September 15, 2005

US children’s hospital on frontline in bird flu war

By Maggie Fox, Health and Science Correspondent

MEMPHIS (Reuters) - It seems an unlikely place to launch a war against a bird virus that health officials believe could soon mutate into a human pandemic that will kill millions -- a hospital filled with children fighting devastating genetic diseases and rare cancers.

But Robert Webster likes the daily reminders, in the form of children pulled around in colorful wagons or sitting propped against a mother's lap, that the work begun in a laboratory has real life-and-death outcomes.

And the private funds raised by St. Jude's Children's Research Hospital in Memphis are helping Webster and his team of international virus experts fight what experts say may be the biggest threat to humanity right now -- avian influenza.

"We could be heading for a global catastrophe," Webster said in an interview in his corner office overlooking the expansive campus of the hospital.

If bird flu were to start spreading among people, more than 25 million hospital admissions and up to 7 million deaths globally would follow within a short period, according to British experts who model epidemics using computer programs.

Webster's team works out of high-tech labs set up by the giant St. Jude organization, launched by Lebanese-American entertainer Danny Thomas in the 1950s to care for children with cancer and other hard-to-treat diseases.

Webster is not exactly calm -- the 73-year-old Webster doesn't say anything calmly. But he has been making ominous warnings for decades and he seems resigned to it.

Ever since Webster and colleagues discovered that aquatic birds such as ducks were the natural reservoirs of influenza, and that the virus has several ways of changing quickly into a mass killer, he has said it is only a matter of time before one flu virus takes on a form that will kill millions of people.

"You just don't know when it is going to happen," Webster said. "But I think some of the policy makers and politicians are starting to listen."


When Webster saw the avian flu strain called H5N1 for the first time in Hong Kong in 1997, he knew this might be it.

The virus hopped from ducks to chickens, killing chickens in a day, and infected 18 people who handled infected birds, killing six, before Hong Kong authorities stopped it with a decisive slaughter of poultry and closings of bird markets.

No one thought it was gone for good and in fact when flu experts first heard about a mysterious virus that was killing people in China's Guangdong Province at the end of 2002, they feared that H5N1 had come back. In fact, it was Severe Acute Respiratory Syndrome or SARS.

The panic over SARS upstaged the reappearance of H5N1 in China in 2003, and this time the authorities did not act so quickly or decisively.

Now it has killed or forced the slaughter of tens of millions of domestic birds in China, Vietnam, Thailand, Indonesia, Cambodia, Japan and elsewhere. It has killed more than 60 people although it does not yet easily infect humans or pass from human to human.

It has been found in wild birds in Mongolia and now in flocks in Kazakhstan and Russia.

"This virus keeps extending its range," Webster said. "It is out there spreading like crazy among the wild birds of Asia."

Not everyone is convinced that it is migrating birds that are spreading H5N1, but Webster is.

He grew up on a farm in New Zealand, where they raised an egg-laying breed of ducks called Khaki Campbells.

Between studying dead birds in Australia and the viruses that infected them in London, Webster and colleagues worked up the idea that influenza viruses originate in birds -- mostly ducks.

These natural hosts, or reservoirs, do not usually become ill when infected but incubate and spread the viruses.


But how do the viruses acquire the ability to infect new species, and how does their disease-causing nature change? Webster also helped discover how viruses do this.

One way is by steady mutation. Influenza is an RNA virus, meaning it is error-prone because it only uses one copy of the genetic code to replicate itself. That results in frequent variation, or mutation, of the virus, and ultimately one form will spread from person to person.

"The clock keeps ticking. Every time this virus replicates, it makes mistakes," Webster said. "Sooner or later it will make the mistakes that will allow it to go human to human."

There is a quicker way. If two different viruses are in a cell together, they can swap pieces of their genes, a process called reassortment. "It's virus sex," said Webster.

This reassortment caused the global flu pandemics of 1957 and 1968 that killed many people -- 4 million in 1968 -- because people had no immunity to the new viruses that arose.

All it takes is for one person to become infected with H5N1 while also infected with ordinary human flu. This may have happened in 1918, when a new strain of flu killed as many as 40 million people globally, most of them healthy young adults.

"We don't even know the mistakes it made in 1918 that allowed it to go human to human," Webster said.

Specialists in the Biosafety Level 3 lab at St. Jude's are studying the genetics of H5N1 to try to find precisely what "mistake" H5N1 needs to make to make it something that people can easily transmit to one another.

In this lab, with its specially sealed doors, air circulation controls and showers to scrub down everyone who exits, it is possible to play around with deadly viruses.

Webster has been working here since 1968, when he was recruited to study influenza coincidentally just as the last global pandemic of disease was getting under way.


His team of international experts has helped lead the way in what progress has been made against H5N1.

German Erich Hoffmann helped develop the "reverse genetics" approach that was used to make the seed virus for the current H5N1 vaccine being tested in volunteers. A seed virus elicits an immune response without causing disease.

Dr. Elena Govorkova, a Russian medical doctor, is testing various combinations of antiviral drugs against H5N1.

There are four antivirals that are used against influenza -- amantadine and rimantadine, and two newer drugs -- Roche's oseltamivir or Tamiflu and GlaxoSmithKline's zanamivir or Relenza.

"Early on in the pandemic there will be no other options except for antivirals," Govorkova said in an interview. Amantadine did at one time work to treat H5N1 but it no longer does because the virus has developed resistance.

She is working to see if combining flu drugs into cocktails will provide better protection and has found some indication that they do. Tamiflu and amantadine may work well together.

And the good news is that, while the virus can also develop resistance to the newer drugs Relenza and Tamiflu, which governments and the World Health Organization are stockpiling, these resistant mutants do not survive well.

The work these scientists are doing now will help not only if the current H5N1 makes the jump into people, but also if some other variant proves to be the next threat. In their freezers in the St Jude laboratory are hundreds of samples of flu viruses.

They also have an approved vaccine factory where a new vaccine could quickly be churned out. All influenza vaccines must be made fresh to precisely match the strain of virus they are targeting.