Every winter, many of us will get the flu. Most people will get better after a few days, but for certain vulnerable people, it can have serious consequences, including pneumonia.
The prevailing strain of virus changes a little every year and an annual programme of immunisation, with a fresh vaccine, is conducted during the autumn in the UK. Some immunity carries over from year to year for this ‘seasonal’ flu, but every few years a quite different flu virus emerges in the world causing a pandemic, to which most people do not have immunity. It can spread quickly because of the susceptibility of the population.
Countries such as the UK have plans in place for pandemics, which include immunisation, treatment, separation of affected people, and health services to manage the potentially large numbers of people who suffer the effects and complications of flu.
Lessons from the last pandemic, in 2009, are still relevant for managing new outbreaks and organising future research. This highlight discusses the results of a number of influential projects funded by the NIHR during this pandemic. It also provides information about a new set of projects, commissioned and currently in ‘hibernation’ - ready to be rolled out in the event of a new pandemic.
Published: December 2016
NIHR research examined two different vaccines developed to tackle the 2009 pandemic.
cases in the UK during 2009 pandemic
deaths in the UK during 2009 pandemic
effectiveness of new (adjuvanted) vaccine
The World Health Organisation defines a flu pandemic as occurring when a new flu virus emerges and spreads around the world and most people do not have immunity.
How did vaccines help in the pandemic?
- Two new vaccines – tested during the last flu pandemic – both offered immunity to the H1N1 strain of flu.
- An ‘adjuvanted’ vaccine (one that uses an additional ingredient as well as the virus) produced immunity in more people but resulted in more adverse reactions such as fever.
- Overall the adjuvanted vaccine appeared the best option, though older people may need two doses to develop immunity.
- The flu vaccine proved highly effective in preventing flu and associated complications such as pneumonia.
How does pandemic flu affect pregnant women and their babies?
- Pregnant women who develop flu have a greater risk of complications such as premature delivery, especially if they smoke, have asthma, are overweight or obese.
- Antiviral drugs given to pregnant women with flu reduced the severity of their illness.
What lessons were learned for future research in a pandemic?
- The NIHR is ready to support vital research in the event of another flu pandemic. A portfolio of approved studies is ready and waiting to start, which will enable faster and more effective research if and when the time comes.
Questions for clinicians and members of the public
- Do we have a reliable system in place to ensure that pregnant women and children receive a seasonal flu vaccination?
- Am in a ‘high risk’ group for flu?
- Do I know how to and when to get a seasonal flu vaccination?
NIHR studies showed that new vaccines, developed for the specific pandemic flu strain, were effective in protecting people.
Two different vaccines were developed to immunise against the new (H1N1) strain. More than one vaccine was needed, firstly to ensure a sustainable supply, and secondly to reduce the chance of an effective vaccine being unavailable.
One was an adjuvant vaccine - using part of the virus and an extra ingredient - to improve the immune response. The other used the whole virus to achieve a response.
Research showed that both vaccines gave people immunity to the H1N1 strain of flu, but that there were some differences.
Which vaccine worked best?
Two vaccine trials were carried out quickly, one in children and the other in adults. The results in the two age groups were broadly similar, with both producing a good immune response. The adjuvanted vaccine produced immunity in more people but it resulted in more adverse reactions, such as fever or pain at the injection site. For example, adjuvanted vaccine gave 98% of under threes immunity compared to 80% in the whole virus. But 22% of under-fives had a fever from the adjuvanted vaccine, compared to just 9% with the whole virus.
"The adjuvanted vaccine.. could induce immune responses which were better than we usually see in young children but with a quarter of the dose.
"This is especially important in the context of a pandemic where it may be necessary to spread as many doses as possible across a population, in order to try to protect as many people as possible."
Professor Andrew Pollard, University of Oxford
In adults, a similar pattern of greater benefit at the expense of an increase in reactions was seen, although overall the adjuvanted vaccine appears the best option and many adults will only need one dose.
Older people have a weaker immune response and the research suggested that they needed two doses of the H1N1 vaccine to develop immunity in the pandemic.
A larger study
As well as trials, NIHR funded the large VIPER study to observe the protection given by the vaccination programme implemented through a sample of general practices in Scotland. This compared flu and hospital admission rates in people who did, and did not, have the vaccine, adjusting for possible confounding factors such as gender, age, deprivation and risk due to morbidity.
This study was possible because of the good system of linked medical records in Scotland. It suggested that the pandemic flu vaccine was 95% effective in preventing flu and 100% effective at preventing complications, such as pneumonia requiring hospital admission. The limitations of the study may mean that the real benefit is slightly less than this, but the vaccine is likely to be very protective.
"An influenza pandemic, with the emergence of a new virus, provides huge challenges to the research community to identify rapidly safe and effective interventions that can reduce the impact of such a virus. The mechanisms developed by NIHR play a key role in enabling that to happen.”
Dr Richard Pebody, Public Health England
Before the 2009 pandemic, it was already known that pregnant women are more susceptible to the complications of flu, such as pneumonia. NIHR research also showed that if women caught flu during the pandemic, their babies were at greater risk of being born prematurely or even stillborn.
The risk to unborn babies is greatest when mothers develop serious complications but treating mothers with antiviral drugs appears to reduce the chance of pneumonia. Therefore it makes sense to make them a priority for the prevention and treatment of flu.
The study made use of existing reliable data collection systems, including the UK Obstetric Surveillance System (UKOSS) and information systems in primary care and hospitals. The researchers were able to identify factors that made women more susceptible to serious illness and estimate the benefits of antiviral drugs. The study was not a ‘gold-standard’ randomised trial, but the results are likely to be reliable and are the best that could be achieved in the heat and urgency of a pandemic.
"It’s important to remember that there are some situations – and a flu pandemic is perhaps one of them – where it’s really difficult to do ‘gold standard’ randomised controlled trials. But we can learn a lot from simply collecting information and observing what happens to women who are treated or not treated, in this case with anti-viral drugs.”
Professor Marian Knight, Professor of Maternal and Child Population Health
Pregnant women who get flu are more likely to need admission to hospital for complications if they smoke, have asthma, or are overweight or obese. In those women needing admission for flu, the risk of their baby dying was nearly four in a hundred whereas it was less than one percent in uninfected women.
Fortunately, there was evidence that antiviral drugs given in hospital can reduce the severity of the mothers’ illness. For instance, they reduced the chance of needing intensive care by 84 percent. While the numbers were too small to see a benefit to babies, it is possible that they too will benefit from their mothers being less unwell.
The emergence of these results during the pandemic was very important and enabled a change of policy to make antiviral drugs more easily available to pregnant women. This research strongly informs public health measures to make flu vaccine and drugs available to pregnant women in future pandemics. It also supports the need for effective public health measures to reduce smoking and obesity in this group as well as the population at large.
As with any condition, research is needed to identify the best treatment and management of flu. The results can be used with routine surveillance data to improve the outcomes for individuals and the population as a whole.
Research results about the usual seasonal flu might not apply in pandemic years, so new studies can be needed, perhaps at short notice, to help with the impact of a rapidly spreading virus.
A commentary on the achievement of the 2009 research programme was published in early 2010, at about the time when results from the research were appearing.
We learned that the research community, funders and regulators can work effectively to get research done quickly, and the whole-system approach of NIHR was very helpful. There will still be difficulties in meeting `real-time’ demand for evidence so with that in mind, NIHR funded some new projects, such as the two described here, which will use pre-existing systems and infrastructure (for example the Practice Team Information system in Scotland or the UK Obstetric Surveillance System) to respond quickly and effectively to the next crisis.
“The series of studies undertaken by NIHR during the 2009 pandemic provided us with a blueprint for how to respond to health emergencies such as pandemic flu. Similar processes were later used to fast-track early-phase studies to evaluate Ebola vaccines in the wake of the Ebola outbreak in West Africa, making the UK the leader in such studies.”
Professor Andrew Pollard, University of Oxford
NIHR gives potential flu research a head start
Getting ethics and other approvals exceptionally quickly was also essential to enable research to be undertaken during the pandemic. This is not always possible; trials, in particular, may need time to develop their protocols and pilot their methods. One way around this is to pre-approve study protocols based on some preliminary preparatory work. This has been done by NIHR, and it is an approach that is endorsed by the Academy of Medical Sciences report Treating Influenza (http://www.acmedsci.ac.uk/policy/policy-projects/treating-influenza/).
There are currently a number of funded, approved, projects ‘in hibernation’ until a pandemic appears again (if one does). This research was fast-tracked to provide answers to uncertainties at the time of the pandemic and in preparation for any future crises.
“I think it’s a fantastic idea that we now have some studies that are ‘hibernated’, ready to be activated in the event of a future pandemic. We all know that our health services are very pressurised when we have emergency situations like that. Now we’ve got these studies ready to go to give us the answers we need, we will be able to get those answers much more quickly next time.”
Professor Marian Knight, leader of the UK obstetric surveillance system
Although they will need reviewing periodically for continuing relevance, this ability to start important research quickly enough for the results to be used in real time during a pandemic is a major step forward in research in a global emergency.
“We can be sure of one thing: there will be another influenza pandemic. We don’t know when that will be or which strain of influenza will cause it. Therefore we need to be ready to respond again next time, just as we did in 2009, to protect the health of our population.”
Professor Andrew Pollard, University of Oxford
This Highlight draws on the following NIHR funded research studies:
Influenza A/H1N1v in pregnancy:
Yates L, Pierce M, Stephens S, Mill AC, Spark P, Kurinczuk JJ, et al.Influenza A/H1N1v in pregnancy: An investigation of the characteristics and management of affected women and the relationship to pregnancy outcomes for mother and infant. Health Technol Assess 2010;14(34).
Simpson CR, Ritchie LD, Robertson C, Sheikh A, McMenamin J.Vaccine effectiveness in pandemic influenza - primary care reporting (VIPER): an observational study to assess the effectiveness of the pandemic influenza A (H1N1) v vaccine. Health Technol Assess 2010;14(34).
Comparing two H1N1 vaccines in children:
Waddington C, Andrews N, Hoschler K, Walker W, Oeser C, Reiner A, et al.Open Label, Randomized, Parallel-Group, Multi-Centre Study to Evaluate the Safety, Tolerability and Immunogenicity of an AS03B /oil-in-water emulsion-adjuvanted (AS03B) split-virion vs. non-adjuvanted whole virion H1N1 influenza vaccine in UK children 6 months to 12 years of age. Health Technol Assess 2010;14(46)
A follow-up study comparing two H1N1 vaccines in children:
de Whalley P, Walker W, Snape MD, Oeser C, Casey M, Moulsdale P, et al.A 1-year follow-on study from a randomised, head-to-head, multicentre, open-label study of two pandemic influenza vaccines in children. Health Technol Assess 2012;15(45)
Comparison of two H1N1 vaccines in adults:
Nicholson KG, Abrams KR, Batham S, Clark TW, Hoschler K, Lim WS, et al.A randomised, partially observer-blind, multi-centre, head-to-head comparison of a two dose regimen of Baxter and GSK H1N1 pandemic vaccines, administered 21 days apart. Health Technol Assess 2011;14(55)
Published outputs from these studies
Pierce, M; Kurinczuk, J; Spark, P; Brocklehurst, P; Knight, M. BMJ 2011;342:d3214
Simpson CR, Ritchie LD, Robertson C, Sheikh A, McMenamin J. Lancet Infectious Diseases 2012;Volume 12, Issue 9, Pages 696 - 702, September 2012 doi:10.1016/S14
Andrews N J, Walker W T, Finn A, Heath P T, Collinson A, Pollard A J, Snape M, Faust S N, Waight P A, Hoschler K, Sheasby L, Waddington C, Kerridge S, Chalk J, John T, Fletcher M, Allen R, Fineman N, Wilkins S, Casey M, Michaelis L, Oeser C, Okiki I, Ladhani S, Miller E. Vaccine 2011;29(45):7913-9
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
Waddington, C. S.; et al. BMJ 2010;340:c2649
T-cell responses in children to internal influenza antigens, 1 year after immunisation with pandemic H1N1 influenza vaccine, and response to revaccination with seasonal trivalent inactivated influenza vaccine
Lambe, T; Spencer, AJ; Mullarkey, CE; Antrobus, RD; Yu, L; de Whalley, P; Thompson, BAV; Jones, C; Chalk, J; Kerridge, S; Hill, AVS; Snape, MD; Pollard, AJ; Gilbert, SC. Pediatric Infectious Disease Journal 2012;31(6):e86-91
H1N1 antibody persistence one year after immunisation with an adjuvanted or whole virion pandemic vaccine and immunogenicity and reactogenicity of subsequent seasonal influenza vaccine: a multi-centre follow-on study
Walker, WT; de Whalley, P; Andrews, N; Oeser, C; Casey, M; Michaelis, L; Hoschler, K; Harrill, C; Moulsdale, P; Thompson, B; Jones, C; Chalk, J; Kerridge, S; John, T; Okike, I; Ladhani, S; Tomlinson, R; Heath, PT; Miller, E; Faust, SN; Snape, MD; Finn, A; Pollard, AJ. Clinical Infectious Diseases 2012;10.1093/cid/cir905
Walley, T;Davidson, P. Lancet 2010; 375.972
Guidance on immunisation is based on the available evidence and best practice.
Public Health England recommend that certain groups who are at increased risk should have a free flu vaccination.
The groups include:
- long-term conditions - heart problems, chest complaints or breathing difficulties, kidney disease, lowered immunity due to disease or treatment, liver disease, had a stroke or a transient ischaemic attack, diabetes, neurological conditions
- aged 65 years or over
- living in a residential or nursing home
- the main carer of an older or disabled person
- a household contact of an immunocompromised person
- a frontline health or social care worker
- all two-, three- and four-year-old children, all children in school years 1, 2 and 3 and all primary school-aged children in some parts of the country, children over the age of six months with a long-term health condition
The Joint Committee on Vaccination and Immunisation (JCVI) advises UK health departments on immunisation programmes. https://www.gov.uk/government/groups/joint-committee-on-vaccination-and-immunisation
They produce their recommendations for public health professionals in the “Green Book” https://www.gov.uk/government/publications/immunisation-procedures-the-green-book-chapter-4
Guidance on influenza immunisation from the JCVI includes:
The use of nasal spray flu vaccine for the UK childhood influenza immunisation programme (2016):
“Given the strong evidence that the NHS childhood flu immunisation programme continues to protect the health of both children and the wider population, JCVI agreed to continue to recommend the use of the children's nasal spray flu vaccine for preventing flu in children, and more widely in our communities.”
The number of doses of flu vaccine that should be offered to children (2013):
“From 2013, a single dose of live attenuated influenza vaccine (LAIV) should be offered to children irrespective of whether influenza vaccine had been received before or not. However, influenza vaccine naïve children who are aged six months to less than nine years in clinical risk groups, or who are offered inactivated influenza vaccine as LAIV is unsuitable for them, may have greater benefit from the direct protection provided by a second dose of vaccine”.
Routine annual influence vaccine programme:
The National Institute for Health and Care Excellence (NICE) have provided guidance on individual influenza vaccines.
Amantadine, oseltamivir and zanamivir (2009) https://www.nice.org.uk/guidance/ta168
Oseltamivir and zanamivir are recommended as possible treatments for people with flu if they meet certain criteria such as being in an at-risk group and the flu virus is going around. Amantadine is not recommended to treat people with flu.
Oseltamivir, amantadine (review) and zanamivir for the prophylaxis of influenza (2008) https://www.nice.org.uk/guidance/ta158
NICE are also developing guidance on how to increase the uptake of flu vaccinations, which will be released in January 2018. https://www.nice.org.uk/guidance/indevelopment/gid-phg96
Further NIHR studies on Pandemic Flu
The NIHR has funded a range of studies from systematic reviews to large clinical trials on pandemic flu. The HTA journal series has 3 special themed editions that showcase such research:
Health Technology Assessment Journal, Volume 14, 2011 http://www.journalslibrary.nihr.ac.uk/hta/volume-14
Editions 34 (6 articles), 46 (5 articles), and 55 (6 articles).
NIHR also funded studies on Heath Preparedness for Emergencies:
A scoping study of emergency planning and management in health care: What further research is needed?
Boyd A, Chambers N, French S, King RA, Shaw D, Whitehead A. NIHR Health Services and Delivery Research programme, 2012.
Emergency planning in health: Scoping study of the international literature, local information resources and key stakeholders.
Lee ACK, Challen K, Gardois P, Mackway-Jones K, Carley SD, Phillips W, Booth A, Walter D, Goodacre S. NIHR Service Delivery and Organisation programme, 2012.