The Next Pandemic?

Laurie Garrett

From Foreign Affairs, July/August 2005

Summary:  Since it first emerged in 1997, avian influenza has become deadlier and more resilient. It has infected 109 people and killed 59 of them. If the virus becomes capable of human-to-human transmission and retains its extraordinary potency, humanity could face a pandemic unlike any ever witnessed.

Laurie Garrett is Senior Fellow for Global Health at the Council on Foreign Relations and is the author of The Coming Plague and Betrayal of Trust.

Traditional Asian methods of buying, slaughtering, and cooking meat make it hard to track the spread of an influenza virus -- and tracking it is critical to preventing the disease from spreading. In Asia, consumers prefer to buy live chickens and other live animals at the market, slaughtering them in home kitchens. Asians thus have a high level of exposure to potentially disease-carrying animals, both in their homes and as they pass through the markets that line the streets of densely packed urban centers. For someone trying to trace a disease, Asia is a nightmare: with people daily exposed to live chickens in so many different environments, how can a sleuth tell whether an ailing flu victim was infected by a chicken, a duck, a migratory heron -- or another human being?

Although most of the 109 known human H5N1 infections have been ascribed to some type of contact with chickens, mysteries abound, and many cases remain unsolved. "The virus is no longer causing large and highly conspicuous outbreaks on commercial farms," a 2005 WHO summary of the human Z+ cases states. "Nor have poultry workers or cullers turned out to be an important risk group that could be targeted for protection. Instead, the virus has become stealthier: human cases are now occurring with no discernible exposure to H5N1 through contact with diseased or dead birds."

If proximity to infected animals is the key, why have there been no deaths among chicken handlers, poultry workers, or live-chicken dealers? The majority of the infected have been young adults and children. And there has been one documented case of human-to-human transmission of the Z+ strain of the H5N1 virus -- in late 2004, in Thailand. Several more such cases are suspected but cannot be confirmed. According to the WHO, there is "no scientific explanation for the unusual disease pattern."

Assessing and understanding H5N1's virulence in humans has also proved elusive. When it first appeared in Hong Kong in 1997, the virus killed 35 percent of those it was known to have infected. (Less severe cases may not have been reported.) The Z strain of the disease, which emerged in early 2003, killed 68 percent of those known to have been infected. In H5N1 cases since December 2004, however, the mortality has been 36 percent. How can the fluctuation over time be explained? One disturbing possibility is that H5N1 has begun adapting to its human hosts, becoming less deadly but easier to spread. In the spring of 2005, in fact, H5N1 infected 17 people throughout Vietnam, resulting in only three deaths. Leading flu experts argue that this sort of phenomenon has in the past been a prelude to human influenza epidemics.

The medical histories of those who have died from H5N1 influenza are disturbingly similar to accounts of sufferers of the Spanish flu in 1918-19. Otherwise healthy people are completely overcome by the virus, developing all of the classic flu symptoms: coughing, headache, muscle pain, nausea, dizziness, diarrhea, high fever, depression, and loss of appetite. But these are just some of the effects. Victims also suffer from pneumonia, encephalitis, meningitis, acute respiratory distress, and internal bleeding and hemorrhaging. An autopsy of a child who died of the disease in Thailand last year revealed that the youth's lungs had been torn apart in the all-out war between disease-fighting cells and the virus.

BAD MEDICINE

According to test-tube studies, Z+ ought to be vulnerable to the antiflu drug oseltamivir, which the Roche pharmaceuticals company markets in the United States under the brand name Tamiflu. Yet Tamiflu was given to many of those who ultimately succumbed to the virus; it is believed that medical complications induced by the virus, including acute respiratory distress syndrome, may have prevented the drug from helping. It is also difficult to tell whether the drug contributed to the survival of those who took it and lived, although higher doses and more prolonged treatment may have a greater impact in fighting the disease. A team of Thai clinicians recently concluded that "the optimal treatment for case-patients with suspected H5 infection is not known." Lacking any better options, the WHO has recommended that countries stockpile Tamiflu to the best of their ability. The U.S. Department of Health and Human Services is doing so, but supplies of the drug are limited and it is hard to manufacture.

What about developing a Z+ vaccine? Unfortunately, there is only more gloom in the forecast. The total number of companies willing to produce influenza vaccines has plummeted in recent years, from more than two dozen in 1980 to just a handful in 2004. There are many reasons for the decline in vaccine producers. A spate of corporate mergers in the 1990s, for example, reduced the number of major international pharmaceutical companies. The financial risk of investing in vaccines is also a key factor. In 2003, the entire market for all vaccines -- from polio to measles to hepatitis to influenza -- amounted to just $5.4 billion. Although that sum may seem considerable, it is less than two percent of the global pharmaceutical market of $337.3 billion. Unlike chemical compounds, vaccines and most other biological products are difficult to make and can easily become contaminated. There is also a large and litigious antivaccine constituency -- some people believe that vaccines cause harmful side effects such as Alzheimer's disease and autism -- adding considerable liability costs to manufacturers' bottom lines.

The production of influenza vaccines holds particular drawbacks for companies. Flu vaccines must be made rapidly, increasing the risk of contamination or other errors. Because of the seasonal nature of the flu, a new batch of influenza vaccines must be produced each year. Should sales in a given year prove disappointing, flu vaccines cannot be stockpiled for sale in a subsequent season because by then the viruses will have evolved. In addition, the manufacturing process of flu vaccines is uniquely complex: pharmaceutical companies must grow viral samples on live chicken eggs, which must be reared under rigorous hygienic conditions. Research is under way on reverse genetics and cellular-level production techniques that might prove cheaper, faster, and less contamination-prone than using eggs, but for the foreseeable future manufacturers are stuck with the current laborious method. After cultivation, samples of the viruses must be harvested, the H and N characteristics must be shown to produce antibodies in test animals and human volunteers, and tests must prove that the vaccine is not contaminated. Only then can mass production commence.