COLUMN ONE : Forecasters Fight to Foil the Flu : Each year, vaccine makers attempt the impossible. They try to guess which strains of the cagey--and dangerous--virus will strike next.
Influenza is not a tidy or predictable disease, and those who attempt to label it and put it in a box do so at risk.
--Virologist Edwin D. Kilbourne, in his landmark 1987 book, “Influenza”
The old people provided the earliest clues.
It was sometime in February when the first reports trickled in from the Northeast--New Hampshire, Vermont, New York. Nursing home residents who had been vaccinated against the flu were nonetheless getting sick.
To epidemiologist Nancy Arden at the Centers for Disease Control and Prevention (CDC) in Atlanta, this could mean just one thing: The wicked influenza virus--which changes shape as fluidly as a chameleon changes colors--had reconfigured itself yet again. It was, she thought, an unsettling harbinger of flu season, 1993-94.
Thus a scientific rite of winter had commenced. Each year, amid sniffling noses, soaring fevers and the aching of countless backs--not to mention hospitalizations and thousands of deaths--scientists attempt to do what Kilbourne insisted could not be done.
They attempt to predict the flu.
It is an intense and delicate chess game. The object: to keep the mercurial virus in check by figuring out, a year in advance, which mutations will emerge as a threat the following season--data that is then used to design a flu vaccine. And as concern heightens among virologists that the world is soon due for another flu pandemic--a devastating global outbreak like the one that killed 20 million people in 1918--the stakes are growing increasingly high.
“We’re just sort of waiting for the next pandemic,” said Carole Heilman, chief of respiratory diseases for the National Institute for Allergy and Infectious Diseases. “I don’t put anything past influenza. . . . This virus is extraordinarily cagey.”
The annual attempt to outsmart the flu is a global endeavor, involving more than 100 World Health Organization laboratories, plus an international network of doctors. As influenza travels about, lab technicians go to work, isolating different types of the virus that doctors have cultured from the throats of the afflicted.
The technicians search for subtle differences in proteins that distinguish one form of flu from the next. The details they cull from their Petri dishes are fed to the U.S. Food and Drug Administration, which uses the information to formulate the next incarnation of vaccine. But there is a catch: The shots must be manufactured and administered months in advance of the arrival of the illness they are supposed to combat.
The entire exercise is based on hunches, history and a bit of crystal ball reading.
As Dr. Arnold Monto, a flu expert at the University of Michigan, explains: “You have an outbreak in the Far East and it hasn’t moved yet, (but) you have to assume that that strain is going to come to North America, when it might--and it might not. . . . It’s a bit of a crapshoot.”
If the crystal ball readers are correct, what is coming our way this winter will be an epidemic of a harsh new strain of Beijing flu that, although not dramatically different enough from old strains to cause a pandemic, will kill more people than usual.
The Beijing flu warning is based on the new strain’s late appearance last season and its spotty showing. New England was hit hard. Georgia, Colorado, Arizona and New Mexico reported outbreaks. California was mostly spared.
Flu forecasters have seen this pattern before. It is a clue, they say, that the late-breaking virus will return for an encore. In flu lingo, there is a name for this signal: “the herald wave.”
The wave convinced CDC experts that the upcoming season’s vaccine should include the Beijing flu strain. Typically, the shots are a blend of three strains; the 1993-94 vaccine will also include a Panama flu that has been making the rounds since 1990 and a strain from Texas that appeared in 1991. What nobody knows for certain, of course, is whether the brew is the perfect blend that will drop next season’s villain in its tracks.
Said Arden: “There is a lot of educated guesswork involved.”
The guesswork is not uniformly successful. Studies have shown that influenza vaccine prevents illness in 70% of healthy children and young adults. Among elderly nursing home residents--a population considered at extremely high risk because of age and the way flu zips through a closed environment--the CDC says the vaccine prevents illness 30% to 40% of the time and death 80% of the time.
Talk of death in connection with the flu may sound surprising to those who think of it as rather benign. This is a common perception--or misperception.
According to the National Center for Health Statistics, there were 129.6 million cases in 1991, the last year for which figures were compiled. That year, flu-stricken Americans missed 89.5 million workdays and 69.1 million school days. The illness claims an average of 20,000 lives each year, most from complications caused by pneumonia. An estimated 90% of the deaths are among the elderly.
Should a pandemic occur, the toll could run much higher. Although most flu epidemics occur in the winter, a pandemic could occur in any season. It would involve a drastically different strain that could sweep through the world more quickly than a vaccine could be developed to fight it. The most recent one occurred in 1968 and was relatively mild, accounting for 28,000 deaths. The 1918 pandemic, which Kilbourne describes as “the worst human disaster of any kind,” killed 196,000 people in a month.
Few people remember that today. Instead, influenza is often mistakenly blamed for minor, unrelated ailments. Colds, upset stomachs and garden-variety sore throats are all dismissed as “just the flu.”
In fact, influenza has very distinct symptoms: cough, sore throat, nasal congestion accompanied by fever, headaches and muscle aches. It is carried through the air in invisible droplets expelled when infected people cough, sneeze or even speak. When a particularly harsh strain is going around, it is not uncommon for 50% of those exposed to get sick.
Still, Americans have little respect for the power of influenza. Among those considered at high risk only 25% to 30% take the vaccine. And even the federal government, it could be argued, does not consider flu a treacherous threat. Only this year, after much lobbying by the American Thoracic Society, did Medicare agree to reimburse for flu vaccine.
There is also an antiviral drug--Amantadine--that helps people recover from flu. But doctors, fearing side effects such as dizziness, do not often prescribe it. A closely related antiviral drug--Rimantadine--has been in development for nearly a decade, has fewer side effects and is reportedly close to approval by the FDA.
Until then, vaccination remains the most promising way to fight the flu. Yet the protection is short-lived, wearing off in nine months to a year. And not many people take the vaccine. An estimated 19 million Americans are vaccinated each year--a puny number compared to the total of those who get sick. Doctors such as Steven Mostow, a Denver flu expert, have spent years trying to turn these numbers around, spouting dire statistics to persuade the public to take flu shots.
It has not worked.
“The U.S. actually at one time had the highest immunization rate for its population of high-risk patients in the world,” Mostow said. “We have now dropped to fifth. I’m ashamed of that.”
He added: “Influenza is a very specific disease, but ‘the flu’ is a wastebasket term used by patients and doctors alike to explain the unexplained. That’s why people think of the flu as being trivial.”
Influenza has been around for centuries. Hippocrates, considered the father of medicine, recorded an epidemic in 412 BC, and other outbreaks were described during the Middle Ages, according to a 1977 Scientific American article written by Martin H. Kaplan and Robert G. Webster, the world’s foremost experts on the virus.
The illness was not named until the 15th Century, they wrote, when the Italians, convinced the disease was influenced by the stars, christened it “influenza.” The English adopted that name; the French called it la grippe .
Even as late as the 1918 pandemic, nobody knew what caused it. “For centuries,” wrote Kaplan and Webster, “men speculated wildly on the cause of influenza: the stars, the weather and poisonous gases from swamps were implicated in turn.”
That changed in the 1920s, when scientists discovered a virus was responsible and isolated a strain in pigs. In 1933, the first human strain was found. Influenza has since become one of the most closely studied viruses in nature.
Yet there is much about it that remains unknown.
Why, for instance, do most pandemics originate in Asia? The prevailing theory is that the dense populations of farm animals and people there give the virus a chance to mix more easily and spread more rapidly. But, as the CDC’s Arden said, “that is only a theory.”
Why is winter the flu season? Perhaps it is because the virus spreads more easily in low humidity, when people congregate inside. But as epidemiologist Paul Glezen of the Baylor Influenza Research Center in Houston said: “There are exceptions that we really can’t explain.”
The most intriguing questions concern flu’s penchant for swift mutation, and how such changes alter its virulence--the strength of the symptoms it produces.
“Those are the same questions I have and I’ve been studying it for 40 years,” said Kilbourne. “The unique thing about flu is it seems to need to select new mutants in order to survive.”
While polio, measles and other viruses retain much the same immunologic character throughout the years, animal studies have shown that very minor changes in the makeup of the flu virus can make a dramatic difference in virulence.
In 1983, virologist Yoshihiro Kawaoka of St. Jude Children’s Research Hospital in Memphis studied two outbreaks of chicken influenza. The first killed less than 5% of the chickens it infected. The second was the equivalent of a pandemic. It involved a seemingly identical virus that hit six months later yet felled more than 70% of chickens in the field and all the birds infected in experiments.
When Kawaoka looked at the viruses, he found that they were exactly alike--with the exception of one crucial amino acid out of more than 4,000.
The same thing may happen in human pandemics, he said. But the most virulent strain of all--the one that hit in 1918--is not available to be studied. Scientists did not know at the time that flu was caused by a virus, so no samples were saved.
“People are trying to look for the virus that caused pandemic in 1918,” Kawaoka said. “If we can get genetic material from that episode, we might be able to tell what was different in that virus from current human viruses, which are not highly highly virulent.”
There are two main types of flu virus, Type A and Type B. Currently, there are three distinct viruses in circulation, two of Type A and one Type B. The major difference is that Type B viruses infect only humans, but Type A viruses also infect animals--chickens, ducks, pigs and horses--that serve as “hosts” or “reservoirs.”
This means that Type B viruses remain relatively stable, but Type A viruses can fluctuate wildly, rearranging themselves genetically when different strains infect the same host. This recombination usually occurs in pigs, which are susceptible to both avian and human flu viruses, and which can spread those viruses to people.
Such a dramatic genetic reshuffling, which occurs extremely infrequently, is known as “antigenic shift.” (An antigen is a substance that is foreign to the immune system). The more common--and much less drastic--method of mutation, which occurs in both Type A and Type B viruses, is known as “antigenic drift.” The Beijing strain that emerged last winter, for example, is a drift, not a shift.
Antigenic shifts are what scientists worry about most, because they cause pandemics. The big question is whether the annual guessing game will be able to predict a shift in time for people to protect themselves.
Many virologists think not.
Thus, a move is afoot among experts to persuade the federal government to develop a plan to avert the next flu disaster. Some, such as Monto of the University of Michigan, say the surveillance network run by the World Health Organization must be beefed up. Others suggest stockpiling huge supplies of Amantadine, the anti-viral drug. And a few, including Kilbourne, believe that the CDC ought to keep a bank of frozen strains that could be used to develop vaccines on short notice.
Kawaoka, the Memphis virologist, takes a far gloomier view. He believes that no amount of preparation--short of developing longer-lasting vaccines and far more effective drugs--would be enough to counter a worldwide outbreak of a deadly new flu. “If a pandemic happens,” he said, “we just pray.”
There have been two pandemics since flu vaccine became available, neither as deadly as the 1918 flu. The 1957 Asian flu accounted for 70,000 deaths. The Hong Kong flu in 1968 killed 28,000--a relatively low number that experts attribute to the partial immunity that some people developed.
It has been a long time since the public felt truly frightened about the flu. The last scare came with the swine flu in 1976--an episode that teaches a lesson about influenza’s unpredictability.
It began at Ft. Dix, N.J., when 230 Army recruits came down with the flu. One of them, a 19-year-old private named David Lewis, died.
Laboratory analysis determined that the virus that infected Lewis was common to pigs. It was also the virus believed by many experts to have caused the 1918 pandemic.
The finding got Congress up in arms and prompted public health officials to launch a massive vaccination campaign. In two months, 43 million Americans took shots. In some cities, people were lined up outside doctors’ offices waiting to be vaccinated, fearing that they could get sick at any minute.
The program was suspended, however, when reports emerged that the shots were causing some people to develop Guillain-Barre syndrome, which causes paralysis.
And the feared swine flu outbreak? It never materialized.
The Making of Flu Vaccine
Each winter, as flu season is in full swing, manufacturers are already at work producing vaccines for the following year. The manufacturing schedule is rigid: The vaccine must be ready by fall, in time for people to take flu shots. What follows is a timetable for production of the 1993-1994 flu vaccine, as provided by Connaught Laboratories, the nation’s largest manufacturer of influenza vaccines.
1) Mid-January: A government laboratory sends the first “seed virus”--a strain of Panama flu--to the Connaught plant in Swiftwater, Pa. The manufacturer grows the virus in chicken eggs, using 115,000 eggs a day. Growing time: six weeks.
2) Early March: The second strain--a Texas flu--arrives. The same six-week growing process gets under way.
3) Late April: The final strain--the new Beijing flu, a particularly harsh strain--arrives and is grown, again for six weeks. In all, more than 2 million eggs have been used to grow the three strains.
4) June: Samples are shipped to the U.S. Food and Drug Administration, which checks them for purity and concentration.
5) July: With FDA approval, the strains are blended into the vaccine.
6) August: The final product is licensed by the FDA. Shipping begins, with 20 million doses sent to doctors in the United States and Europe. Industrywide, an estimated 35 million doses will be sent out.
7) September: The final batches of vaccine are shipped.
8) October: Patients get their flu shots.
SOURCE: Connaught Laboratories
