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Swine flu science: the story so far

Jonathan Wood

When the first reports of swine flu cases in Mexico emerged in early April, it wasn’t just health authorities and governments that leapt into action. Researchers – including many at Oxford – also rushed to find out more about the new flu virus and its spread to help guide public health responses in the UK and worldwide.

The vast majority of people with swine flu continue to experience mild symptoms and there is little evidence so far that the virus is changing. But as we wait for an expected second wave in the autumn or winter, researchers are investigating questions that will guide the next phase of the response.

In August, the National Institute for Health Research (NIHR) announced funding for a number of projects around the UK to provide evidence to guide the government’s response in the coming months. These projects cover everything from how to tell which patients with suspected swine flu should be admitted to hospital to the impact of school closures in preventing spread of the virus.

Oxford is heavily involved in two of these studies: a comparison of two swine flu vaccines in children and an investigation of the effect of flu in pregnancy.

Which vaccine for children?
Professor Andrew Pollard of the Oxford Vaccine Group is chief investigator of a study running this month that is comparing head-to-head the use of two vaccines in children. The two vaccines are the ones the Department of Health has purchased to control the expected second wave this autumn, and from this week they are already beginning to be used among high-risk groups and frontline healthcare workers. Use of the vaccines could be expanded more widely later, but information about their most effective use in children is limited.

‘We will look at the immune response each vaccine generates in children, and also carefully study any side-effects that might occur such as soreness at the injection site and fever,’ says Professor Pollard. ‘Results should be available later in the autumn to inform government and guide immunisation strategy, but also to help decisions by healthcare workers and parents. The study will tell us the balance of protection against swine flu and side-effects.’

Around 1,000 children aged between six months and 12 years at five centres around the country (including Oxford’s Children’s Hospital) are being given two doses of a swine flu vaccine three weeks apart in the study being undertaken in collaboration with the Health Protection Agency. Blood tests are also taken using a local anaesthetic cream before and after the two immunisations to check each child’s response to the vaccines.

‘Children have poorer responses to influenza vaccines but are also one of the age groups likely to be most vulnerable to swine flu infection, so it is vital that we obtain information on their response to these vaccines. This study will help in decisions about which vaccine will be best for protecting children,’ Professor Pollard explains.

Advice for pregnant women
Pregnant women are known to be a group at higher risk from all types of flu including normal seasonal flu. To make sure the best information is available about managing swine flu during pregnancy, Dr Marian Knight at the National Perinatal Epidemiology Unit [NPEU] will be logging all admissions of women with swine flu at maternity units across the UK. This will go hand-in-hand with work led by Professor Simon Thomas at Newcastle University that will review how cases are handled by GPs and midwives in the community.

‘We’ll be looking at what treatments are used and the timing of those treatments to see what’s helpful. We’ll also see if any characteristics – the mother’s age, whether they’ve had babies before, when they got ill – are associated with any risk of complications for the mother or infant,’ explains Dr Knight. ‘It will help doctors and midwives give the best care during a pandemic.’

Data are already being recorded and the Oxford team are reporting the latest results monthly from the middle of this month. The researchers are collaborating with the Royal Colleges of Obstetricians, Midwives and General Practitioners, the Department of Health, and the Health Protection Agency, so that the best use of the data is assured.

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Swine flu origins
It’s easy to forget how little was known about swine flu in the very beginning with the first reported cases in Mexico and the US, not least its severity and where it came from. Right back at the start of the outbreak, when health agencies were racing to understand the new flu strain and how virulent it might be, Oliver Pybus of the Department of Zoology was part of international research groups that sought to characterise the new virus genetically.

The early papers they published in Science and Nature in June showed that the virus had come from pigs and had probably been circulating in people since the beginning of 2009 – three months before it was first identified. ‘This was reassuring at the time, as it suggested that the new H1N1 swine flu wasn’t very virulent in humans because it would have been picked up sooner,’ says Dr Pybus.

One other finding from that work might become more important in the future, Dr Pybus notes. Before it jumped into humans, the research suggest the new swine flu virus may have been hiding in pigs for around 10 years without being noticed by scientists.

‘Although we have good surveillance systems for monitoring flu strains in circulation in birds and humans, there may be a surveillance gap in pigs,’ says Dr Pybus. He is now part of an international consortium that aims to plug this gap.

Global response
Professor Jeremy Farrar also got involved at the start. He leads the University’s Clinical Research Unit [CRU] in Vietnam, which has been working on flu since 2004 when bird flu reached the country. The unit also coordinates the South-East Asia Infectious Disease Clinical Research Network (SEAICRN), supported by the US National Institutes of Health, the World Health Organisation, and the Wellcome Trust. Its largest focus is on flu.

With an interdisciplinary team of clinicians, pharmacologists, virologists, immunologists and ethicists, the unit aims to help lead thinking on how the world responds to pandemic threats, along with collaborators in the US and Europe. This also includes how the research world can put systems in place to be able to respond swiftly and learn lessons from new epidemics of infectious disease.

Professor Farrar has been involved in guiding the responses to swine flu in Mexico and Argentina, both countries that have seen a large number of cases. For example, he visited Mexico in May at the peak of the outbreak there, to share ideas and experiences from his involvement in H5N1 bird flu. Hospitals there were particularly keen to understand how they could share information better and work together as a group. Their initial response to swine flu had been slowed when no one hospital saw a noticeable increase in number of flu cases above the normal level. Teams in Mexico have now adapted research protocols from the CRU in Vietnam and translated them into Spanish.

He has also been involved in discussions in the UK to try and link the blood transfusion service and intensive care (ITU) units. The aim is to conduct a trial in the UK of plasma therapy for optimising the use of ITU beds in the event of a large number of severe cases this winter, making sure as many people as possible won’t require intensive care beds.

But there is still a lack of clinical research about some aspects of influenza, according to Professor Farrar. ‘For example, pregnant women and obese people seem to be more at risk, yet we don’t know why or whether such people need different doses of antiviral drugs and whether their bodies handle the drug differently. As part of the SEAICRN, we are conducting a large trial to determine appropriate does of oseltamivir (Tamiflu) in cases of severe influenza, whether that’s H5N1 bird flu, seasonal flu, or H1N1 swine flu.

‘We are also concerned about the potential for the virus to become resistant to the available drugs and there are individual reports now from many countries. Such a development could have major implications for treatment of more severe cases in a second wave.’

Use of antivirals
Drs Matthew Thompson and Carl Heneghan in the Department of Public Health have also been interested in the use of antivirals for flu. When swine flu emerged, they were working on a review of the available evidence on the effectiveness of antivirals in children for seasonal flu. Their paper, published in the BMJ in August, received a great deal of interest.

They showed that the benefits of taking Tamiflu or Relenza in terms of shortening the duration of flu symptoms and reducing spread of the virus were quite small. They suggested that the UK Government’s policy of making Tamiflu available to all who reported swine flu symptoms, regardless of their severity, was neither ‘a necessary nor appropriate strategy’.

Although the Government have stood by their ‘safety-first’ strategy, Matthew Thompson believes that the emphasis of the World Health Organisation and US Centre for Disease Control’s advice subsequently shifted to emphasise that antiviral use is not necessary in those with mild flu-like symptoms.

‘The Government’s vaccination programme for swine flu is now starting, added onto the normal seasonal flu programme’ says Dr Thompson, who is also a GP. ‘And there is likely to be a benefit for some patients, the same patients who get the flu jab every year. But Tamiflu will continue to be recommended on the flu helpline. With winter coming on, it will also become increasingly difficult to distinguish typical coughs and colds from the similar symptoms of swine flu, possibly leading to further inappropriate use of antivirals.’

Dr Thompson is now shifting his attention slightly. The research team to which he belongs is hoping to secure funding to carry out a trial of antibiotic use in children with flu. This would help show whether it is bacterial infections on top of flu that tend to cause the most severe complications, and whether antibiotics might have a beneficial effect.

It's clear from all of these examples that Oxford’s research on swine flu will continue to guide the public health measures taken and the care provided for us all.