Tuesday, July 14, 2009

Has swine flu started to mutate?

Has swine flu started to mutate? Does the death of a healthy six-year-old girl mean we have underestimated swine flu? Tracking the way the virus mutates is the key to controlling it, says Wendy Barclay.

By Wendy Barclay Published: 7:49PM BST 14 Jul 2009

The very sad news of fatalities from swine flu sends a shiver of fear through us. The first deaths in Britain of people who were previously considered healthy, including a six-year-old girl, bring home the realisation that this is a virus that can affect us all. Deaths in otherwise healthy people after infection with influenza virus are uncommon, but not unheard of. They usually go relatively unnoticed because each year there are so few. In the autumn of 2003, the seasonal flu strain H3N2 caused a relatively large outbreak, and young children were particularly affected. In Britain there were 17 deaths in those aged under 18 after infection with this strain, none of whom were considered to be in an "at risk" group.

It is an uncomfortable truth that as the numbers of people infected with swine-origin H1N1 influenza virus continue to rise, we will begin to see some fatalities in groups of people who were previously healthy, in addition to those who are predisposed to fare badly, such as asthmatics, people with cardiovascular problems and those who are immuno-compromised.

It is very difficult to be sure of the case-to-fatality rate because we, like many other countries, have stopped counting our case numbers – there are simply too many people infected with this virus to keep track of them all. None the less, it is obvious that the more cases we have, the more people will succumb to severe or even fatal outcomes.

Cutting-edge research by groups in America and Holland published in the past two weeks in key scientific journals such as Science and Nature shows that the swine flu virus is more virulent – in a variety of experimental animal models – than the viruses that have been circulating among humans in recent years. The virus appears to penetrate deeper into the lungs of the infected animals and, at very high doses, this leads to death.

Pneumonia and respiratory failure are hallmarks of swine origin H1N1 infections in countries such as Mexico and the US, which have seen many more cases than we have in Britain. It is important to bear in mind that the severe outcomes in the animals that were experimentally infected only occurred after exposure to high doses of virus. This may be one of the factors that determine why different people fare more or less well upon infection with swine flu. In a naturally acquired infection, it is impossible to know exactly what dose of virus a person got infected with, but it is likely to be much less than is used in the experiments that have been described. Thus, most people who get infected via a natural route will manage to control the virus replication by mounting a robust immune response, and will get better within days.

But, in addition to the dose to which a person is exposed, there are other reasons why different individuals may do more or less well after infection. For the first time, we are experiencing a global infection in an era when we have knowledge of the sequence of our own genome.

This is the largest natural infection experiment ever performed on mankind and it may reveal that there are genetically determined factors that affect how a person copes with virus infection that previously we did not know about.

And on a much smaller genetic scale, we can also study the virus's own genome because we know already from our experience of other flu strains, such as H5N1 bird flu, that very small changes in the virus sequence can have drastic effects on its virulence. It is crucial that we track this type of information in real time at the start of this pandemic.

We need to understand if small changes in the particular strain isolated from severe and fatal cases lead to different behaviours that suggest the virus is "hotting up".

We know from pandemics of the 20th century that there are often two or more waves of disease as the virus sweeps around the world. But we don't really understand why that is: whether the virus from the first wave was an early, milder form that mutated into something more deadly, or whether other factors such as changes in climatic conditions enhanced the spread and infectivity of the virus.

The transmissibility of any altered forms of swine flu will in the end determine how the severity of the disease progresses over the coming months. It may be that more virulent forms transmit less well or not at all, so it is not a given that things will get worse before they get better.

Another trick we have learnt from our intensive study of bird flu in the past decade is how to make vaccines to protect ourselves against new strains of influenza. We always knew that there would be a lead time of several months before a vaccine could be manufactured in sufficient quantities. It is an astounding achievement that this prophylactic strategy may be available to most of us in Britain by the early winter. The vaccine used will be an inactive form of the virus, which means that you cannot catch swine flu from getting the jab. Instead, your immune system will learn how to recognise and respond to the virus, if and when you are exposed. If a second wave does arrive in Britain, then vaccination will be our major public health defence, reducing the number of people infected and the severity of the disease.

Although flu has notoriously been difficult to keep up with because of its fast mutation rate – meaning that vaccines from one year usually won't work against newly emerging strains – it looks as if the way that the new types of swine flu vaccine are to be given will, at least partly, overcome this.

It will be important to keep track of the virus as it circulates through the winter to watch for the drift that will signal that perhaps next year's swine flu vaccine will need to be updated. Because it is highly likely that there will be a next year. This virus has not fizzled out like some thought it might. If anything, it may even displace those flu strains that were circulating in recent years and become the predominant human influenza. We will need to keep a close surveillance on it as it spreads among us, watching out for its ability to cross back into pigs or other animal species, monitoring how it changes as it adapts to its new-found human host and what counter-strategies it may possess or evolve that will affect our policies for its control.

Wendy Barclay is professor of influenza virology at Imperial College London

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