Public health officials preparing to battle what they view as an inevitable influenza pandemic say the world lacks the medical weapons to fight the disease effectively, and will not have them anytime soon.
Public health specialists and manufacturers are working frantically to develop vaccines, drugs, strategies for quarantining and treating the ill, and plans for international cooperation, but these efforts will take years. Meanwhile, the most dangerous strain of influenza to appear in decades -- the H5N1 "bird flu" in Asia -- is showing up in new populations of birds, and occasionally people, almost by the month, global health officials say.
If the virus were to start spreading in the next year, the world would have only a relative handful of doses of an experimental vaccine to defend against a disease that, history shows, could potentially kill millions. If the vaccine proved effective and every flu vaccine factory in the world started making it, the first doses would not be ready for four months. By then, the pathogen would probably be on every continent.
Theoretically, antiviral drugs could slow an outbreak and buy time. The problem is only one licensed drug, oseltamivir, appears to work against bird flu. At the moment, there is not enough stockpiled for widespread use. Nor is there a plan to deploy the small amount that exists in ways that would have the best chance of slowing the disease.
The public, conditioned to believe in the power of modern medicine, has heard little of how poorly prepared the world is to confront a flu pandemic, which is an epidemic that strikes several continents simultaneously and infects a substantial portion of the population.
Since the current wave of avian flu began sweeping through poultry in Southeast Asia more than 18 months ago, international and U.S. health authorities have been warning of the danger and trying to mobilize. Research on vaccines has accelerated, efforts to build up drug supplies are underway, and discussions take place regularly on developing a coordinated global response.
The U.S. Department of Health and Human Services will spend $419 million in pandemic planning this year. The National Institutes of Health's influenza research budget has quintupled in the past five years.
"The secretary or the chief of staff -- we have a discussion about flu almost every day," said Bruce Gellin, head of HHS's National Vaccine Program Office. This week, a committee is scheduled to deliver to HHS Secretary Mike Leavitt an updated plan for confronting a pandemic.
Despite these efforts, the world's lack of readiness to meet the threat is huge, experts say.
"The only reason nobody's concerned the emperor has no clothes is that he hasn't shown up yet," Harvey V. Fineberg, president of the National Academy of Sciences' Institute of Medicine, said recently of the world's efforts to prepare for pandemic flu. "When he appears, people will see he's naked."
Other scientists are sounding the alarm as well.
The most outspoken is Michael T. Osterholm, director of the Center for Infectious Disease Research and Policy at the University of Minnesota. In writing and in speeches, Osterholm reminds his audience that after public calamities, the United States usually convenes blue-ribbon commissions to pass judgment. There will be one after a flu pandemic, he believes.
"Right now, the conclusions of that commission would be harsh and sad," he said.
In hopes of slowing a pandemic's spread, public health specialists have been debating proposals for unprecedented countermeasures. These could include vaccinating only children, who are statistically most likely to spread the contagion; mandatory closing of schools or office buildings; and imposing "snow day" quarantines on infected families -- prohibiting them from leaving their homes.
Other measures would go well beyond the conventional boundaries of public health: restricting international travel, shutting down transit systems or nationalizing supplies of critical medical equipment, such as surgical masks.
But Osterholm argues that such measures would fall far short. He predicts that a pandemic would cause widespread shutdowns of factories, transportation and other essential industries. To prepare, he says, authorities should identify and stockpile a list of perhaps 100 crucial products and resources that are essential to keep society functioning until the pandemic recedes and the survivors go back to work.
Since late 2003, 109 people are known to have been infected with the emerging H5N1 virus in Asia. About half -- 55 -- have died.
Ironically, for the current H5N1 strain of avian flu to gain "pandemic potential," it will have to become less deadly. Declining lethality is a key sign that the microbe is adapting to human hosts. That is one reason the 34 percent mortality observed in the most recent outbreak -- a cluster of cases in northern Vietnam -- has scientists worried.
Pandemic influenza is not an unusually bad version of the flu that appears each winter. Those outbreaks are caused by flu viruses that have been circulating for decades and change slightly year to year.
Pandemics are caused by strains of virus that are highly contagious and to which people have no immunity. Such strains are rare. They arise from the chance scrambling and recombination of an animal flu virus and a human one, resulting in a strain whose molecular identity is wholly new.
In the 20th century, pandemics occurred in 1918, 1957 and 1968. Although the 19th-century record is less certain, there appear to have been four flu pandemics -- in 1833, 1836, 1847 and 1889. On a purely statistical basis, the nearly 40 years since the last one suggests the time may be ripe.
The microbe called influenza A/H5N1 appeared in East Asia in 1996 and has flared periodically since. It is highly contagious and lethal in chickens, but it can be carried without symptoms in some ducks -- a combination that helps keep it in circulation.
Birds occasionally infect humans, and scientists recently found evidence that the virus is sometimes passed person to person. That form of transmission is now difficult and rare, but the virus could evolve so that it becomes easy and common.
If H5N1 never becomes easily transmissible in human beings, it will never become a pandemic. If it does become transmissible, the consequences are difficult to imagine. But history provides some clues.
The "Spanish flu" in 1918 and 1919 was the biggest and, along with AIDS, the most important infectious disease outbreak of the 20th century. It is on the short list of great disasters in human history.
At least 50 million people, and possibly as many as 100 million, died when the world's population was 1.9 billion people, one-third its current size.
The best defense
Tests are underway at three U.S. hospitals on an experimental vaccine against H5N1. But it is not the first H5N1 vaccine.
When a slightly different strain of the virus surfaced in Hong Kong in 1997, killing thousands of chickens and a half-dozen people, researchers used viruses from birds and people to make experimental vaccines. But neither offered much protection in lab tests, and nobody knows why.
Instead of working on the problem, researchers dropped it. First SARS (severe acute respiratory syndrome), and then a different avian flu strain that arose in Europe (H7N7), took their attention.
"The urgency around this issue kind of dissipated," said John Treanor, a physician at the University of Rochester and one of the leaders of the vaccine project. "I think it's an example of how unpredictable things are. We got distracted."
The urgency is back.
As the first, small hedge against disaster, the government last fall ordered 2 million doses of H5N1 vaccine from Sanofi Pasteur, one of the country's three flu vaccine makers, even though nobody yet knows whether it works.
A half-dozen other countries are also working on pandemic vaccines. But making enough to fight an outbreak is a tall order.
About 300 million flu shots are made worldwide each year. The vaccine protects against three flu strains. If the global production capacity were directed to make only H5N1 vaccine, the output could be 900 million shots.
Unfortunately, virologists are almost certain people will need two doses about a month apart to mount a successful immune response against a wholly new strain such as H5N1. That would cut the theoretical number of recipients worldwide to 450 million. If each shot requires a larger-than-usual amount of vaccine to work, the number will be even smaller.
Can the world produce more flu shots? Not easily.
Because nearly all flu vaccine is made by growing the virus in fertilized chicken eggs, special factories and a steady supply of eggs are required. Consequently, a key element of pandemic planning is getting more people to get yearly flu shots, which will give companies a larger market and an incentive to expand their plants.
Around the world, flu vaccine production has risen by just one-third in the past decade. New plants in Brazil, South Korea and the Netherlands will boost global production by an additional 25 percent in the near future.
In theory, even a modest amount of vaccine might be useful. Fighting disease outbreaks is like fighting fires. You do not have to hose down the whole world to put the fire out, but you do have to hose down the perimeter to keep it from spreading. It might be possible to contain an H5N1 outbreak at its source if the surrounding population were immediately vaccinated.
Would the United States, Europe and Japan be willing to donate their precious vaccine supply to mount this long-shot defense? This is perhaps the biggest unanswered question in pandemic flu planning -- and one likely to be answered only at the moment of truth.
Officially, it is a possibility.
"If it was done in consultation with the WHO [World Health Organization] -- and with other governments that would make contributions, as well -- we would be more likely to consider it," said Gellin at HHS. But observers both in and out of the government said, not for quotation, that they doubt the U.S. government would ever send a significant amount of its vaccine stockpile overseas.
Only one drug
In the absence of a vaccine, the only pharmaceutical bulwark against H5N1 is oseltamivir. It can shorten the illness's duration, and if taken immediately after exposure, it can even prevent infection. But the world's supply of the drug is limited.
Sold as Tamiflu, it is manufactured by just one company, the Swiss giant Roche, in a laborious, expensive process that takes eight months.
Twenty-five countries have ordered oseltamivir to stockpile, and five others have expressed interest, a Roche spokesman, Terence J. Hurley, said recently.
The United States already has a stockpile, but it is enough to treat less than 1 percent of the population. The government has ordered enough to treat 3 million more people, or about 2 percent total.
At a congressional hearing in late May, the company's medical director, Dominick A. Iacuzio, said it will begin producing oseltamivir in the United States soon. The company says it could supply 13 million more courses of treatment in 2006 and an additional 70 million in 2007 -- provided the government orders them.
Would having lots of vaccine or oseltamivir make a difference?
In a study published last year, Ira M. Longini Jr. of Emory University ran a mathematical model of what might happen if a pandemic such as the 1957 Asian flu, which was caused by a virus far milder than bird flu, hit the United States.
He and his colleagues estimated that with no vaccine or antiviral drugs, there would be 93 million cases and 164,000 deaths. Vaccinating 80 percent of people younger than 19 -- the group most responsible for spreading the virus -- "would reduce the epidemic to just 6 million total cases and 15,000 total deaths in the country."
Giving that group eight weeks of oseltamivir would have the same effect, at least temporarily. But it would take the equivalent of 190 million courses of treatment -- more than anyone thinks the country will have in the next few years.
Somewhat more realistic is deploying the drug to where the outbreak begins. One researcher, Neil M. Ferguson of Imperial College in London, said in an interview that results of his not-yet-published mathematical modeling "are encouraging."
But unless antiviral drugs squelch a pandemic at the outset, their ultimate usefulness will be small. Without widespread immunity through vaccination or infection, the virus will simply move into a population when the drugs run out.