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, which 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 million 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.
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, perhaps including 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.
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.
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.