How do you contain an evolving avian flu and the threat to people?

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How do you contain an evolving avian flu and the threat to people?

By LaFee, UNION-TRIBUNE STAFF WRITER

January 25, 2006

No one can yet say whether 2006 will be the year of the flu pandemic,

whether a particularly virulent strain will mutate sufficiently to

easily infect and kill tens of thousands of people, possibly

millions.

But there is cause for concern. Recent outbreaks of a strain of avian

flu called H5N1 in Asia suggest the virus may have already made the

biological leap from bird host to human victim. In China, Vietnam,

Cambodia, Indonesia, Thailand and Turkey, at least 149 human cases of

H5N1 infection have been reported, with 80 deaths, according to the

World Health Organization.

Bird versions of H5N1 have spread beyond Asia, perhaps transported by

wild migratory birds, to portions of eastern Europe, Russia, Kuwait

and Canada. More human cases seem inevitable. President Bush has

launched a $7.1 billion plan to prepare for a global flu epidemic.

" Our country has been given fair warning, " he said last November.

But how do you prepare for a disease whose infectious agent is not

only unseen, but also ever-changing? The influenza virus is a

notorious shape-shifter. It mutates constantly, randomly. Vaccines

that work against identified strains one year do not the next.

Looming or not, the prospect of a flu pandemic has sharpened

everyone's focus. In labs around the country, researchers flush with

new funding and interest are racing to improve existing vaccines and

create new, more effective drugs. Whether they will succeed in time

remains to be seen.

Know thy enemy

No organism is hardier than a virus, in part because it's not really

alive. Unlike bacteria and other cell-based life forms, viruses

consist only of incomplete bundles of RNA or DNA. To replicate, they

require the reproductive machinery of a host cell.

In humans and other flu-susceptible mammals, such as horses, pigs,

birds, whales, dogs and seals, the immune system combats viral

infections by creating specific antibodies after just a single

exposure.

That means viruses must constantly change to survive. And because

they reproduce so quickly, without careful, precise duplication of

their genomes, mistakes happen. A gene sequence is transcribed, a

protein added, dropped or reassigned. In other words, random

mutations.

In addition, viruses freely swap genes upon contact with each other,

a process called reassortment that can generate new strains as well.

In 1918, a strikingly virulent and infectious strain appeared, dubbed

the " Spanish flu " because some of the earliest human cases were

reported in Madrid. In less than two years, roughly one-third of the

world's population, primarily in Europe and North America, had caught

the Spanish flu. Between 20 to 50 million people died worldwide, with

some estimates as high as 100 million. In the United States, roughly

675,000 Americans – 0.6 percent of the country's population at the

time – died from flu-related causes in 1918 alone, a percentage that

equates to 2 million Americans today.

No pandemic since has matched that epic deadliness. Pandemics in 1957

and 1968 killed millions worldwide, but their mortality rates – the

percentage of infected who died – were lower. All subsequent flu

outbreaks have been minuscule by comparison, a fact that worries Dr.

Fang Fang, chief scientific and medical officer at NexBio, a San

Diego-based company working on new antiviral therapies.

" It's been more than three decades since we've seen a significant flu

outbreak. We're overdue, " she said. " But more importantly, we are now

seeing incidences of human infections by novel flu strains in

unprecedented numbers. The high density of infection from these

strains is troubling. It does not bode well. "

Viruses thrive, in part, because their method of infection is

stunningly simple. The surface of every flu virus is studded with a

protein called hemagglutinin, which readily attaches to receptors on

vulnerable host cells, such as those lining the lungs, mouth, nose

and eyes. Hemagglutinin is a molecular Trojan horse, inducing the

unwitting cell to draw the virus inside.

Once inside, the virus bursts its own membrane, spilling out genetic

material that quickly moves into the nucleus of the cell to

commandeer needed reproductive machinery. Components for new virus

particles are churned out and assembled. These particles migrate to

the host cell's outer membrane, where another viral protein called

neuraminidase snips the connection. The virus is now free to invade

other cells and spread the infection.

Vaccines

Traditional vaccines, which contain whole, killed virus, are designed

to stimulate the body's production of antibodies and other immune-

system responders. Creating a flu vaccine is educated guesswork.

Scientists anticipate which strains (up to three) are likely to

predominate during the next flu season and design the vaccine

accordingly. It's a six-to eight-month, costly process, involving

millions of special, fertilized chicken eggs that are used to grow

sufficient quantities of viral material for vaccine doses.

The resulting vaccine must be used that year, not only because it's

fragile and requires refrigeration but because future viral strains

are likely to have mutated enough to render any unused vaccine

ineffective.

Numerous companies are striving to improve the current vaccine

process, either by speeding production technologies, extending shelf

life or changing the way the vaccine is delivered or works.

Vical Inc. of San Diego, for example, is developing a vaccine that

contains only specific, conserved sequences of viral DNA, according

to Alan Embring, executive director of investor relations. These

segments of DNA, said Embring, don't change with passing viral

generations, thus providing a steady, reliable target for the immune

system.

A DNA-based vaccine, Embring said, would be safer because no whole

virus is used, eliminating the chance of getting the flu from the

vaccine. It can be more quickly designed and manufactured through

cell culturing, rather than using chicken eggs. It requires no

refrigeration. And most important, it would provide basic protection

against a broad range of influenza viruses, including perhaps

emerging strains like H5N1.

It is also nowhere near completion. Embring said Vical has received

initial federal approval for animal testing, but not yet human

application. Clinical trials of new human drugs and therapies

typically take years, though there are truncated procedures for times

of emergency, such as during a pandemic.

PowderMed, a biotech firm in Oxford, England, is also working on a

DNA-based vaccine cultured from E. coli bacteria. Its vaccine would

involve coating flu genes with gold, then injecting them into the

body with high-pressure helium. Clinical trials are ongoing.

Facilities for building the injection devices won't be finished until

2007.

A Philadelphia company call INB, meanwhile, is cultivating harmless

bits of flu virus and other human pathogens in fast-growing spinach.

The virus proteins are extracted, deactivated, chopped up and

injected. INB says the spinach-virus has provoked immunity in test

animals. Human trials using U.S. Navy personnel are being planned.

In his November speech, President Bush outlined increased spending on

vaccine research and production and called upon states to stockpile

the antiviral drugs oseltamivir and zanamivir. Better known by their

trade names, Tamiflu and Relenza are neuraminidase inhibitors (NIs).

They work at the end of the flu infection process, when the viral

enzyme neuraminidase releases new viruses from the host cell.

Neuraminidase inhibitors block the activity of the enzyme. Viral

particles are not released, limiting the spread of infection. Tamiflu

has been used to treat and slow the spread of H5N1 in recent Asian

outbreaks.

But popular proposals to deploy Tamiflu widely in future outbreaks

worry some people, among them NexBio's Fang, who was recently in

China assessing the situation. The more Tamiflu is used, the faster

viruses develop resistance, she said.

Making a cheap, generic version widely available would likely

encourage Asian farmers to give the drug to their farm animals,

hoping to fend off further massive animal deaths that might spell the

end to their livelihoods.

That's happened before. In the 1990s, an older flu drug called

amantadine was broadly distributed. Asian farmers fed it to their

chickens. Viral resistance soared. Amantadine is now deemed useless

against H5N1.

There is, in fact, some evidence of viral resistance to Tamiflu. In

Vietnam, eight of 10 people recently infected by H5N1 died despite

being treated with Tamiflu.

There are other problems with Tamiflu and neuraminidase inhibitors.

To be effective, current versions must be taken within two days of

infection. Treatment requires twice-daily doses for up to eight days.

And there isn't enough of the drug around. Bush's flu epidemic plan

calls for stockpiling 22 million treatment courses. Existing

stockpiles can treat just 2.3 million people. Some infectious disease

experts advise stockpiling enough Tamiflu to treat up to half the

population in the event of a pandemic, more than 130 million courses.

Still, neuraminidase inhibitors continue to be a major avenue of flu

research. BioCryst Pharmaceuticals in Birmingham, Ala. is developing

a new NI called peramivir that would require just a single injection.

Hemispherx Biopharma of Philadelphia is exploring whether combining

its antiviral drug, Ampligen, with Tamiflu or other NIs will increase

their overall effectiveness.

" Basically, we're looking for a kind of synergy, " said Doug Hulse,

president of Hemispherx. " From tests, it looks like adding a very

small amount of Ampligen reduces the amount of Tamiflu needed by a

factor of 10 or 20. That means you could dramatically boost the

number of available doses. "

The company has applied to the FDA for approval to begin treating

avian flu next year.

Fludase

Successfully fighting the flu, though, will require ideas beyond

vaccines or neuraminidase inhibitors. One such approach, cited by

Scientific American magazine as one of the top 50 scientific

innovations of 2005, is NexBio's drug, Fludase.

Fludase acts against influenza and other viruses before the infection

process begins. Inhaled, the drug coats respiratory lining cells,

zeroing in on the same receptors that are exploited by viral

hemagglutinin.

" Fludase acts as an enzyme, chopping off the flu viral receptors,

disabling them, " said Mang Yu, who conceived the idea and founded

NexBio. " The virus can't get into the cells. It just sits there until

the immune system removes it. "

All flu viruses enter cells the same way, said Yu, a molecular

biologist, which means that, in theory at least, Fludase should

effectively prevent infection by any existing or future stain of flu.

" There is no reason to believe a virus would be able to evolve a

different mode of entry, " he said. " If you disable the gateway into

the host cell, you take care of all viruses. "

All that is needed now, of course, is conclusive, FDA-acceptable

proof. Yu and Fang say first phase safety trials are slated for

midyear, involving about three dozen healthy volunteers and lasting

three months. They hope to mimic Tamiflu's rapid approval process and

have a drug ready for market within three years. If a pandemic

strikes sooner, Yu said the company will seek authorization from the

FDA for emergency use.

Other battlefronts

From basic scientists to biotech entrepreneurs, everybody is looking

for new weapons to fend off a flu pandemic.

Some efforts are relatively straightforward. A Pennsylvania firm

hopes to market face masks treated with compounds it says kill or

prevent the passage of most viruses. University of Chicago

researchers are investigating drugs not previously used against the

flu, in particular compounds that reduce inflammation – an immune

response that can cause more bodily damage than the disease itself.

(In the 1918 pandemic, the majority of victims were young and

healthy, with robust immune systems. It was that robustness that

killed them, say experts. They died from immune response overkill.

H5N1 appears to provoke a similarly strong reaction. In Thailand, for

example, the death rate from bird flu has been 89 percent for victims

younger than 15.)

Other anti-flu efforts are more experimental. An Oregon

pharmaceutical company is testing a drug that targets the genetic

code in viruses responsible for replication, slowing it enough to

allow the body's immune response to kick into gear. At the

Massachusetts Institute of Technology, researchers are investigating

whether a kind of RNA called " short interfering RNA " can effectively

disrupt virus reproduction in host cells.

" RNA interference is cool stuff, " said Shane Crotty, a vaccine

researcher at the La Jolla Institute for Allergy and Immunology, " but

it's way off in the distance. A lot of very basic science still needs

to be done, including how you would deliver the RNA into the cell. "

Whether RNA interference or other, more immediate efforts will

actually pay off is hard to say. They offer hope, but the harsh

reality is that the enemy they must defeat – or at least render less

deadly – has long defied subjugation, let alone eradication.

The virus H5N1 causes the greatest current concern because, as an

avian flu bug, there is no existing human immunity to it. Some

researchers say the transition of H5N1 from bird flu to human flu

will be difficult, requiring one of two things to happen.

In one scenario, the virus would acquire the ability to easily infect

humans through random mutation. There's no way to determine how,

when – or if – that will happen.

In the second scenario, a person would be infected simultaneously by

both H5N1 and an existing human virus. The viruses would exchange

genetic material – reassort – and produce an easily transmitted

hybrid.

The odds of contracting both H5N1 and a human flu at the same time

are generally remote, say health officials, except perhaps among

Asian farmers and others who spend much of their time in close

proximity to potentially infected animals.

Other scientists, however, see no great hurdles to H5N1 evolving into

a pandemic threat. They note that it would take changes in just a few

amino acids to convert the bug from bird virus to human virus.

Henry Niman, a veteran flu researcher who once worked at Scripps

Research Institute and founded a biotech company that became Ligand

Pharmaceuticals in San Diego, believes conversion is inevitable, that

H5N1 will become an established human flu virus within the next year

or two.

" What that will mean in terms of a pandemic depends on exactly what

version of the virus gains human status, " he said. " Some versions of

H5N1 are milder than others. If one of them prevails, any resulting

pandemic might be more like 1957 or 1968. If a more deadly version

prevails, it might be 1918 all over. "

Flu scientists, public health officials – even Niman himself – hope

he is wrong, that H5N1 will not blossom into a global killer. In the

meantime, they watch, work and wait: hoping for the best, preparing

for the worst.

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