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Scientists race to develop a vaccine against a killer flu

WASHINGTON—Under a microscope it's only a tiny ball covered with knobs and bumps, hardly worthy of its reputation as a mass killer. But within its shell, it harbors biological machinery that can be deadlier than a nuclear war.

This fearsome creature is the virus that causes bird flu. It usually infects chickens, ducks and turkeys, but it can also jump to humans. Under the right conditions it could spread like wildfire and kill millions of human beings.

Health authorities consider another worldwide flu pandemic, like the three mass infections that killed as estimated 50 million people in the 20th century, to be both inevitable and overdue.

"There is a storm brewing that will test us all," World Health Organization Director-General Lee Jong-wook warned late last month. "Failure to take this threat seriously and prepare appropriately will have catastrophic consequences."

President Bush summoned leaders of three vaccine manufacturers to the White House Friday and urged them to step up their efforts to make a vaccine that would be effective against bird flu.

"The world is obviously unprepared or inadequately prepared for the potential of a pandemic," Secretary of Health and Human Services Mike Leavitt told an international flu conference at the State Department on Friday.

Bird flu is different from—and potentially far more dangerous than—the domestic flu virus that afflicts millions of Americans every year. Even though there are vaccines against domestic flu, it still causes about 36,000 deaths a year.

There's no approved vaccine, so far, against the new, virulent strain of bird flu, which was discovered in Hong Kong in 1997 and is now coursing throughout Asia. It already has killed at least 60 people, more than half of those it infected.

This strain, known as H5N1, is considered so alarming because most humans have not been exposed to it—or to a vaccine against it—and hence have developed no immunity to it.

Scientists, however, have learned a great deal about how the virus works. Its genes have been decoded and its inner mechanism laid bare. Researchers can observe the sneaky tactics it employs to evade the body's immune system, invade and destroy living cells.

Like any virus, the bird flu variety consists of a small clump of RNA, a simpler version of DNA which carries the genetic instructions for all living cells. The RNA is surrounded by a coat of proteins—chains of molecules called amino acids.

The virus isn't technically alive. It cannot reproduce on its own but must kidnap the genes of a living cell to make more "daughter" viruses.

The bird flu virus has only eight RNA genes. Six of them handle basic housekeeping chores; the other two make up the killing machine.

One nasty gene, known as HA (short for hemagglutinin, pronounced he-mah-GLUE-tin-in), produces a protein that resembles a button on the outside of the virus's coat. When the virus bumps into a healthy cell in the throat or lung, the HA protein pries open the cell's outer membrane, slips inside and hijacks its genetic machinery.

"Given that HA is responsible for so much pathology in the lung, if we could identify the mechanism for how that happens and then block it, perhaps it would be useful for antiviral development," Terrence Tumpey of the Centers for Disease Control and Prevention in Atlanta, reported in last week's edition of the journal Science.

The other bad gene, known as NA (for neuraminidase, pronounced new- rah-MINI-dase), makes another protein that lets the daughter viruses escape from their unwilling host—which is now doomed—and rush out to infect other cells. If NA is blocked, the virus can't spread.

There are 16 known varieties of the HA gene, labeled H1 to H16, and nine varieties of the NA gene, tagged N1 to N9. Many different combinations are possible, some relatively harmless, some deadly.

Currently, the most worrisome flu strain is H5N1. Its first human fatalities were reported in Hong Kong in 1997.

Ominously, several genes in the H5N1 virus resemble the "Spanish flu" bug that killed 50 million people or more at the end of World War I, according to a report in last week's Nature by Jeffrey Taubenberger of the Armed Forces Institute of Pathology in Rockville, Md.

Usually people get the H5N1 virus from contact with birds, but at least one probable case of a fatal, person-to-person infection occurred in Thailand in 2004. An 11-year-old girl caught the disease from household chickens. Before she died, she apparently passed the virus on to her mother and aunt, Kumnuan Ungchusak of the Thai Ministry of Public Health reported in the New England Journal of Medicine on Jan. 27. The two women perished a few days later.

The major defense against flu is a vaccine, a modified form of the flu virus delivered by a shot in the arm or a nasal spray. The vaccine prompts the body's immune system to produce swarms of protective molecules known as antibodies. The antibodies attach themselves to the HA or the NA protein, rendering them harmless.

The domestic flu vaccine being distributed in the United States this fall protects against two combinations of viral genes_ H1N1 and H3N2—which have been circulating worldwide since 1997. This vaccine, however, offers little or no protection against H5N1.

Two years ago, an experimental H5N1 vaccine was developed by Robert Webster, a viral expert at St. Jude Children's Research Hospital in Memphis, Tenn. Webster's vaccine is being tested in laboratories, but it won't be available for public use this flu season.

In the last few weeks, the National Institute for Allergy and Infectious Diseases, in Bethesda, Md., awarded multimillion-dollar contracts to companies in California, Maryland and Pennsylvania to develop and stockpile future bird flu vaccines.

Meanwhile, Kanta Subbarao, a viral expert at the National Institute of Allergy and Infectious Diseases, and her colleagues are working to develop vaccines against the H2, H7 and H9 proteins, as well as the dreaded H5.

In addition to vaccines, doctors have a number of drugs to treat patients exposed to or infected with flu.

One such drug, Tamiflu, made by Roche Laboratories in Nutley, N.J., interferes with the NA protein. This prevents the release of daughter viruses, so an infected person can't relay the disease to others. However, Tamiflu is only partially effective against the H5N1 virus.

Another drug, amantadine, works against a different flu gene named M2, which removes the virus's protein coat after it enters the cell. Without a working M2 gene, further infection is blocked. Most flu viruses, unfortunately, have developed resistance against amantadine, rendering it virtually useless.

A major problem is the fact that flu genes are constantly mutating—making little changes in their genetic structure—so that vaccines or drugs no longer recognize them. A mistake in a single "letter" of the RNA genetic code can be enough to conceal a shape-shifting virus.

A successful flu vaccine "requires being able to predict which viral strains will be circulating," Suzanne Epstein, a senior biologist at the Food and Drug Administration, reported in the Journal of Emerging Infectious Diseases. "If an unexpected strain or even a pandemic emerges, appropriate vaccines may take too long to prepare."

Even worse, animal and human viruses occasionally exchange some of their genetic material, producing an entirely new strain, like H5N1, to which people have no natural immunity.

For instance, a pig might be infected with a bird flu virus and a human flu virus at the same time. The pig serves as a "mixing bowl" in which viruses mingle their genes in a process known as reassortment. If the reassorted virus infects a human, it can spread rapidly and lead to a pandemic.

"One possible cause for influenza pandemics is the mixing through reassortment of an avian influenza strain with a human strain," Steven Salzberg, a biologist at the University of Maryland in College Park, reported in last week's Nature. "The greatest concern is that it will mutate to become easily transmissible between humans."

"These complete changes in the virus are rare but very big events," Subbarao said. "This is what happened in 1918, 1957 and 1968. People were not protected."

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For more information: www.who.int/mediacentre/factsheets/avian(underscore)influenza

To see an animation of the flu gene reassortment process:

www.hhmi.org/biointeractive/animations/subunit/sub(underscore)middle(underscore)frames.htm

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(c) 2005, Knight Ridder/Tribune Information Services.

PHOTOS (from KRT Photo Service, 202-383-6099): AVIANFLU

GRAPHIC (from KRT Graphics, 202-383-6064): 20050506 AVIANFLU

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