UOA01-10: Preventing the Spread of H1N1: Immunisation Trials in UK Children
Submitting InstitutionUniversity of Oxford
Unit of AssessmentClinical Medicine
Summary Impact TypeHealth
Research Subject Area(s)
Medical and Health Sciences: Clinical Sciences, Immunology, Medical Microbiology
Summary of the impact
Clinical Trials undertaken by the Oxford Vaccine Group led to the
recommended immunisation of three million UK children during the 2009 H1N1
influenza pandemic. This research was also used to inform World Health
Organization (WHO) global policy. The 2009 H1N1 influenza pandemic, or
"Swine Flu", was first identified in April 2009 and declared a pandemic by
the WHO in June 2009. After acquiring two novel flu vaccines for the 2009
H1N1 influenza virus, the UK government approached the Oxford Vaccine
Group to provide paediatric data on the safety of each vaccine. Rapidly
recruiting 943 children to the study, the Group delivered essential data
to the Department of Health prior to the onset of the winter influenza
season. In August 2010, the WHO declared the H1N1 pandemic over.
The 2009 H1N1 influenza pandemic was a devastating world health crisis.
It claimed the lives of over 294,500 people globally between 2009 and
In autumn 2009, just months after H1N1 flu was declared a pandemic, two
novel influenza A H1N1 vaccines were supplied to the United Kingdom prior
to the winter influenza season. Both vaccines differed in crucial aspects
from the standard `seasonal' influenza vaccines used each season. One,
known as the `split-virion' vaccine (Pandemrix), was the first licensed
vaccine to contain a new adjuvant (AS03B), while the other (Celvapan) was
made from an inactivated version of the whole virus, rather than virus
sub-units. Both vaccines were designed to improve immunogenicity, but
potentially would increase the rates of adverse reactions. Due to the
urgent need for effective vaccines against the H1N1 virus, both Pandemrix
and Celvapan had been licensed for use without having ever been
administered to children — one of the highest risk groups and primary
transmitters of influenza infection. Accordingly, the UK Scientific
Advisory Group for Emergencies (UK-SAGE) identified an urgent need to
obtain paediatric data on the immunogenicity and reactogenicity and other
adverse effects of these vaccines before the expected influenza season in
December. This was judged a national priority.
In view of its extensive experience with paediatric vaccine studies the
University of Oxford's Oxford Vaccine Group was approached to lead an
urgent clinical trial to provide essential data on the safety and
efficiency of these vaccines in children. With protocol development,
ethical, NHS and regulatory approval all `fast-tracked', recruitment of
the first participant came in late September - just five weeks after
provisional funding approval was granted1.
Five weeks later 943 children aged between six months and 12 years were
recruited across five sites. Children received two doses of either the
split-virion or whole-virion vaccine, and blood tests were taken prior to
and three weeks after the immunisation course. Parents mailed diaries
recording immunisation reactions to study sites to allow rapid acquisition
of these data. Crucially, by mid-November the study team provided the
Department of Health with an interim analysis demonstrating that both
vaccines were well tolerated by most children. Immunisation with either
vaccine induced antibody levels above the correlates of protection in most
children, however the split-virion vaccine was the more immunogenic. In
children under 3 years of age antibody concentrations were over ten times
higher following immunisation with the split-virion vaccine than the
whole-virion vaccine2, 3. Surprisingly, children previously
immunised with seasonal influenza vaccines had a lower response to the
`swine-flu' vaccines than influenza vaccine-naïve participants4.
The following year the NIHR funded a `follow-on' study, demonstrating
that 98% of children receiving the split-virion vaccine maintained
Influenza A H1N1 antibodies above the threshold of protection one year
after immunisation, compared with only 51% of children receiving the
whole- virion vaccine5,6. This showed that the administration
of a seasonal influenza vaccine was safe and immunogenic and confirmed the
superiority of the Pandemrix vaccine.
References to the research
1. Pollard AJ et, al. Expediting clinical trials in a pandemic. BMJ.
2009; 339: 1099 - 1100. doi:10.1136/bmj.b4652 Letter
outlining the benefit of an expedited approval process in obtaining
rapid data in an influenza pandemic.
2. Waddington CS et, al. 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:c2649.
doi:10.1136/bmj:c2649 Manuscript reporting results of the head to
head pandemic influenza vaccine study. This article has been cited 67
times in the 2 years since publication (source Harzing's Publish or
3. Waddington C et, al. Open-label, randomised, parallel-group,
multicentre study to evaluate the safety, tolerability and immunogenicity
of an AS03(B)/oil-in-water emulsion-adjuvanted (AS03(B)) split-virion
versus non-adjuvanted whole-virion H1N1 influenza vaccine in UK children 6
months to 12 years of age. Health Technol Assess. 2010;14:1-130.
doi:10.3310/hta14460-01 Extended report on the head to head
pandemic influenza vaccine study included in themed H1N1 influenza and
Pandemic flu publication by NIHR HTA.
4. Andrews NJ et, al. Predictors of immune response and reactogenicity to
AS03B-adjuvanted split virion and non-adjuvanted whole virion H1N1
pandemic influenza vaccines. Vaccine. 2011; 29: 7913-9.
doi:10.1016/jvaccine.2011.08.076 Additional analysis of predictors
of immunogenicity in the influenza vaccine study.
5. Walker WT et, al. H1N1 antibody persistence 1 year after immunization
with an adjuvanted or whole-virion pandemic vaccine and immunogenicity and
reactogenicity of subsequent seasonal influenza vaccine: a multicenter
follow-on study. Clin. Infect Dis. 2012 (Epub Jan 19 ahead of
print). doi:10.1093/cid/cir905. Manuscript reporting results of the
6. de Whalley P et, al. A 1-year follow-on study from a randomized,
head-to-head, multicenter, open-label study of two pandemic influenza
vaccines in children Health Technology Assessment. 2011; 15:1
- 128. doi:10.3310/hta15450 Extended report of results from the
This research was funded by the National Institute for Health Research.
Details of the impact
In the autumn of 2009 public health officials in the United Kingdom were
faced with an emerging influenza A H1N1 pandemic with the potential to
overwhelm the NHS. One of the most effective methods of controlling the
pandemic was likely to be immunisation of children (the `super-spreaders'
of influenza), however there was an almost complete absence of paediatric
data on the two vaccines available in the UK7.
The Oxford Vaccine Group's rapid provision of reactogenicity and
immunogenicity data on the two novel Influenza A H1N1 vaccines to the
Joint Committee for Immunisation and Vaccination (JCVI) and Department of
Health therefore had a profound impact on the immunisation policy for the
2009-2010 influenza A H1N1 pandemic. Specifically, data from an interim
analysis on the rates of systemic and local reactions to immunisation were
provided to the JCVI in mid-November, and gave reassurance that concerns
regarding theoretical risks of high rates of febrile convulsions with
these vaccines were unfounded8,9.
These data were a key element in this committee's subsequent
recommendation to the Department of Health that an influenza vaccine be
offered to all children less than 5 years of age10. By February
2010, 518,000 children had received an influenza A H1N1 vaccine, with
immunisation uptake rates in children varying from 23.6% in England to
44.6% in Scotland11. Almost all of these received the
split-virion vaccine, with the whole-virion vaccine being reserved for
those with an egg allergy.
Although it is not possible to precisely determine the effect of the
immunisation campaign on reducing childhood disease and community spread
of the influenza A H1N1 virus, a single dose of the split-virion vaccine
was found to be 77% (95% C.I. 11% to 94%) effective in preventing
influenza infection in children aged 0- 9 years12. While 70
children died as a result of influenza A H1N1 between June 2009 and March
2010 in England13, only two of these had been immunised,
however, as deaths occurred within 48 hours of immunisation these were not
considered vaccine failures. It is arguable that without the expedited
influenza A H1N1 study, immunisation rates in children would have been
considerably lower with a resultant increase in the paediatric disease
The study received extensive coverage in local and national media14,
15, 16, and its high media profile provided very public evidence
that determining the side-effect profile of the vaccines was an important
aspect of the Department of Health's pandemic influenza strategy. Data on
vaccine reactogenicity and immunogenicity was important not only in
informing the national immunisation strategy, but also in providing an
evidence base for clinicians in their discussions regarding immunisation
with parents. As a result of this research parents could be reassured that
rates of fever after a single dose of split-virus vaccine were low, and
that no unexpected reactions had been observed.
Sources to corroborate the impact
- Scientific Advisory Group for Emergencies (SAGE), Swine Flu. Minutes
of meeting held on 20th May 2009 [online]. Available at:
[Accessed 20th June 2013]. Items 3 and 4 of these minutes relate
SAGE's assessment of the lack of data on the use of the pandemic
influenza vaccines in children, and the urgent need to obtain
reactogencity data on the novel vaccines as a research priority. NB
archived but still available by clicking on link to the UK Government
- Joint Committee on Vaccination and Immunisation (JCVI). Minute of
meeting head on 8th October 2009 [online]. Available at:
[Accessed 20th Junes 2013] Point 24 of these minutes
relates the ongoing attention paid to the paediatric
Influenza A H1N1 vaccine study by the JCVI.
- JCVI updated advice on H1N1v vaccination. 8 December 2009 [online]
[Accessed 20th June 2013] This advice from the JCVI to the
Department of Health recommends use of a single dose spilt virus
vaccine (Pandemrix) for children. Evidence cited in support of this
includes `preliminary data on the reactogenicity of H1N1v vaccine
from a paediatric trial coordinated by the Health Protection
Agency'. This refers to the head to head study led by the Oxford
Vaccine Group - data on reactogenicity was collated and analysed by
the Health Protection Agency.
- Department of Health Pandemic H1N1 (2009) influenza- letter from
Chief Medical Officer, Sir Liam Donaldson (27th January
2010). [online] Available at
[Accessed 20th June 2013]This letter from the Chief Medical
Officer was distributed to all health professionals in the UK, and
outlines the ongoing influenza immunisation policy (including
routine immunisation of children aged 6 months to 5 years), as well
as referencing data on the comparative immunogenicity of the two
vaccines obtained, in part, from the OVG influenza vaccine study.
- Health Protection Agency. Epidemiological report of pandemic (H1N1)
2009 in the UK. October 2010 [online]. Available at:
[Accessed 20thJune 2013]. Page 45 of this report outlines
- Andrews N, Wright, O, Yung CF, Miller E. Age -specific effectiveness
of an oil-in-water adjuvanted pandemic (H1N1) 2009 vaccine against
confirmed infection in high risk groups in England. J. Infect. Dis;
203:32 - 39 (2011). Doi:10:1093/in fdis/jiq014.This
manuscript provides an estimate of effectiveness of immunisation
against pandemic influenza A H1N1 in children.
- Sachedina N, Donaldson LJ. Paediatric mortality related to pandemic
influenza A H1N1 infection in England: an observational population-based
study. The Lancet; 376: 1846 - 52 (2010).
doi:10.1016/S0140-6736(10)61195-6 This manuscript, co-authored by
the then chief medical officer, reports the numbers of childhood
deaths from pandemic influenza.
- BBC news `Babies will test swine flu jabs' [online]. 23rd
September 2009 Available at:
[Accessed 20th June 2013] BBC media report announcing
the impending pandemic influenza vaccine study, evidence of the high
public profile of the study and providing public reassurance that
collecting data on the safety of these vaccines was a Department of
- BBC news `UK children receive swine flu jab' [online] 29th
September 2009 Available at
[Accessed 20th June 2013]. Further media report on the
pandemic influenza vaccine study, which followed the first weekend
of recruitment. This was accompanied by television interviews with
- The Guardian `Children respond well to swine flu vaccines, trial
shows' 28th May 2010 [online] . Available at: http://www.guardian.co.uk/world/2010/may/28/children-swine-flu-vaccine-trial
[Accessed 20th June 2013]. Print media report on the
final publication of study results.