 14 weeks and 9 months of age, as per EPI schedule in South Africa | Biological: Pneumococcal conjugate vaccine (PCV13 ) 2+1<br>* PCV13 2+1, 6&14 weeks & 9 months<br>* Other names: Prevenar 13;|

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) one month following the booster dose | The serotype-specific GMC measured 1 month after the 9-month booster dose for each 1+1 vaccine group and comparing it to the 2+1 group of the same vaccine | 1 month post booster vaccine | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Immunogenicity: percentage of children with vaccine-serotype specific serum IgG antibody concentration above the WHO-defined putative threshold for protection (≥0.35 µg/mL) at 9 months of age, prior to the booster dose of differing 1+1 dosing schedules | 1. To evaluate the percentage of children with vaccine-serotype specific serum IgG antibody concentration above the WHO-defined putative threshold for protection (≥0.35 µg/mL) at 9 months of age, prior to the booster dose of differing 1+1 dosing schedules (i.e. primary dose given at either 6 or 14 weeks of age) compared to that of children who received a 2 dose primary series (i.e. 2+1 dosing schedule group).. | 9 months of age | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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immunogenicity