The government's strategy to prevent a flu pandemic is inadequate because the H5N1 virus can develop resistance to the only drug being stockpiled in the UK, scientists warned today.

A report by the Royal Society and the Academy of Medical Sciences said that in order to properly combat a pandemic, the UK should stockpile not only Tamiflu but also Relenza, another antiviral drug.

The report - called Pandemic influenza: science to policy - says two patients being treated with Tamiflu in Vietnam died after the H5N1 bird flu virus in their bloodstream rapidly developed resistance to the drug.

It also questions whether the government has stockpiled enough Tamiflu to deal with a pandemic. As of September, there were 14.6m courses of the drug, enough for a quarter of the population.

The document raises concerns that the Department of Health (DoH) did not appear to have sought advice over the size of the stockpile from either its own public health advisory body, the Health Protection Agency, or the drug's manufacturer, Roche.

"We are concerned that decisions are being made, as the UK prepares for a possible pandemic, that fail to take account of expert advice," Sir John Skehel, the chairman of the report's working group, said.

"For example, the decision to continue to stockpile just one antiviral drug is a major concern. This needs to be reconsidered.

"New evidence that H5N1 can develop resistance to Tamiflu indicates that a combination of antivirals should be stockpiled by the UK for the most effective management of a pandemic.

"The government was right to order Tamiflu in early 2005. However, we are concerned that it is not updating its plans as the landscape of what we know about influenza changes."

The report criticises current proposals for infected people to obtain antiviral drugs by phoning a friend who would deliver them, warning that this method of delivery could leave many people living on their own without access to drugs and could be open to fraud.

A special scientific advisor, working alongside the chief medical officer and the chief scientific adviser, should be appointed to help ministers plan for a pandemic, the document says.

It calls on the DoH to bring together researchers and pharmaceutical companies to develop new vaccines in the event of a pandemic.

However, it says it would not be possible to immunise everyone before a pandemic because scientists would not know the exact make-up of the virus until it started to spread.

Experts call for better flu plans

BBC News: 20 November 2006

Leading scientists say the UK government is failing to take advantage of scientific developments in the fight to prevent a flu pandemic.

A Royal Society and Academy of Medical Sciences report says more than one anti-viral drug should be stockpiled.

It warns the H5N1 virus can develop resistance to Tamiflu, and says the drug Relenza should also be stockpiled.

Tamiflu's makers said there were only two instances of H5N1 patients showing resistance to the drug after treatment.

The report also calls for a special scientific advisor - to work alongside the Chief Medical Officer and the Chief Scientific Adviser - to advise ministers on planning for pandemic flu.

It also said the expert should work alongside the Chief Medical Officer and the Chief Scientific Adviser, to advise ministers.

And it calls on the government to work more with industry on vaccine production.

Sir John Skehel, chair of the report's working group, said: "We are concerned that decisions are being made, as the UK prepares for a possible pandemic, that fail to take account of expert advice.

"For example, the decision to continue to stockpile just one antiviral drug is a major concern. This needs to be reconsidered.

"New evidence that H5N1 can develop resistance to Tamiflu indicates that a combination of antivirals should be stockpiled by the UK for the most effective management of a pandemic."

He said the government was right to order Tamiflu in early 2005 - a stockpile of 14.6 million courses of anti-viral drugs is being built up

But Sir John added: "We are concerned that it is not updating its plans as the landscape of what we know about influenza changes."

Roche, the company which makes Tamiflu, said in a statement: "Resistant mutations of H5N1 virus have been detected in two patients at the end of treatment with Tamiflu."

By the end of the year, Roche would have the capacity to produce 400 million courses of Tamiflu per year, the statement added.

It would be up to the government and Department of Health (DoH) to determine strategies "along the lines of the principles established and outlined in the pandemic plan", it said.

The RSM said the government should consider increasing the size of the stockpile and should think about using the drug as a prophylaxis, a preventative treatment.

'Most prepared'

The report calls on the DoH to bring together academic researchers and pharmaceutical companies to develop vaccines which could be used to protect the public in the event of a pandemic.

It says it would not be possible to manufacture enough influenza vaccines globally in a pandemic - because experts will not know the make-up of a pandemic virus until it starts to spread meaning it would not be possible to immunise everyone.

However, the report adds that limited vaccine supplies can "go-further" if they are combined with adjuvants - agents which boost the effectiveness of a vaccine.

Sir John said: "We find limited evidence that the UK government is engaging with industry to research and develop new vaccines.

"Encouraging researchers and drug manufacturers to share information would speed up the development of adjuvants and vaccines to make the UK more responsive during a pandemic."

He added: "The UK is recognised as one of the most prepared countries in the world however research in this area must continue and up-to-date scientific information should be central to the government's decision making process.

"It will ensure we are prepared not only for a possible influenza pandemic, but also for any future emerging infectious diseases which may affect the UK."

'Adequate stockpile'

But Professor Lindsey Davies, the Department of Health's Director of Pandemic Influenza Preparedness, said: "We are already addressing many of the report's recommendations in our ongoing pandemic preparedness planning.

"We will consider the recommendations of the report as we continue to develop this work."

She said the UK would continue to work with international partners, including the European Union and the WHO, on preparedness vaccine development.

Professor Davies added: "Our antiviral strategy is informed by international consensus and expert advice, and the current stockpile should be adequate to treat all those who fall ill in a pandemic of similar proportions to those in the 20th Century."

Shadow health secretary Andrew Lansley said further action was needed.

"If you believe, as I do, that there's a major risk of a pandemic flu on the scale of the 1918 pandemic of Spanish flu, we should think about stockpiling more antiviral drugs, stockpiling face-masks.

"And we should think about getting an H5N1 vaccine now, on the basis it will offer limited protection.

Liberal Democrat health spokesman Steve Webb said: "A national bird flu strategy must take into account the latest scientific advice on what will best tackle any pandemic.

"We cannot wait until after a case has been discovered to check if our contingency plans are the most effective to deal with this potential threat."

Clues to pandemic bird flu found

Thursday, 16 November 2006, 00:49 GMT

International scientists believe they have identified some of the key steps needed for bird flu to develop into the deadly pandemic strain of the disease.

The team pinpoints two genetic mutations that would need to occur to the H5N1 virus for it to potentially spread readily between humans.

Writing in the journal Nature, the scientists said the findings would help them to detect pandemic strains.

At present, H5N1 can pass only from bird-to-bird or, rarely, bird-to-human.

So far, there have been a total of 258 cases of H5N1 in humans, causing 153 deaths, according to figures from the World Health Organization.

But flu viruses mutate and evolve quickly, and scientists believe the virus could acquire the ability to pass between humans.

They fear this could trigger a repeat of the devastation of the 1918 flu pandemic, which is thought to have killed 50 million people.

Docking station

To investigate how the virus might do this, the researchers looked at samples of H5N1 that had been taken from birds and also from infected humans.

In a small number of the human samples, they found the virus had acquired small changes to a protein called haemaggluttinin, which sits on the surface of the H5N1 molecule.

This protein helps the flu virus to spread by binding to the receptors on cells, which are like docking stations, allowing the virus to invade and infect the cells.

While the haemaggluttinin in most of the samples could only bind to bird cell-receptors, the researchers discovered that in some of the human samples, the haemaggluttinin had acquired the ability to bind to both bird and human cell-receptors.

It is thought this is a key step needed for H5N1 to be able to spread from human to human.

Further analysis revealed two separate mutations at different positions on the protein had enabled H5N1 to recognise human receptors.

The researchers said the discovery of the location of the mutations would help identify H5N1 strains that might be on the way to developing pandemic potential.

Pandemic pathway

Lead researcher Yoshihiro Kawaoka, a virologist at the University of Wisconsin-Madison School of Veterinary Medicine, US, said more mutations would be required for the virus to fully adapt to humans, but it is not known how many mutations are needed for such a change.

The team thought these changes were most likely to occur when a human influenza virus mingled with H5N1, particularly if it could already bind to human receptors.

Dr Wendy Barclay, a molecular virologist from Reading University, UK, said: "This work shows that at least two changes in the haemaggluttinin protein are needed for H5N1 to transform to strain that could infect humans, and knowing what these are will help to inform surveillance."

But, she said, the fact these mutations had already been seen in viruses isolated from human H5N1 cases, and a pandemic had not yet struck, suggested a number of other steps might be needed for the virus to be able to pass from human to human.

Outbreaks Show Bird Flu Virus Is Changing

Clues to pandemic bird flu found

By E.J. Mundell,  HealthDay Reporter Wed Nov 22, 5:04 PM ET

WEDNESDAY, Nov. 22 (HealthDay News) -- Detailed data on clustered human cases of avian flu have experts agreeing that the H5N1 virus is evolving -- but in what direction?

"The virus is always changing, and the mutations that make it more compatible with human transmission may occur at any time," warn Drs. Robert Webster and Elena Govorkova, both virologists at St Jude's Children's Research Hospital in Memphis, Tenn.

Their commentary accompanies reports from Indonesia and Turkey, both published in the Nov. 23 issue of the

New England Journal of Medicine.

However, another expert believes that, so far, H5N1 has given no indication it is mutating toward human-to-human transmission.

"It's far from a certainty," said Dr. Marc Siegel, a clinical associate professor of medicine at New York University School of Medicine, and author of Bird Flu: Everything You Need to Know About the Next Pandemic. "The virus could move closer to human-to-human transmission, and it could move farther away. I don't think that you can conclude from these articles in the NEJM that the thing is becoming easier to transmit."

The two studies' most basic data is not new. They focus on three clusters of H5N1 infection in Indonesia in mid-to-late 2005, involving four deaths, and an eight-patient cluster treated in the first weeks of 2006 at a hospital in far-eastern Turkey. Four of the Turkish patients died.

Details published in the journal do point to some intriguing trends, however.

As noted in other cases, almost all infections were linked to close handling of domestic fowl. More troubling was the fact that the Turkish group, led by Dr. Ahmet Oner, of Yuzuncu Yil University, in Van, found it very difficult to diagnose H5N1 in humans at its earliest stages.

Two standard tests turned up negative for the virus, and only a high-tech "polymerase-chain-reaction assay" confirmed H5N1 as the culprit. Infection also "causes a wide spectrum of illnesses in humans," the study authors wrote, with symptoms varying widely among patients.

In the Indonesian report, led by epidemiologist Dr. Timothy Uyeki of the U.S. Centers for Disease Control and Prevention, researchers found that H5N1 affected some patients more severely than others, suggesting that there are genetic factors influencing patient vulnerability. They also noted that certain drugs, such as oseltamivir (Tamiflu), could help fight the predominant Indonesian strain, but these drugs are only effective when given a day or two after infection. That's probably too early for most patients, however.

"In the countries that have reported human H5N1 cases, patients generally do not seek medical care early in their illness," Uyeki explained. "They usually present for medical care when their illness is advanced, e.g., they have pneumonia, and therefore they are not able to receive early oseltamivir treatment."

In their commentary, Webster and Govorkova noted that the number of documented human cases of H5N1 infection is rising worldwide. A total of 251 cases have been recorded globally since 1997, they said, and "by mid-August, 97 humans had been infected in 2006 -- the same number as in all of 2005."

No definite case of human-to-human transmission has yet been reported, suggesting that "the current H5N1 virus is apparently not well 'fitted' to replication in humans," the two experts wrote. However, "the intermittent spread to humans will continue, and the virus will continue to evolve," they added. "Clearly, we must prepare for the possibility of an influenza epidemic."

Siegel believes this kind of language can be misleading.

"We don't know enough about H5N1, and the science hasn't evolved to the point where we can predict when an epizoonotic problem -- a disease that has killed a lot of birds -- is going to start killing a lot of humans," he said.

And, while reports do suggest a rise in human cases over time, Siegel noted that, prior to 1997, no one was keeping close tabs on the epidemiology of H5N1. "I think there may have been previous clusters that might have gone unreported because of a lack of attention -- they may have been misdiagnosed as other kinds of flu," he explained.

Underreporting of prior outbreaks means it also impossible to say that the avian flu is mutating in any one direction, Siegel said. "There's just no way of telling from these clusters that this virus is evolving in the direction of easier transmission -- we can't tell if these clusters are anything new, or if there was a precedent for them," he said.

Finally, he said, H5N1's genetic "leap" to human-to-human transmission -- if it ever happens -- will be much tougher than media reports have let on.

"I've talked to a top expert at the U.S.

National Institutes of Health," Siegel said. "He has tried [in the lab] to manipulate H5N1 to make it transmit more easily human-to-human, and he hasn't been able to do it. He's tried different mutations, including using proteins from the 1918 Spanish flu."

While that doesn't mean the right combination of random mutations won't happen in the natural world, it suggests that a bird flu pandemic is a possibility -- but not a certainty. "There's no sense of 'imminence' here," Siegel said.

All of the experts agreed that more needs to be done to curb the spread of the virus among birds, however.

"H5N1 viruses are a 'moving target' and are evolving globally," Uyeki said. "Therefore, what is needed is ongoing, expanded surveillance of highly pathogenic avian influenza A (H5N1) viruses in animals (including poultry and wild birds) and humans in many countries."

Webster and Govorkova noted that countries that have implemented tough, bird-focused interventions did reduce the threat. But with winter approaching, they worry that H5N1 will finally make its way from Eurasia to the Americas via migrating flocks.

However, Siegel said, vaccinating every bird in the United States does not make sense right now. That's because the virus would simply go "underground," infecting fowl but not producing outward symptoms.

"You want to vaccinate susceptible populations, and then control outbreaks by killing affected birds," Siegel said.

But he also stressed that, "here, in the U.S., we as yet have no birds that have this virus. We don't even have a problem yet, except for fear."