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Safety and immunogenicity of AS03B adjuvanted split virion versus non-adjuvanted whole virion H1N1 influenza vaccine in UK children aged 6 months-12 years: open label, randomised, parallel group, multicentre study

BMJ 2010; 340 doi: https://doi.org/10.1136/bmj.c2649 (Published 27 May 2010) Cite this as: BMJ 2010;340:c2649
  1. Claire S Waddington, clinical research fellow1,
  2. W T Walker, Wellcome Trust clinical research facility fellow2,
  3. C Oeser, clinical research fellow3,
  4. A Reiner, project manager1,
  5. T John, clinical team lead1,
  6. S Wilkins, research nurse4,
  7. M Casey, children’s senior research sister2,
  8. P E Eccleston, data manager5,
  9. R J Allen, research network manager5,
  10. I Okike, clinical research fellow3,
  11. S Ladhani, consultant in paediatric infectious diseases36,
  12. E Sheasby, quality manager6,
  13. K Hoschler, advanced healthcare scientist and clinical scientist6,
  14. N Andrews, senior statistician6,
  15. P Waight, senior scientific data analyst6,
  16. A C Collinson, consultant paediatrician, co-director of Medicines for Children Research Network, south west4,
  17. P T Heath, reader, honorary consultant in paediatric infectious diseases, executive officer paediatric studies3,
  18. A Finn, David Baum professor of paediatrics, director of Medicines for Children Research Network, south west5,
  19. S N Faust, senior lecturer in paediatric immunology and infectious diseases, director Wellcome Trust clinical research facility2,
  20. M D Snape, consultant paediatrician and vaccinologist1,
  21. E Miller, professor, consultant epidemiologist6,
  22. A J Pollard, professor of paediatric infection and immunity, director of the Oxford Vaccine Group, honorary consultant paediatrician1
  1. 1Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford OX3 7LJ
  2. 2University of Southampton Wellcome Trust Clinical Research Facility and Division of Infection, Inflammation and Immunity, Southampton SO16 6YD
  3. 3St George’s Vaccine Institute, London SW17 0QT
  4. 4Royal Devon and Exeter NHS Foundation Trust, Exeter EX2 5DW
  5. 5Bristol Children’s Vaccine Centre, University Hospitals Bristol NHS Foundation Trust and University of Bristol, Bristol BS2 8AE
  6. 6Centre for Infections, Health Protection Agency, London NW9 5EQ
  1. Correspondence to: C S Waddington claire.waddington{at}paediatrics.ox.ac.uk
  • Accepted 12 May 2010

Abstract

Objectives To compare the safety, reactogenicity, and immunogenicity of an adjuvanted split virion H1N1 vaccine and a non-adjuvanted whole virion vaccine used in the pandemic immunisation programme in the United Kingdom.

Design Open label, randomised, parallel group, phase II study.

Setting Five UK centres (Oxford, Southampton, Bristol, Exeter, and London).

Participants Children aged 6 months to less than 13 years for whom a parent or guardian had provided written informed consent and who were able to comply with study procedures were eligible. Those with laboratory confirmed pandemic H1N1 influenza or clinically diagnosed disease meriting antiviral treatment, allergy to egg or any other vaccine components, or coagulation defects, or who were severely immunocompromised or had recently received blood products were excluded. Children were grouped by age: 6 months-<3 years (younger group) and 3-<13 years (older group). Recruitment was by media advertising and direct mailing. Recruitment visits were attended by 949 participants, of whom 943 were enrolled and 937 included in the per protocol analysis.

Interventions Participants were randomised 1:1 to receive AS03B (tocopherol based oil in water emulsion) adjuvanted split virion vaccine derived from egg culture or non-adjuvanted whole virion vaccine derived from cell culture. Both were given as two doses 21 days apart. Reactogenicity data were collected for one week after immunisation by diary card. Serum samples were collected at baseline and after the second dose.

Main outcome measures Primary reactogenicity end points were frequency and severity of fever, tenderness, swelling, and erythema after vaccination. Immunogenicity was measured by microneutralisation and haemagglutination inhibition assays. The primary immunogenicity objective was a comparison between vaccines of the percentage of participants showing seroconversion by the microneutralisation assay (fourfold rise to a titre of ≥1:40 from before vaccination to three weeks after the second dose).

Results Seroconversion rates were higher after the adjuvanted split virion vaccine than after the whole virion vaccine, most notably in the youngest children (163 of 166 participants with paired serum samples (98.2%, 95% confidence interval 94.8% to 99.6%) v 157 of 196 (80.1%, 73.8% to 85.5%), P<0.001) in children under 3 years and 226 of 228 (99.1%, 96.9% to 99.9%) v 95.9%, 92.4% to 98.1%, P=0.03) in those over 3 years). The adjuvanted split virion vaccine was more reactogenic than the whole virion vaccine, with more frequent systemic reactions and severe local reactions in children aged over 5 years after dose one (13 (7.2%, 3.9% to 12%) v 2 (1.1%, 0.1% to 3.9%), P<0.001) and dose two (15 (8.5%, 4.8% to 13.7%) v 2 (1.1%, 0.1% to 4.1%), P<0.002) and after dose two in those under 5 years (15 (5.9%, 3.3% to 9.6%) v 0 (0.0%, 0% to 1.4%), P<0.001). Dose two of the adjuvanted split virion vaccine was more reactogenic than dose one, especially for fever ≥38ºC in those aged under 5 (24 (8.9%, 5.8% to 12.9%) v 57 (22.4%, 17.5% to 28.1%), P<0.001).

Conclusions In this first direct comparison of an AS03B adjuvanted split virion versus whole virion non-adjuvanted H1N1 vaccine, the adjuvanted vaccine, while more reactogenic, was more immunogenic and, importantly, achieved high seroconversion rates in children aged less than 3 years. This indicates the potential for improved immunogenicity of influenza vaccines in this age group.

Trial registration Clinical trials.gov NCT00980850; ISRCTN89141709.

Footnotes

  • We thank the parents and children who participated in the trials and are grateful for the clinical and administrative assistance of the National Institute of Health Research (NIHR), National Research Ethics Service (NRES), Medicines and Healthcare Products Regulatory Agency (MHRA), National Health Service (NHS), Thames Valley, Hampshire and Isle of Wight, and South London NIHR CLRNs, NIHR Medicines for Children Research Network (MCRN), the Southampton University Hospitals NHS Trust Research and Development Office, Child Health Computer Departments of Primary Care Trusts in Oxford, Southampton, Bristol, Exeter, and London (Wandsworth), the NIHR Oxford Biomedical Research Centre (BRC), the Health Protection Agency Centre for Infections for both administrative assistance and laboratory support, the staff of the Clinical Trials Research Governance, University of Oxford, members of the trial steering committee (Stephen Evans (chair), Simon Bevan, Heather House, Simon Knoll, Stephen Welch, Elizabeth Miller, and Andrew Pollard) and the data monitoring committee (Philip Monk (chair), Delane Shingadia, Chris Verit, and Paula Williamson).

  • Contributors: AJP, MDS, EM, SNF, AF, PTH, ACC, NA, KH, and CSW designed the study with critical input from all authors. AJP was chief investigator. MDS, SNF, AF, PTH, and ACC were local principal investigators. NA was responsible for statistical analysis, KH for laboratory analysis and PW, PEE and ES for data management, all with oversight and guidance by EM (lead investigator). AR and RJA were project managers. CSW, WTW, CO, TJ, SW, MC, PEE, RA, IO, SL, ACC, PTH, AF, SNF, MDS, and AJP enrolled patients and/or contributed to data collection. CSW drafted this report, which was subsequently reviewed by all authors. All authors have seen the final submitted report and agree with its contents. All authors had full access to all the data (including statistical reports and tables) in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

  • Funding: This study was funded by the NIHR Health Technology Assessment Programme and was supported by the NIHR Oxford Comprehensive Biomedical Research Centre programme (including salary support for AR, TMJ, and MDS), and the Thames Valley, Hampshire and Isle of Wight and Western (salary support for CDS) Comprehensive Local Research Networks and the Southampton Respiratory NIHR Biomedical Research Unit. None of the funders had a role in study design, data collection, data analysis, data interpretation, or writing of the report. This study was adopted by the NIHR Medicines for Children Research Network and supported by their South West and London-South East, North, Central, and East (SENCE) Local Research Networks. AJP is a Jenner Institute Investigator.

  • Competing interests: Vaccines were manufactured by GlaxoSmithKline vaccines and Baxter, both of whom donated the vaccine but had no role in study planning or conduct. All authors have completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare that they had (1) No Financial support for the submitted work. (2) AJP, AF, PTH, SNF, and ACC have received research grants and honoraria from vaccine manufacturers. All grants and honoraria are paid into accounts within the respective NHS trusts or universities, or to independent charities; AJP, AF, PTH, and SNF have participated in advisory boards for vaccine manufacturers but receive no personal payments for this work. MDS, PTH, and AF have received financial assistance from vaccine manufacturers to attend conferences. (3) No authors have spouses, partners, or children with relationships with commercial entities that might have an interest in the submitted work. (4) No authors have financial interests that may be relevant to the submitted work.

  • Ethical approval: This study was approved by the Oxfordshire Research Ethics Committee A (No 09/H0604/107), the UK Medicines and Healthcare Products Regulatory Agency (EUDRACT 2009-014719-11), and local NHS organisations by an expedited process.32 Parents or guardians gave written informed consent; children aged 7 and over gave verbal consent.

  • Data sharing: The authors will consider appropriate requests for data sharing that do not breach the consent obtained from the participants’ parents. Please contact claire.waddington{at}paediatrics.ox.ac.uk.

  • Accepted 12 May 2010

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