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When it happens, the world will change forever. We will almost certainly be unprepared. Millions upon millions will die—not in developing countries, but in our country, in our state. In Birmingham, thousands of people will die.

No one is arguing over whether or not there will be another global influenza epidemic. It will happen; we just don’t know when, or what kind of flu it will be. Will it be a shift in the same version of flu virus that has traveled the planet ceaselessly for the last three decades—or a more radical mutation that will take human immune systems by total surprise?

The answer to this question will determine whether the next flu pandemic has a mortality rate of, say, 8 percent of all people who become infected, as did the infamous 1918 pandemic, or something closer to 50 percent—which is the death rate so far in human cases of the “avian flu” that is decimating chicken and bird populations in Southeast Asia.

Whatever form it takes, influenza is a killer; even the regular old flu that we suffer through year after year devastates some countries and is the sixth leading cause of death in the United States, killing about 36,000 people every year. And flu morbidity is no less significant: Every year around 20 percent of Americans come down with the flu, and 200,000 of them require hospitalization during the course of their illness.

Our Fine Feathered Friends

For thousands, maybe millions of years, influenza viruses lived quiet, peaceful lives in the bodies of their natural hosts: birds. Most researchers believe that aquatic birds were the primordial incubators of human influenza; they carried the viruses but didn’t become sick from them. Then somewhere in time, certain flu viruses began making a slow migration from birds, through an intermediary mammal (pigs, perhaps), and into a new frontier—the human host.

So although the strain of flu that’s got everyone worried is being called the avian flu, every influenza virus is, at its core, an avian flu. Mutations allow the viruses to move from birds to other animals and into humans, explains UAB researcher Ming Luo, Ph.D.—and the type of mutation determines how pathogenic each virus will be.

There are two major antigens on the surface of virus particles that influence how sick we become when we are infected with influenza: hemagglutinin (H) and neuraminidase (N). “You usually hear scientists calling a flu virus H1N2, or H3N2, something like that,” Luo says. “In humans right now influenza strains have either H1, H2, or H3 antigens on their surfaces.” He notes that the H2 version, which hasn’t been seen since 1968, is the version that was mistakenly distributed in a small batch of lab test kits this spring, sparking renewed pandemic concerns among health officials.

“When a flu virus mutates, we describe the type of mutation as either antigenic shift or antigenic drift,” Luo says. “Antigenic shift is when the virus totally changes a type of surface antigen. Every time you have a major shift—if an H2 strain comes around next year, for example—you’ll probably see a much more severe epidemic because the human immune system is not used to seeing that type of H strain.”

The more common type of mutation is antigenic drift, which allows flu to recur year after year, without humans ever developing full immunity. “So if last year you had H1N2, this year you’ll still have H1N2, but with some minor changes. The Beijing 1997 flu and the Beijing 2000 flu are two strains of the same type of virus.” But even these small changes are enough to keep flu vaccines just shy of full effectiveness.

Plague of the Century

Antigenic shifts—wherein the type of H or N changes—are what precipitate pandemics. “From 1918 to 1957, we saw predominantly H1 viruses,” says UAB travel medicine specialist David O. Freedman, M.D. “In 1957, it changed to H2. Then in 1968 it changed to H3, and we’ve been at H3 ever since.” At the time of each shift, there was a flu pandemic. “So for people who got the ‘new’ flu, the rates of morbidity and mortality were much higher than normal because nobody had sufficient antibodies to fight it.”

The pandemics in 1957 and 1968 were called pandemics because illness rates worldwide were unusually high, and millions more people died from the flu in those years than in typical flu seasons. “But the worst pandemic ever was 1918, because the strain of virus circulating at that time was completely unknown in humans before,” says Freedman. “Nobody had any immunity to it at all, and 1 percent of the world population died in that pandemic. Now we’re worried because the virus that we’re calling ‘avian flu’ is an H5 type—just like with the 1918 strain, nobody has any immunity to H5. It is completely different.”

The numbers from 1918 are nothing short of ghastly: In that one epidemic, more Americans died than in all the wars fought in the 20th century combined. The death toll in this country was approximately 675,000; worldwide the toll reached somewhere between 20 and 50 million. It is estimated that 25 percent of the global population became infected by that influenza virus, and 1 percent of the entire world’s population died from it.

Overwhelming the System

Much of what heightened mortality in 1918 would not apply to a flu pandemic today. At that time, scientists didn’t yet have microscopes capable of seeing viruses, and they were never able to discover the source of the epidemic. They vaccinated for bacteria and gave people masks that were far too porous to keep viruses out. Furthermore, the epidemic came during World War I, when rallying parades, military recruitment, and military transport brought hordes of people together in confined spaces. If anything, global circumstances helped that particular flu do its worst.

“Also,” says Max Michael, M.D., dean of the School of Public Health, “the clear difference between any potential pandemic today and the 1918 pandemic is the availability of a health-care system that could respond to complications from the flu. In 1918, most patients died from secondary infections, particularly pneumonia. Today we have better antibiotics; we have effective medical strategies to treat complications.”

But Michael is quick to point out that it also wouldn’t take long for our current health-care system to be overwhelmed if an epidemic were to occur. “The occupancy rates of ICU beds on any given day in our community can be 80 or 90, even 100 percent. Well, 90 percent of 200 beds on a normal day leaves you with 20 beds that are available for a disaster on that day. So if you’ve got a pandemic on your hands, you’ve got no place to put your patients.”

The Alabama Department of Health, like its counterparts in other states, has been working to solve this infrastructure problem by developing “swing spaces” that could be used in emergencies, says Michael. “They’re looking at places like school gyms, and they’ll keep a stockpile of beds and medicines and other equipment that they’ll be able to use to respond quickly.”

These swing spaces will be useful for any number of public-health crises, but the department is gearing up specifically to prepare for the flu. State health officer Donald Williamson told The Birmingham News in June that Alabama is using part of its funds from the U.S. Department of Homeland Security to create a state pandemic plan. He told the News that, regardless of whether influenza becomes a problem this year or in some other year, “The one thing that will absolutely happen is an influenza pandemic.”

But no one knows if the deadly H5 avian flu will become the agent of this anticipated pandemic. That’s because, even though almost 120 human cases have been documented since 2003, it’s still hard for people to catch this particular bug. “With normal influenza, if you go to a friend’s house and sneeze, six or seven people could become infected,” says pediatric infectious disease specialist Richard Whitley, M.D. “With H5, there has to be more direct contact; you need extensive contact with birds that have the virus, and even when it gets inside humans, it doesn’t seem to have the right factors to be contagious from person to person. So it doesn’t appear right now that it’s as easily transmissible as some of the influenza strains we’ve had before.

“Now having said that, the downside is that the mortality of individuals infected with H5N1 is about 50 percent,” he says. “This virus is more likely to infect organs in the body other than the lung and the upper respiratory tract; we’re seeing gastrointestinal disease, as well as disease of the central nervous system. Overall it’s just a far more lethal virus than the 1918 flu.” And that’s saying quite a bit: In the pandemic of 1918, the United States literally ran out of coffins in which to bury the dead. Physicians described cases in which young, healthy people in their 20s and 30s became symptomatic in the morning and were dead by nightfall.

What would it take to trigger an H5 pandemic? “Our original concern was that this bird virus would infect a person at the same time that a human influenza strain infects him, and that the viruses would recombine with each other,” says Freedman. “The resulting virus could have the infectiousness of a human virus plus the different surface molecules, the H5, of the bird virus. So it would transmit very easily from human to human, and the people who got it wouldn’t have any immunity to it.

“But more recent studies of the 1918 influenza have shown that it was a ‘pure’ avian virus. That means that it didn’t recombine with a human strain, it just spontaneously mutated in such a way that it became able to infect humans. These studies have also shown that some of the mutations that took place in the 1918 strain have already taken place in the H5 strain we’re looking at now—which is causing a lot of concern among scientists.

“However,” Freedman notes, “there are lots of people living in areas where H5 exists—all over China, all over Southeast Asia, and even Russia and Eastern Europe now—and these are densely populated areas. So you could argue that if it was going to happen with this particular virus, it would have by now. So it could be nothing, or in a few months it could be dominating everybody’s life; people could stop going to work for fear of getting the flu, and the country could be crippled.”

Blocking the Action

Every fall people are urged to get flu shots as the new vaccine is shipped around the world from its few manufacturers. It’s fitting that the vaccine for this bird-borne virus is grown in chicken eggs, but it’s also unfortunate, because the eggs take six months to incubate the virus. The eggs also require more space than their small size would suggest: At one egg per dose of vaccine, imagine the size of the hatcheries needed to generate enough doses to vaccinate all 300 million Americans, let alone the world.

“And if the vaccine is for a completely new strain like H5, one dose isn’t going to be enough to induce immunity,” says Freedman. “It’s going to take at least two doses of vaccine to protect everybody.”

Moreover, the formula of the vaccines has yet to be perfected. “It’s hard to develop flu vaccines for the same reason it’s hard to develop vaccines for viruses such as HIV and ebola,” says Luo. “They mutate and change too often. Each year scientists reformulate the flu vaccine according to their prediction of what strain will predominate the next year, but that’s a complicated guess. And even if you have low-level immunity from a flu shot, you can still get as sick as if you never got the shot. So there’s something special about this virus that makes our traditional approach to vaccines inappropriate. For flu viruses we simply need a whole new concept—we just don’t know what that is yet.”

In the absence of a true vaccine, researchers such as Luo are developing antiviral drugs that avoid this guesswork altogether. Luo and his colleagues use protein crystallography—the study of the 3-D structure of proteins—to design these drugs, and he says the most successful efforts to date have focused on one of the flu virus’s surface antigens: neuraminidase. “If you look at the structure of neuraminidase,” he says, drawing a lumpy-looking pod, “it looks like a tetramer [or four-part] head on a stalk. There are four identical copies of this protein that come together to form a knob, and a stalk anchors this knob to the outer shell, or envelope, of the influenza virus.

“In each of these proteins there’s a pocket called the active site,” he says. “When neuraminidase mutates, you see the mutations around these pockets. But the active site does not change. Over the 60 years that we’ve been monitoring flu viruses, all of the changes in the structure of neuraminidase from strain to strain are around the active site—the active site itself never changes.”

Luo explains that the active site is required for the protein’s function, and the protein’s function is essential to the virus’s survival. Neuraminidase acts as a pair of scissors, clipping off the molecules (called receptors) at the surface of the infected cell, releasing thousands of newly formed viral particles to infect other cells. “So when the virus tries to get free from the infected cell, it has to detach from that receptor molecule,” says Luo. “And if you block neuraminidase, then the virus gets stuck. So we’re using crystallography, computer modeling, chemistry, and virology to design a drug-like molecule that will fit into this active site and stay there. Then the function of neuraminidase will be blocked.”

Drug Dilemmas

In fact, such drugs already exist: The drug Tamiflu is a neuraminidase inhibitor, and it has been shown to be effective against even the H5 “bird” flu. Tamiflu is currently used to shorten the duration of the illness, but it’s also effective as a prophylactic. In other words, when taken upon the first sign of physical discomfort (within 48 hours of infection), Tamiflu can get you back on your feet faster than just letting flu take its natural course; but if taken before any illness develops—even before exposure to the virus—Tamiflu could keep you from getting sick at all.

So if we have a drug that works against even the most deadly influenza, what’s the problem? First of all, says Whitley, the drug is not approved for children less than one year old. “UAB is taking a leadership role nationally in terms of trying to identify safe dosages of Tamiflu in children less than one year old,” he says.

The drug is also expensive: For a one-week course, a person with decent health insurance could expect to pay around $75. The price would likely drop if the demand went sky-high, but demand could be the biggest problem of all, because only one company, Roche Pharmaceuticals, makes Tamiflu. And though they plan to quadruple their pre-2004 production rates by the end of next year, Roche factories simply don’t have the capacity to manufacture enough Tamiflu to provide enough people with enough doses to keep a burgeoning epidemic in check.

To make the drug easier to transport and distribute, Roche has begun manufacturing Tamiflu powder in bulk, to be stockpiled in buckets by public-health authorities. Part of the Alabama Department of Health’s pandemic plan is stockpiling Tamiflu to provide to local health-care workers. The governments of several countries, including Australia, Canada, and the United Kingdom, have been stockpiling doses to provide to as much as 60 percent of their populations, according to Whitley. Roche is doing its best to meet increased demand, but no company would risk its financial neck to ramp up production of any drug for global prophylaxis without a promise that their product would be bought. And there can be no promise of purchase without a pandemic—and by then it will be too late.

Other Options

Other effective neuraminidase inhibitors could soon be added to our pandemic armamentarium. Relenza, which is also a neuraminidase inhibitor, is an effective drug that’s already on the market. There are only two problems with Relenza: one is that it’s taken by inhalation—and an epidemic of a flu that attacks and cripples the lungs could make inhaling a tough proposition for patients. Whitley says the drug is currently being presented to the FDA for consideration as a prophylactic. Another problem is that production of Relenza has been almost negligible in recent years, and production is just now being ramped up. For now, it won’t be enough to supplement shortages of Tamiflu.

BioCryst hopes to begin human trials, using the injection delivery method and with funding from the NIH, in Southeast Asia this winter. The FDA has said that, though safety and efficacy tests cannot be sidestepped, the drug could be rushed through the testing process should a pandemic occur. “So we should have a couple of drugs down the road to help us,” says Whitley. “I think everybody’s just concerned about time.”

Impact of the American Way

“We might get lucky enough to have the time and the resources to create a solid infrastructure before the next pandemic,” says Max Michael. “But certainly there’s the potential—whether it’s avian flu or the ‘regular’ flu at a pandemic level—for people to get sick and die. And at some point we’ll have hard choices to make within a system that is highly stressed.”

Freedman agrees that our system, regardless of preparedness, will only go so far in times of crisis. “The CDC is working on a national preparedness plan, but it’s going to depend an awful lot on cooperation by state and local employees,” he says. “Everybody thinks that the government has sweeping powers, but the CDC actually has very little authority. If there’s a problem that crosses state jurisdictions, the CDC has the power to quarantine or stop travel. But when you hear that there’s an outbreak of disease in Minnesota and the CDC has sent a team, they’re only there because the State of Minnesota has invited them; they have no jurisdiction to go in on their own. In any given state, the state health department has control.”

“To me, a real concern is how we as individuals are going to respond,” says Michael. “If we’re talking about a society that says, ‘I’m going to shoot you if you pull in front of me on the interstate’—then what does that society do when people fear for their lives and everyone is standing in line for a shot or a pill? That’s what worries me—the potential absence of civility.”

In fact, health officials in 1918 had the war to thank in one respect: World War I stirred great feelings of patriotism and loyalty to government, so Americans were trustful and readily followed government orders. Would they behave the same way today?

“Men and women in the military basically give up their ego and almost their sense of self for the greater good,” says Michael. “It’s really remarkable when you think about it. And the men and women who do emergency rescue work—they don’t see themselves as heroes, they are just doing their jobs. But as for the rest of us, I’m not sure that, as a culture, we see it as our responsibility to say, ‘I’ll wait my turn, even if it’s possible that while I wait I will get sick and die.’ That requires a willingness to lose self-identity. And in this country we honor the individual so much.”

Will We Beat the Bug?

As Michael Specter pointed out in a February 2005 issue of The New Yorker, SARS—the most frightening infectious outbreak to touch American shores in recent memory—has killed fewer than 1,000 people since it was identified; in that time, more people have drowned in their bathtubs or pools. And many more people have also died of the flu—our “ordinary” strains of flu. Cases of human avian influenza continue to be reported sporadically in Southeast Asia, but the victims are people who’ve ingested or had close contact with sick chickens. For now, then, avian influenza remains largely an economic crisis, as it continues to put poultry farm after poultry farm out of business in these countries.

“So there might be a worldwide pandemic of avian influenza, and there might not be,” says Freedman. Whatever form the next flu pandemic takes, it will happen much faster than past epidemics because of the mobility of today’s global population. “In the 1918 outbreak, it took four to six months for the disease to spread around the world,” he says. “Today, it would probably take a few weeks at the most.

“I just don’t think it’s possible to be properly prepared for something of that magnitude. We just don’t have the physical infrastructure to make vaccine fast enough, to make enough Tamiflu, or to ramp up medical-care facilities. So the only answer might be containment. I think we might see some things that we haven’t seen in our lifetimes, such as quarantine.

“Or we might choose to put people in camps,” he says. “For example, if you’re an American who is outside the U.S. and you want to get back home, we know that the maximum incubation of influenza is two weeks, so we’re going to hold you for two weeks. But there’s a danger with that too, of course. Because if you put 1,000 people together and even one of them is incubating the influenza virus, then the people who didn’t have it in the first place could all of a sudden get it.”

Despite such gloomy visions of possible world crises, many scientists remain optimistic that flu vaccines will eventually improve. It’s just a matter of time and luck as to which comes first, the vaccine or the epidemic. “There are thousands of people, in maybe hundreds of labs around the world, who’ve been working on flu for 60 years now,” Luo says. “We still don’t have a final answer, so it will continue to take a lot of effort. But we’ll keep working until we find a solution.”