The future of influenza vaccines

The emergence of a novel influenza A (H1N1) virus in Mexico in March
2009, and the realisation of a new pandemic threat to the UK, presents a
challenge to the systems for rapid and urgent deployment of clinical
trials to test vaccines in the United Kingdom. Since swine A (H1N1)
influenza was first recognised in the UK in April 2009, there have been
more than 120 deaths and many thousands of cases with a second wave
predicted to occur this Autumn. Two vaccines have been purchased for use
in the UK and current UK policy focuses on children in high risk groups.
No data were available on the immunogenicity and tolerability of A (H1N1)
vaccines in children and only limited unpublished data on A (H5N1)
vaccines are available leading to a need for data to inform use of these
vaccines in this age group.

In response to this urgent need for paediatric head to head data to
compare the two novel A (H1N1) vaccines in the UK before the onset of a
second wave of influenza, and a call for proposals related to novel A
(H1N1) by National Institute for Health Research (NIHR), we designed a
clinical trial to compare the immunogenicity and tolerability of the two
vaccines in children aged 6 months-12 years. We submitted a collaborative
funding application to NIHR on July 24th 2009, receiving an award letter
on 1st September 2009. We re-deployed trials staff, funded by the NIHR
Oxford Biomedical Research Centre, NIHR Comprehensive Local Research
Networks, Health Protection Agency, Southampton Wellcome Trust Clinical
Research Facility, NHS R&D Departments, St Georges, University of London
and NIHR South West Medicines for Children Local Research Network, to
prepare submissions for ethical, regulatory and NHS R&D approval.
Prioritisation of the review process and the dialogue between
investigators and the senior staff in the reviewing agencies allowed rapid
review and resolution of queries so that three days after submission, the
Oxfordshire research ethics committee reviewed the application, providing
written approval just 18 days later. Submission of a clinical trials
authorisation to the UK regulator (Medicines and Healthcare Regulatory
Agency, MHRA), including dossiers for the two vaccines provided by the
manufacturers, was made on 11th September with written approval after 7
days; NHS research governance approval was received after 19 days.
Furthermore, two separate substantial amendments to the protocol were
reviewed and approved by both the ethics committee and MHRA within 48
hours. The first vaccine was administered on 26th September 2009 and by
the end of the first week almost 500 children had been enrolled, just over
4 weeks after initial submission of the study for ethical and regulatory
review. We expect to complete enrolment of almost a 1000 children 4 weeks
from the administration of the first dose of vaccine.

The efforts, directed by NIHR, the National Research Ethics Service
(NRES), MHRA and NHS research governance departments to get important H1N1
trials off the ground are unprecedented and demonstrate a welcome
responsiveness to this urgent need. Despite the expedited process, the
bureaucratic burden was undiminished such that the capacity provided by
NIHR-funded trials staff at site to initiate the clinical trial
applications proved essential, supporting the need for investment in UK
clinical trials infrastructure by NIHR. These exceptional processes used
for swine flu trials should now be evaluated carefully to provide pointers
towards improved timelines for setting up clinical trials in the UK beyond
the unique situation of a pandemic threat.

AJP, AR, TJ, MS, Oxford Vaccine Group, Department of Paediatrics,
University of Oxford, Oxford

ES, EM, Immunisation Department, Centre for Infection, Health
Protection Agency, Colindale

SF, University of Southampton Wellcome Trust Clinical Research
Facility, Southampton

AC, Royal Devon and Exeter NHS Foundation Trust, Exeter

AF, Bristol Children’s Vaccine Centre, University of Bristol, Bristol

PH, St Georges Vaccine Institute, University of London, London

Competing interests:
Competing interest statement: All authors are involved in the delivery of clinical trials of vaccines on behalf of their institutions and believe that both commercial and non-commercial trials will benefit from improved timelines for review and set up of trials in the UK. The institutions employing the authors are in receipt of research funding for clinical trials from many pharmaceutical and vaccine manufacturers who might benefit from improved delivery of clinical research in the UK.