Pneumococcal conjugate vaccine 13 delivered as one primary and one booster dose (1 + 1) compared with two primary doses and a booster (2 + 1) in UK infants: a multicentre, parallel group randomised controlled trial

David Goldblatt*, Joanna Southern, Nicholas Andrews, Polly Burbidge, Jo Partington, Lucy Roalfe, Marta Valente Pinto, Vasilli Thalasselis, Emma Plested, Hayley Richardson, Matthew D. Snape, Elizabeth Miller

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

71 Citations (Scopus)

Abstract

Background: Infants in the UK were first offered a pneumococcal conjugate vaccine (PCV7) in 2006, given at 2 and 4 months of age and a booster dose at 13 months (2 + 1 schedule). A 13-valent vaccine (PCV13) replaced PCV7 in 2010. We aimed to compare the post-booster antibody response in UK infants given a reduced priming schedule of PCV13 (ie, a 1 + 1 schedule) versus the current 2 + 1 schedule and to assess the potential effect on population protection. Methods: In this multicentre, parallel group, randomised controlled trial, we recuited infants due to receive their primary immunisations aged up to 13 weeks on first vaccinations by information booklets mailed out via the NHS Child Health Information Service and the UK National Health Application and Infrastructure Services. Eligible infants were randomly assigned (1:1) to receive PCV13 at 2, 4, and 12 months (2 + 1 schedule) or 3 and 12 months of age (1 + 1 schedule) delivered with other routine vaccinations. Randomisation was done by computer-generated permuted block randomisation, with a block size of six. Participants and clinical trial staff were not masked to treatment allocation. The primary endpoint was serotype-specific immunoglobulin G concentrations values (geometric mean concentrations [GMC] in μg/mL) measured in blood samples collected at 13 months of age. Analysis was by modified intention to treat with all individuals included by randomised group if they had a laboratory result. This trial is registered on the EudraCT clinical trial database, number 2015-000817-32, and ClinicalTrials.gov, number NCT02482636. Findings: Between September, 2015, and June, 2016, 376 infants were assessed for eligibility. 81 infants were excluded for not meeting the inclusion criteria (n=50) or for other reasons (n=31). 213 eligible infants were enrolled and randomly allocated to group 1 (n=106; 2 + 1 schedule) or to group 2 (n=107; 1 + 1 schedule). In group 1, 91 serum samples were available for analysis 1 month after booster immunisation versus 86 in group 2. At month 13, post-booster, GMCs were equivalent between schedules for serotypes 3 (0·61 μg/mL in group 1 vs 0·62 μg/mL in group 2), 5 (1·74 μg/mL vs 2·11 μg/mL), 7F (3·98 μg/mL vs 3·36 μg/mL), 9V (2·34 μg/mL vs 2·50 μg/mL), and 19A (8·38 μg/mL vs 8·83 μg/mL). Infants given the 1 + 1 schedule had significantly greater immunogenicity post-booster than those given the 2 + 1 schedule for serotypes 1 (8·92 μg/mL vs 3·07 μg/mL), 4 (3·43 μg/mL vs 2·55 μg/mL), 14 (16·9 μg/mL vs 10·49 μg/mL), and 19F (14·76 μg/mL vs 11·12 μg/mL; adjusted p value range <0·001 to 0·047). The 2 + 1 schedule was superior for serotypes 6A, 6B, 18C and 23F (adjusted p value range <0·0001 to 0·017). In a predefined numerical subset of all of the infants recruited to the study (n=40 [20%]), functional serotype-specific antibody was similar between schedules. 26 serious adverse events were recorded in 21 (10%) infants across the study period; 18 (n=13) were in the 2 + 1 group and eight (n=8) in the 1 + 1 group. Only one serious adverse event, a high temperature and refusal to feed after the first vaccination visit in a child on the 2+1 schedule was considered related to vaccine. Interpretation: Our findings show that for nine of the 13 serotypes in PCV13, post-booster responses in infants primed with a single dose are equivalent or superior to those seen following the standard UK 2 + 1 schedule. Introducing a 1 + 1 schedule in countries with a mature PCV programme and established herd immunity is likely to maintain population control of vaccine-type pneumococcal disease. Funding: NIHR and the Bill & Melinda Gates Foundation.

Original languageEnglish
Pages (from-to)171-179
Number of pages9
JournalThe Lancet Infectious Diseases
Volume18
Issue number2
DOIs
Publication statusPublished - Feb 2018

Bibliographical note

Funding Information:
MDS acts on behalf of the University of Oxford and Oxford Vaccine Group (OVG) as Chief or Principal Investigator on clinical trials sponsored and/or funded by vaccine manufacturers including Pfizer and GSK and JP, MVP, and EP are employed by the OVG. MDS has participated in advisory board for vaccine manufactures and at industry sponsored symposia; payment for these activities was made to the University of Oxford and MDS received no personal financial benefit. DG has served on ad-hoc advisory boards for GSK, Merck and Sanofi and is a National Institute of Health Research (NIHR) Senior Investigator. The UCL GOSICH Lab (DG, PB, VT, LR, HR) has received contract research funding from GSK, Merck and Sanofi. JS, NJA, and EM declare no competing interests.

Funding Information:
Acknowledgments We thank the participants and their parents, the Buckinghamshire NHS Child Health Information Service for their assistance, Pauline Kaye for managing the laboratory database at PHE and the PHE study nurses in Gloucestershire and Hertfordshire and Oxford Vaccine Group nurses in Oxford for their help in recruitment, vaccination and follow up of participants. The report is based on independent research commissioned and funded by the NIHR Policy Research Programme (Evaluation of suitability of accines for the national immunisation programme. National Vaccine Evaluation Consortium, grant number 039/0031?grant holder EM) and the Gates Foundation (OPP1126431?grant holder DG). The views expressed in the publication are those of the author(s) and not necessarily those of the NHS, the NIHR, the Department of Health, arms length bodies, other government departments, or the Bill & Melinda Gates Foundation.

Funding Information:
We thank the participants and their parents, the Buckinghamshire NHS Child Health Information Service for their assistance, Pauline Kaye for managing the laboratory database at PHE and the PHE study nurses in Gloucestershire and Hertfordshire and Oxford Vaccine Group nurses in Oxford for their help in recruitment, vaccination and follow up of participants. The report is based on independent research commissioned and funded by the NIHR Policy Research Programme (Evaluation of suitability of accines for the national immunisation programme. National Vaccine Evaluation Consortium, grant number 039/0031—grant holder EM) and the Gates Foundation (OPP1126431—grant holder DG). The views expressed in the publication are those of the author(s) and not necessarily those of the NHS, the NIHR, the Department of Health, arms length bodies, other government departments, or the Bill & Melinda Gates Foundation.

Publisher Copyright:
© 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license

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