Clipping Its Wings
Scientists hope a new technique will help them develop a vaccine against the bird flu virus before it leaps to humans
By Fred Guterl
Newsweek InternationalFeb. 9 issue - The life of a poultry farmer in the sleepy Cambodian village of Phuong Peay is not exactly eventful, but the job does have its worries. Like many of his fellow farmers, 50-year-old Chheng Kim Seang's biggest concern is usually the health of his birds. His livelihood depends on it. So when he walked into the ramshackle wooden shed that houses his chickens one morning late last December and found a few dead chicks, and when a week later perfectly healthy roosters and hens also starting dying, he assumed the worst: cholera. To cut his losses, he injected the live birds with medicine and sold them to a wholesaler. Shortly afterward, on Jan. 13, government officials showed up to carry out tests on the farm opposite Chheng's. Their conclusion, announced on Jan. 24, didn't confirm Chheng's worst fears, it surpassed them. His chickens were likely victims of H5N1—the bird-flu virus sweeping Asia. The virus has been known on occasion to kill people with deadly efficiency. Now Chheng fears for his life. "When I breathe at night," he says, "I wonder if I am sick."
Whether Chheng really is sick or just hypochondriacal, his fear is warranted. So far H5N1 has claimed mainly chickens—millions of them have died from the flu in recent weeks and 25 million more have been burned, or bagged and buried alive, in an effort (vain, so far) to keep the disease from spreading. The virus has infected only 11 people so far this year: most of them, like Chheng, had probably come into contact with the birds' feces or perhaps inhaled infected dust kicked up by flapping wings. Those who do catch the bug die at an alarming rate—of 31 cases reported since 1997, 15 people have died. Health officials are concerned less about the danger to a handful of farm workers, though, than to the wider public. Should H5N1 acquire the ability to pass from human to human, instead of from bird to human, the consequences, says a World Health Organization official, would make the SARS epidemic look like "a picnic."
For years now, health experts have been anxiously awaiting the Big One—a new virus perfectly adapted to the current environment of global living, able to spread among continent-hopping humans with the ease of influenza but with a devastatingly high rate of mortality. The Asian bird flu is beginning to look more and more like a precursor to such a global killer. In the past few weeks health officials have grown increasingly alarmed at H5N1's rapid spread. Despite warnings and aggressive culling of fowl, the epidemic has engulfed most of East Asia—moving from South Korea to Vietnam, Japan, Thailand, Cambodia and Indonesia. Last week outbreaks were reported in China, the world's No. 2 poultry producer. This rapid progression has not been met with an orderly response. Indonesia has agreed to kill only those birds that seem sick. Thai farmers have been killing chickens without proper safety procedures, endangering themselves and, experts say, raising the risk of a human pandemic.
Each time a chicken passes H5N1 along to a farmer, the virus gets one more chance to shuffle its genetic cards with human flu viruses and hit upon the perfect killer combination. Health officials from the United Nations and the WHO have grown so alarmed at the prospect that in the past few weeks they've decided to take the unprecedented step of developing a vaccine for a human strain of influenza even before one emerges. What's more, they're going to use a new technique of making vaccines that has been tried only in a lab experiment. The technique, called reverse genetics, relies on direct manipulation of a virus's genetic code—a radical departure from the traditional approach to vaccine-making that's been in use for four decades.
Reverse genetics could be the best thing to happen to virology in years. It may cut the time needed to develop a new vaccine from several months to a few weeks. That kind of speed may prove to be invaluable for preventing a human H5N1 virus (should one emerge) from sparking a pandemic. It would also go a long way toward improving the more mundane work of preparing next year's flu vaccine, which has been criticized as too cumbersome to keep up with fast-evolving viruses. On the other hand, the technology is new, and there's no guarantee that everything will go smoothly. A vaccine made with reverse genetics may carry the stigma of genetic manipulation and wait years for regulatory approval. And a vaccine for H5N1 may not be effective. The stakes are high. If—or when—H5N1 turns on humans, there might not be much time to head off a catastrophe.
The bird flu now making the rounds in Asia first came to the attention of scientists in 1997, when 18 people were infected with H5N1 in Hong Kong. Six died. Although scientists are cautious about fixing a mortality rate from such low numbers, the deadliness of H5N1 raised eyebrows. By comparison, the flu of 1918 killed up to 4 percent of those infected, and SARS last year killed 11 percent. Scientists had seen birds succumb to flu before, but H5N1 seemed especially eager to make the cross-species jump to humans. "There have been outbreaks of highly lethal influenza in chickens, but it was thought that these viruses were self-contained—that they only affected chickens," says Daniel Perez, a virologist at the University of Maryland. "In 1997, that notion changed completely." To contain the disease, Hong Kong killed 1.5 million chickens and put in place testing and other safeguards against infection. The disease seemed to peter out. Then last year a father and son from Hong Kong contracted the virus while visiting Fujian province. (The father died.) Health experts knew they had a robust bug on their hands.
What really concerned scientists about H5N1 was not only its mortality rate, but its persistence in trying to cross the species barrier. Sooner or later, they feared, it would infect a human and, through random mutation, adopt a form that allowed human-to-human transmission. Or, it could acquire this ability by swapping genes with another flu bug already adapted to humans. Or the same thing could happen in a pig infected with both the bird flu and a human flu. Any one of these events might not lead to a full-blown pandemic for months. John Barry, a medical historian and author of "The Great Influenza," a forthcoming book about the 1918 pandemic, believes that that crisis started as a relatively mild and largely unnoticed flu epidemic in Kansas. Six to eight months later, however, a second, far deadlier wave of infections arose simultaneously in Sierra Leone; Brest, France, and Boston, then a week later in Bombay, New Orleans and many other cities. By the time it ran its course, the pandemic had killed 50 million people, by some reckonings.
When H5N1 recurred last year, its potential for devastation wasn't lost on health experts. They began casting around for a strategy of prevention. One obvious tack was to develop a vaccine for H5N1 before it emerged as a human pathogen. With a vaccine in hand, officials might be able to act quickly enough to stop an outbreak in its tracks, potentially saving millions of lives. Conventional vaccine-making techniques, though, wouldn't work, for two reasons. H5N1 changes so quickly that they would have been too slow to keep up. Scientists would first have to culture a sample of the H5N1 virus with another known virus (known as a "master-seed virus"), and then laboriously sift through the different genetic combinations of the two bugs until they found one that would trigger the immune system without causing disease. The job of sifting can take three months or more. The bird flu, though, posed an additional problem. Vaccine cultures are grown in chicken eggs, and bird flu kills chickens and eggs.
The idea of breeding vaccines in chicken-egg cultures already seemed outdated back in the 1980s, when researchers began kicking around the idea of using genetic manipulation instead. First, though, they had to come up with a way of handling RNA, a more gossamer, single-stranded genetic material than the double-stranded DNA that scientists had begun to master. In 1992, Peter Palese of Mount Sinai Hospital in New York came up with a technique for turning RNA into DNA and back again, which gave scientists a way of handling RNA (and put the "reverse" into genetics). Over the next few years several different research teams refined the technique. Virologists Robert Webster and Richard Webby —from St. Jude Children's Research Hospital in Memphis, Tennessee, used these techniques to produce an experimental vaccine for the 1997 strain of H5N1. First they clipped off genetic material so that the virus was no longer contagious. Then they combined RNA from the virus and the master strain, turned the whole lot into DNA, and tested it to make sure the combination worked. They turned the DNA back to RNA, and—voila!—they had a GM flu virus.
It didn't generate much interest. Vaccine companies were concerned about licensing arrangements with MedImmune, the firm that holds the patents for reverse genetics, and regulators were wary of genetic manipulation. The vaccine, says Webster, "died on the vine."
In the past few weeks H5N1's rapid spread has changed everything. Last Wednesday, WHO's head flu coordinator, Klaus Stohr, chaired a teleconference of regulators and vaccine makers, who seemed willing to work through the myriad logistical issues of large-scale vaccine distribution. Webster and Webby went to work on another preparation—live, not experimental. They obtained samples from the ssaliva of two Vietnamese patients. Last week at St. Jude, they were trying to take two surface proteins off the H5N1 virus and attach them to the master-seed virus. Webster expects to have a vaccine in a month.
Will that be quick enough? Nobody knows if H5N1 will make the leap to humans. But the virus has demonstrated that it can spread farther, more quickly, than other bird flus of recent years. "I'm very concerned," says Perez. "The spread of the virus, and its ability to go to humans on many occasions, is an early-warning sign that something bigger could happen." Even if a silent pandemic has already started, though, scientists are now optimistic that a vaccine could be delivered before it reaches a second (deadlier) wave. Naturally there's a possibility that H5N1 will remain a disease of birds. But it's nice to know that scientists like Webster and Webby aren't counting on it. |
