The Effect of Fractional Doses of Pneumococcal Conjugate Vaccines on Immunogenicity and Carriage in Kenyan Infants (FPCV)

• ClinicalTrials.gov Identifier: NCT03489018
• Recruitment Status: Active, not recruiting
• First Posted: November 21, 2018
• Last Update Posted: November 7, 2023
• Sponsor: London School of Hygiene and Tropical Medicine
• Collaborators: University College, London; KEMRI-Wellcome Trust Collaborative Research Program; Bill and Melinda Gates Foundation; National Institute of Health Research (NIHR) Mucosal Pathogens Research Unit (MPRU); Wellcome Trust
• Information provided by (Responsible Party): London School of Hygiene and Tropical Medicine

Study Description

Brief Summary:

Before the introduction of pneumonia vaccines in 2000, between 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 10 USD per child, they are not affordable to most low-income countries without financial support from Gavi, the Vaccine Alliance.

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. The results could be used to increase the affordability of the pneumonia vaccine, and enable delivery of the vaccine to continue in the absence of Gavi support.

Condition or disease	Intervention/treatment	Phase
Pneumococcal Infection; Streptococcus Pneumoniae Infection; Invasive Pneumococcal Disease, Protection Against	Biological: PCV10; Biological: PCV13	Phase 4

Detailed Description:

Background:

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 low and middle income countries (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 could convert new 4-dose vials of PCVs into 10- or 20-dose vials, ready for immediate implementation in LMIC programmes.

Primary objective:

Non-inferior immunogenicity at 1-month post-boost (10 months of age). Non-inferiority will be reached if the lower CI around the ratio of geometric mean concentrations (GMC) of IgG (fractional/full dose) is >0.5 (i.e. the 2-fold criterion).

Secondary objectives:

Non-inferior immunogenicity at 1-month post-primary series (18 weeks of age). Non-inferiority will be achieved if the lower limit of the 95% confidence interval (CI) around the difference in the proportion of 'responders', children with IgG>=0.35 mcg/ml, (fractional dose group - full dose group) is >-10% for at least 8 of the 10 vaccine types in the PCV10 arms and at least 10 of the 13 vaccine types in the PCV13 arms.

The opsonophagocytic activity of the antibody response to 7 serotypes after full/ fractional doses at the 1-month post-boost time point.

The direct vaccine effectiveness of full/fractional doses of PCV13 against carriage of serotypes 6A and 19A, with primary analyses at 18 months of age and secondary analyses at 9 months of age.

The proportion of children with evidence of vaccine-serotype carriage by trial arm at 9 and 18 months of age.

The geometric mean concentration (GMC) of serotype-specific IgG after the primary series of the 2p+1 schedule, prior to boost, at 9 months of age.

The geometric mean concentration (GMC) of serotype-specific IgG after three doses of vaccine in a 2p+1 schedule at 18 months of age.

The carriage prevalence at 9 and 18 months of age and IgG concentrations at 4 weeks after the primary series after full dose of PCV10 in a 3p+0 schedule, and full/ fractional doses of PCV10/13 in a 2p+1 schedule.

Trial design:

A phase IV individually-randomised controlled trial of full or fractional (20% or 40%) doses of PCV10/ PCV13, given as a 3-dose schedule to infants: 2 doses at 6 and 14 weeks of age and a booster dose at 9 months (the 2p+1 schedule) or 3 full doses at 6, 10 and 14 weeks of age (the 3p+0 schedule).

At 6-8 weeks of age, 300 infants will be enrolled at random into each of the seven trial arms and followed until 18 months of age.

The seven trial arms:

A. Full dose PCV13 vaccination in a 2p+1 schedule. B. 40% fractional dose PCV13 vaccination in a 2p+1 schedule. C. 20% fractional dose PCV13 vaccination in a 2p+1 schedule. D. Full dose PCV10 vaccination in a 2p+1 schedule. E. 40% fractional dose PCV10 vaccination in a 2p+1 schedule. F. 20% fractional dose PCV10 vaccination in a 2p+1 schedule. G. Full dose PCV10 vaccination in a 3p+0 schedule. This arm would represent the current vaccine and schedule in the Kenyan routine immunisation programme and would act as an additional comparison arm.

Study procedures:

No study procedures will be conducted without prior parental informed consent. Participants in trial arms A-F will provide 3 or 5 blood samples in the course of the trial at enrolment, 4 weeks post-primary series (approximately 18 weeks of age) and 4 weeks post-boost (approximately 10 months of age); additionally a random selection of half the participants will contribute blood samples pre-boost (9 months of age) and at the last study visit (18 months of age).

Participants in trial arm G will provide 2 blood samples (at enrolment and at 4 weeks post-primary series (approximately 18 weeks of age).

All participants will provide 2 nasopharyngeal swabs at approximately 9 and 18 months of age and contribute safety data.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 2100 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment

Intervention Model Description

Participants will be randomised to one of seven groups for the duration of the study:

A. Full dose PCV13 vaccination in a 2p+1 schedule; B. 40% fractional dose PCV13 vaccination in a 2p+1 schedule; C. 20% fractional dose PCV13 vaccination in a 2p+1 schedule; D. Full dose PCV10 vaccination in a 2p+1 schedule; E. 40% fractional dose PCV10 vaccination in a 2p+1 schedule; F. 20% fractional dose PCV10 vaccination in a 2p+1 schedule; G. Full dose PCV10 vaccination in a 3p+0 schedule.

• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Masking Description: Participants, parents of participants and all of the study team apart from the vaccinator will be masked with respect to the infant's allocation to a trial arm between A-F. If randomly allocated to trial arm G, parents and study personnel will be unmasked due to the necessity for trial arm G to receive a different vaccine schedule compared to trial arms A-F. It is thought that this unmasking will have minimal impact on retention, follow up and outcome assessment across the trial arms for primary and secondary outcomes.
• Primary Purpose: Prevention
• Official Title: The Effect of Fractional Doses of Pneumococcal Conjugate Vaccines (PCV10 and PCV13) on Immunogenicity and Vaccine-serotype Carriage in Kenyan Infants
• Actual Study Start Date: March 21, 2019
• Actual Primary Completion Date: September 30, 2022
• Estimated Study Completion Date: December 30, 2024

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Full dose PCV13 (2p+1 schedule); Full dose PCV13 administration in 2p+1 schedule	Biological: PCV13; Experimental arms will receive a lower dose of the intervention than the marketed dose.; Other Names: Prevnar 13 (Pfizer Inc.); 13-valent pneumococcal conjugate vaccine; Prevnar13
Experimental: 40% dose PCV13 (2p+1 schedule); Fractional (40%) dose PCV13 administration in 2p+1 schedule	Biological: PCV13; Experimental arms will receive a lower dose of the intervention than the marketed dose.; Other Names: Prevnar 13 (Pfizer Inc.); 13-valent pneumococcal conjugate vaccine; Prevnar13
Experimental: 20% dose PCV13 (2p+1 schedule); Fractional (20%) dose PCV13 administration in 2p+1 schedule	Biological: PCV13; Experimental arms will receive a lower dose of the intervention than the marketed dose.; Other Names: Prevnar 13 (Pfizer Inc.); 13-valent pneumococcal conjugate vaccine; Prevnar13
Active Comparator: Full dose PCV10 (2p+1 schedule); Full dose PCV10 administration in 2p+1 schedule	Biological: PCV10; Experimental arms will receive a lower dose of the intervention than the marketed dose.; Other Names: Synflorix (GlaxoSmithKline plc.); 10-valent pneumococcal conjugate vaccine
Experimental: 40% dose PCV10 (2p+1 schedule); Fractional (40%) dose PCV10 administration in 2p+1 schedule	Biological: PCV10; Experimental arms will receive a lower dose of the intervention than the marketed dose.; Other Names: Synflorix (GlaxoSmithKline plc.); 10-valent pneumococcal conjugate vaccine
Experimental: 20% dose PCV10 (2p+1 schedule); Fractional (20%) dose PCV10 administration in 2p+1 schedule	Biological: PCV10; Experimental arms will receive a lower dose of the intervention than the marketed dose.; Other Names: Synflorix (GlaxoSmithKline plc.); 10-valent pneumococcal conjugate vaccine
Active Comparator: Full dose PCV10 (3p+0 schedule); The current vaccine (PCV10) and schedule (3p+0) in use in the Kenyan routine immunisation programme as an additional comparison arm.	Biological: PCV10; Experimental arms will receive a lower dose of the intervention than the marketed dose.; Other Names: Synflorix (GlaxoSmithKline plc.); 10-valent pneumococcal conjugate vaccine

Outcome Measures

Primary Outcome Measures :

1. Immunogenicity: The ratio of IgG GMCs at 1-month post boost [ Time Frame: 4-weeks post-boost (approximately 10 months of age) ]
   The ratio of the geometric mean concentrations of IgG after vaccination with 3 full or fractional doses of PCV

Secondary Outcome Measures :

1. Immunogenicity: the proportion of children who 'seroconvert' to vaccine-serotypes after vaccination [ Time Frame: 4-weeks post-primary series (approximately 18 weeks of age) ]
   The proportion of children with vaccine-serotype specific IgG antibody concentrations more than or equal to 0.35 mcg/ml after vaccination
2. The proportion of children with evidence of vaccine-serotype carriage [ Time Frame: Approximately 18 months of age ]
   Vaccine-type carriage prevalence across arms
3. The proportion of children with evidence of vaccine-serotype carriage [ Time Frame: Approximately 9 months of age ]
   Vaccine-type carriage prevalents across arms
4. The direct vaccine effectiveness of full/fractional doses of PCV13 against carriage of serotypes 6A and 19A [ Time Frame: Approximately 18 months of age ]
   The direct effectiveness of full/fractional doses of PCV13 in preventing carriage of serotypes 6A and 19A compared to that of full dose PCV10
5. Opsonophagocytic activity of vaccine-induced antibody to 4 serotypes [ Time Frame: Approximately 18 months of age ]
   Functionality of the antibody response

Other Outcome Measures:

1. Immunogenicity: the geometric mean concentration (GMC) of serotype-specific IgG [ Time Frame: 4-weeks post-primary series (approximately 18 weeks of age) ]
   IgG GMCs elicited post-primary series
2. Safety: the prevalence of adverse events following immunisation by arm [ Time Frame: Infants 6weeks-18 months of age ]
   The proportion fo children with adverse events following immunisation by arm
3. Immunogenicity: The geometric mean concentration (GMC) of serotype-specific IgG after the primary series of the 2p+1 schedule, prior to boost (9 months of age) and at the end of study follow-up at 18 months of age. [ Time Frame: Approximately 9 and 18 months of age ]
   IgG GMCs at 9 and 18 months of age

Eligibility Criteria

• Ages Eligible for Study: 6 Weeks to 8 Weeks (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

Inclusion Criteria:

• Healthy infants aged 6-8 weeks of age (HIV positive or negative but with no symptoms of current clinical immunosuppression i.e. HIV infection at WHO clinical stage 1);
• Parents are willing to provide informed consent for their child to participate in the study
• Parents and infant are likely to remain in the study area until the infant is 18 months of age and comply with study requirements including the requirement to return to the same health facility to obtain all other childhood vaccines.

Exclusion Criteria:

• Infants >8 weeks of age at time of enrolment
• Signs or symptoms of immunosuppression or HIV infection clinical stage 2 or above.
• Acute illness (e.g. febrile disease) on the day of vaccination
• Contraindications precluding vaccination (e.g. hypersensitivity to any component of the vaccine, including diphtheria toxoid)
• Previous PCV vaccination
• Family are planning to migrate out of the study areas before the end of the study follow-up
• Family are planning to obtain the subsequent vaccine doses of the routine immunisation schedule elsewhere and therefore their child may receive a full dose under the routine vaccination programme.

Contacts and Locations

Locations

Kenya

KEMRI Wellcome Trust Research Programme

Kilifi, Kenya

Sponsors and Collaborators

London School of Hygiene and Tropical Medicine

University College, London

KEMRI-Wellcome Trust Collaborative Research Program

Bill and Melinda Gates Foundation

National Institute of Health Research (NIHR) Mucosal Pathogens Research Unit (MPRU)

Wellcome Trust

Investigators

• Principal Investigator: J. Anthony G Scott, DTMH FMedSci; London School of Hygiene & Tropical Medicine, Keppel Street, London

  Study Documents (Full-Text)

Documents provided by London School of Hygiene and Tropical Medicine:

Study Protocol, Statistical Analysis Plan, and Informed Consent Form  [PDF] May 1, 2018

More Information

• Responsible Party: London School of Hygiene and Tropical Medicine
• ClinicalTrials.gov Identifier: NCT03489018
• Other Study ID Numbers: QA1075
• First Posted: November 21, 2018
• Last Update Posted: November 7, 2023
• Last Verified: March 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: The data will be open access and held in the LSHTM data repository (http://datacompass.lshtm.ac.uk/cgi/request_doc?docid=1); Data access will be granted upon reasonable request after the primary analyses of the trial, as specified, are published.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Clinical Study Report (CSR)
• Time Frame: After the primary analyses of the trial are published
• Access Criteria: Upon reasonable request with pre-specified hypothesis
• URL: http://datacompass.lshtm.ac.uk/cgi/request_doc?docid=1

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes

Keywords provided by London School of Hygiene and Tropical Medicine:

Pneumococcal Vaccines; Immunogenicity, Vaccine; 10-valent pneumococcal vaccine; 13-valent pneumococcal vaccine; Schedule; Pneumococcal Infection; Kenya; Infant; Vaccines, Conjugate; Humans; Immunization schedule; Streptococcus pneumoniae; vaccine; Dose-Response Relationship, immunologic; Equivalence Trial as Topic

Additional relevant MeSH terms:

Infections; Communicable Diseases; Pneumonia; Pneumonia, Pneumococcal; Pneumococcal Infections; Disease Attributes; Pathologic Processes; Respiratory Tract Infections; Lung Diseases; Respiratory Tract Diseases; Streptococcal Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Pneumonia, Bacterial; Vaccines; Heptavalent Pneumococcal Conjugate Vaccine; Immunologic Factors; Physiological Effects of Drugs