Viral Time Bomb

At a hastily called press conference in Washington on Oct. 5, Health and Human Services Secretary Tommy Thompson sought to explain the bad news he had learned hours earlier-the supply of this season's flu shots would be short by nearly 50 million doses, half the amount officials had planned to have on hand, due to manufacturing problems at one of only two companies licensed to sell the vaccine in the United States.

Every year, 36,000 Americans die of flu on average-more than 30 times the number of troops who have died in the American occupation of Iraq. Given the shortage of vaccine, federal officials urged healthy Americans to forgo flu shots this year and save the vaccine for those most vulnerable, primarily the elderly.

But as serious as the news was, a far more worrisome situation was occurring 8,600 miles away in a northern province of Thailand. There, public health officials were investigating the death of a 9-year-old girl from avian influenza. The child was among a small group of people who health officials believe died from a deadly form of the virus that jumped from chickens to humans-and in one case was transmitted through human-to-human contact. World Health Organization officials were so troubled by developments in Thailand that they called for an emergency closed-door meeting of vaccine manufacturers and international health officials in mid-November to consider responses to a potential widespread epidemic, known as a pandemic.

Both the shortage of flu vaccine in the United States and the fears of a global pandemic point to serious shortcomings in public health officials' ability to respond to influenza outbreaks. The method for developing flu vaccine is a yearlong, labor-intensive process. It starts with meticulous epidemiological sleuthing to try to anticipate, months in advance, the most likely flu viruses that will be circulating. Once those are estimated, millions of fertile chicken eggs are injected with the three most virulent viruses, which are then harvested, combined into a vaccine and prepared for human injection. The entire process is rife with opportunities for error and bacterial contamination-the problem that caused health officials to condemn the vaccine produced by manufacturer Chiron early this fall, resulting in the vaccine shortage in the United States.

Because the flu virus is continually mutating, the vaccine must be reformulated annually. It would be almost impossible for vaccine manufacturers to respond quickly with adequate amounts of an effective vaccine if an especially deadly strain of the virus were to emerge, as seems to be the case in Asia. What's more, using chicken eggs to create a vaccine for avian flu is especially problematic because the virus will generally kill the embryo before a usable vaccine can be produced.

"We have a situation that shows a lot of shortfalls," says Elin Gursky, senior fellow for biodefense and public health at the ANSER Institute for Homeland Security in Arlington, Va. "We don't seem to understand that disease is a security issue-a major, global security issue, and certainly a security issue for the United States."

According to Janet Heinrich, director of public health issues for the Government Accountability Office, experts estimate that a pandemic spawned by recurring avian flu in Asia could kill up to 207,000 people in the United States and cause major social disruption. The National Vaccine Program Office at HHS released a draft Pandemic Influenza Preparedness and Response Plan in August, but it fails to resolve critical questions about how a vaccine would be purchased and distributed. "Consequently, states are left to make their own decisions, potentially compromising the timing and adequacy of a response to an influenza pandemic," Heinrich says.

What's more, the document doesn't address the possibility of vaccine shortages-the very situation U.S. health officials are grappling with this winter, and one they would certainly face in the event of a pandemic, whether it occurs this winter or in the future.

Dodging the Issue

Vaccine manufacturers never have produced more than 260 million doses of flu vaccine worldwide in a single year. In a world of 6 billion people, there is no way adequate numbers could begin to be vaccinated in the event of a pandemic, says Laurie Garrett, author of Betrayal of Trust: The Collapse of Global Public Health (Hyperion, 2001) and a senior fellow for global health at the Council on Foreign Relations. "Part of the problem is we don't have a really good, rapid way of making flu vaccine, as we do for most other vaccines. The other problem is we've never approached tackling flu in a genuine global way. We've always thought of flu as a nation-state problem," Garrett says.

The danger in this thinking was evident a few years ago when Garrett sat in a meeting in Washington with U.S. and Canadian health officials. "Canada was told that if there were a pandemic, we would deny Canada vaccine while providing it to our own people," she says. "And of course it would be the same for Mexico-and needless to say, if we wouldn't give it to our immediate neighbors, we wouldn't be sharing it anywhere. And in truth, we would have a hell of a time just trying to make doses for our own use.

"We've always been on the edge of a serious foreign policy issue here, but we've never really addressed it. We've always dodged it," Garrett says.

Experts in infectious disease believe that the days of being able to dodge the issue are numbered. There were three influenza pandemics in the 20th century. In each case, a virus spread globally within a year of its detection, according to the Centers for Disease Control and Prevention. The worst was the 1918 Spanish flu, which killed more than 500,000 people in the United States and as many as 50 million worldwide. Most of those who died were young, healthy adults, who succumbed within a few days of exposure to the virus. In 1957, Asian flu killed 70,000 Americans. It was first discovered in late February in China; by June it had spread to the United States. Most recently, the 1968 Hong Kong flu caused about 34,000 deaths in the United States.

A number of animals, especially waterfowl, are known to act as hosts for the avian influenza virus. Wild birds usually do not get sick from the virus, but they can spread it to domesticated birds. Chickens are especially vulnerable. Avian influenza outbreaks among poultry appear periodically, with the most virulent forms killing between 90 percent and 100 percent of flocks infected.

In 1997, the first cases of humans contracting avian influenza from birds were documented in Hong Kong. One and a half million chickens were quickly slaughtered in an attempt to remove the source of the virus, a response that many officials believe may have averted a pandemic. But outbreaks of highly pathogenic influenza among poultry have continued throughout the world.

There are 15 avian influenza virus subtypes, according to the World Health Organization. Of particular concern is the subtype known as H5N1, because it mutates rapidly and can cause severe disease in humans. H5N1 has been circulating widely in poultry this year in Cambodia, China, Indonesia, Japan, Laos, South Korea, Thailand and Vietnam. According to the CDC, last winter more than 100 million birds in Asia either died from the disease, or were killed to prevent it from spreading.

Public health officials are concerned that people already infected with human influenza virus will become infected with the H5N1 virus and serve as a "mixing vessel" for the emergence of a novel subtype that could be easily transmitted from person to person. This "would mark the start of an influenza pandemic," the World Health Organization stated in January 2004. Such a pandemic "is inevitable and possibly imminent," WHO concluded.

Since 1997, dozens of humans have contracted avian influenza, including H5N1. The majority have been in Asia, where humans and poultry tend to live in closer quarters and where poverty and a lack of education preclude widespread vaccination and effective public health measures. From the beginning of this year until early November, 16 humans contracted H5N1 virus in Thailand alone. Eleven of the cases were fatal. In at least one instance, the virus is believed to have been passed from an 11-year-old girl to her mother, alarming public health officials around the world.

"To my mind, long before flu reaches our shores we ought to have been assisting China, Hong Kong, Taiwan, Vietnam and the other nations in that region in preventing the emergence and spread of flu on the ground at the source site," says Garrett.

The Health Horizon

It's not clear how severe this year's flu season will be, or whether the transmission of human-to-human avian influenza in Thailand really signals a pandemic-inducing shift in the virus. What does seem clear to many health officials is that the United States and other nations must find new ways to deal with flu, or risk major social and economic upheaval when the next pandemic inevitably emerges.

"Like a lot of others, I've been working on issues like this for a long time," says Gursky. "I always hope that the silver lining to these tragedies is we become better prepared. But we have short memories. We're always playing catch-up."

Among the challenges facing U.S. public health officials is that vaccine manufacturing and distribution are largely the province of the private sector, Gursky says: "We have allowed the market to drive vaccine production rather than health security and health defense issues. I don't think the answer is for the U.S. government to get into the vaccine business, but certainly we have to incentivize greater production."

Flu vaccine development is a high-risk, low-profit endeavor. What's more, despite the fact that anywhere from 15,000 to 50,000 Americans die of influenza and more than 200,000 others are hospitalized with flu every year, the market for vaccine is unpredictable, with as much as 10 percent of the supply going unused. Because it cannot be reused the following year, it must be destroyed-a loss manufacturers must absorb.

Thompson says he favors the federal government guaranteeing the flu vaccine market to eliminate the losses manufacturers face when doses go unused. He and others in the Bush administration and public health communities believe that it is essential that better methods for developing vaccine be found, eliminating the need for millions of chicken eggs.

In its last two budget requests for HHS, the Bush administration asked for $100 million to invest in cell-culture development of flu vaccine, as well as for year-round egg development for egg-based vaccine, yet Congress authorized only $50 million in 2004.

Officials at HHS are focusing on averting what many believe may be an impending influenza crisis. In November, the agency awarded a $10 million contract to Aventis Pasteur to develop an "egg supply plan" that will enable year-round production of vaccine in the future, allowing manufacturers to ramp up vaccine production when shortages occur and, if necessary, to respond more quickly with vaccine designed to combat an influenza pandemic. In addition, the National Institute of General Medical Sciences announced in mid-November that it was developing computer models to simulate the potential outbreak of avian flu among humans in an effort to plan to contain the virus. Also, the National Institute of Allergy and Infectious Diseases has begun an influenza genome sequencing project to help researchers understand how flu viruses evolve, spread and cause disease.

"The fact is that the flu vaccine marketplace has been withering for years, through most of the 1990s. Ten years ago, in 1994, we had five manufacturers of injectable flu vaccine. Today, we have two that are licensed in the United States," Thompson says. In late October, HHS announced it had stockpiled enough antiviral medicines to treat 7 million people with flu, should such treatment be needed this winter.

In the meantime, H5N1 influenza continues on its unknown path.