Protocol No: ECCT/18/08/03 Date of Protocol: 09-01-2018

Study Title:
The effect of fractional doses of pneumococcal conjugate vaccines (PCV10 and PCV13) on immunogenicity and vaccine-serotype carriage in Kenyan infants

 

Study Objectives:
Primary objective

To determine whether fractional doses of PCV13/ PCV10 elicit non-inferior immunogenicity compared to full doses when delivered in a 2p+1 schedule with primary analyses at 4 weeks after the booster dose (10-13 months of age) and secondary analyses at 4 weeks after the primary series (18 weeks of age). For the primary objective, immunogenicity will be assessed as the proportion of infants achieving antibody levels above the threshold for protection (0.35 mcg IgG/ ml).

 

Secondary objectives
  • To compare the carriage prevalence of serotypes in the fractional dose arms against the carriage prevalence in the full dose arms, with primary analyses at 6 months after the booster dose (15-18 months of age) and secondary analyses at 9 months of age.
  • To compare vaccine efficacy against carriage of non-PCV10 serotypes 6A and 19A in the full dose PCV13 arms when compared to the fractional dose arms, using the full dose PCV10 2p+1 arm as a control, with primary analyses at 6 months post boost and secondary analyses at 9 months of age.
  • To compare frequency and severity of local injection-site reactions and vaccine-related adverse events in the 28 days following immunization after fractional dose delivery and a full dose delivery.
  • To compare carriage prevalence at 9 and 15-18 months of age after full dose of PCV10 in a 3p+0 schedule, and full/ fractional doses of PCV10/13 in a 2p+1 schedule
  • To compare serotype specific IgG concentrations after full doses of PCV10 in a 3p+0 schedule and full/ fractional doses of PCV10/13 in a 2p+1 schedule, at 4 weeks after the primary series.
Laymans Summary:

Lay Title: A trial to compare the immune response and the proportion of infants still carrying bacteria in their nose after varying doses of the pneumonia vaccines (‘PCV10’ and ‘PCV13’) in Kenyan infants.

What is the problem/background? Before the introduction of pneumonia vaccines in 2000, around 700,000- 1 million children died each year as a result of infection with the bacteria Streptococcus pneumoniae and the resulting diseases, namely, meningitis, sepsis and pneumonia. Most of the deaths were in Africa and Asia. Where the vaccines have been introduced, they have been highly effective and have already reduced disease. However, at USD 10 per child, they are not affordable to most low-income countries without financial support from Gavi, the Vaccine Alliance. In Kenya, a 10-valent PCV has been implemented since 2011. The greater part of the vaccine cost is subsidized by Gavi. However, in 2022 Gavi will begin to reduce its subsidies to Kenya over a 5-year period so that by 2027 Kenya will be paying the whole cost alone. A reduction in the cost of the PCV programme may be necessary for Kenya to keep delivering its PCV programme.

What questions are we trying to answer? This project aims to assess whether lower doses of the two commercially available pneumonia vaccines can protect Kenyan infants as well as the full dose and can be delivered safely. The results could be used to enable countries unable to afford the full cost of the pneumonia vaccine, to continue delivering it in the childhood immunisation programme in the absence of Gavi support.

Where is the study taking place, how many people does it involve and how are they selected? The study will take place at multiple health facilities in Kilifi County. A total of 2100 infants will be involved. Infants will be selected from those eligible for routine immunisations. Infants with acute illness will be excluded from enrolment into the study. HIV infection will be recorded but not used as an exclusion criterion. 

What does the study involve for those who are in it? Participants will be randomised in equal numbers to one of seven groups to receive either PCV10 or PCV13 at the full dose or lower dose schedules.  

Infants will receive the first dose of the three-dose schedule at 6 weeks of age and then mothers and infants will be invited back to the study clinic 6 further times during the course of the study. Infants will receive the 2nd and third doses of the vaccine, at 10 and 14 weeks or at 14 weeks and 9 months of age. They will have a small amount of blood taken 4 weeks after the 2nd and 3rd doses, some participants will also have a small amount of blood drawn at the time of the 3rd dose and at their last study visit at 18 months of age. Two swabs will be taken from the mucous in the nose to look for the presence of the bacteria.

What are the benefits and risks/costs of the study for those involved?  There is a small risk that the children in this study who receive the lower dose schedules will be less well protected than those who receive the full dose. However, because the vaccine has been in use for 6 years already in Kenya and will continue to be in use in the routine immunization system throughout the study, the bacteria is much less common than it was and the likelihood of developing disease is very low. As participants in the study, infants will have access to the study medical staff and will be able to present with any illness at an early stage and receive free treatment and/or referral to the sub-district hospital up until the age of 18 months (when the study ends). If, after final analyses, the lower doses are found to not give a good enough immune response, all infants in those groups will be given a single booster vaccination with the full dose.

If a low dose of the vaccine stimulates a protective immune response, infants who were randomly selected to be given the PCV13 will have the added benefit of immunization against three additional pneumococcal bacterial types (3, 6A, 19A) contained in the study vaccine (PCV13) but not contained in the vaccine used in the national programme (PCV10). 900 of the 2100 children recruited into the study will receive PCV13.

How will the study benefit society?  If the pneumonia vaccines are effective at lower doses, the whole community may benefit. If lower doses can be administered the cost of the vaccine will fall meaning it may continue to be delivered by the government for longer.

When does the study start and finish? The study will start upon receipt of ethical clearance. Data collection, analysis and write up will take place over 42 months.

Abstract of Study:

Currently, two pneumococcal conjugate vaccines (PCV) are licensed for inclusion in routine immunisation schedules in low- and middle-income countries (LMICs). Both vaccines have proven highly effective in stimulating vaccine-serotype-specific immune responses, reducing vaccine-serotype carriage and reducing the incidence of invasive pneumococcal disease (IPD) and hospitalised pneumonia. Worldwide, over 50 LMICs have introduced PCV with the support of Gavi, the Vaccine Alliance; however, as economies grow and countries transition out of Gavi support, the sustainability of their PCV programmes is at risk. PCV is currently the most expensive vaccine in the routine immunisation schedule in Gavi-supported countries. This study aims to provide evidence which may enable a substantial decrease in the cost of PCV programmes, therefore increasing the sustainability of PCV programmes in LMICs. We propose to assess whether fractional (20% and 40%) doses of pneumococcal conjugate vaccine (PCV10 and PCV13) in a 2p+1 schedule (2 primary doses followed by a booster dose) induce non-inferior immunogenicity and effects on vaccine-serotype carriage when compared to the full dose. These lower doses would convert new 4-dose vials of PCVs into 10- or 20-dose vials, ready for immediate implementation in LMIC programmes.