Chasing a stealthy influenza virus
Nearly 70 years ago, a team of doctors entered a state mental colony and injected extracts from mice lungs into the arms of nearly 250 “feebleminded males.” The liquid was teeming with influenza virus, a tiny infectious agent that had been discovered just three years earlier.
Some of the boys and men got sore arms. Others developed rashes. As a flu epidemic swept through the nearby city of Philadelphia in the winter of 1936, the scientists crossed their fingers and hoped that what they had already seen in pigs and ferrets would prove true for people -- that a shot of crude virus into the muscle would protect the patients from getting sick.
That is just what happened. Fully 200 of the colony’s 800 residents became ill -- but those who had received the shot succumbed at one-fourth the rate of those who had not.
It was the first demonstration that a vaccine against influenza was in reach, and it created keen medical interest in a world still reeling from the 1918 flu that had killed more than 20 million people.
Today, nearly 70 years later, mental institutions no longer offer up their patients for human experimentation. Influenza vaccine is manufactured not in mouse lungs but in gleaming, automated factories.
But the production of vaccine remains a never-ending headache -- and, by some measures, primitive.
One of the reasons is biology.
Influenza has proved a stealthier foe than those 1930s scientists imagined, for a central reason: The virus is constantly changing its shape. Anyone who would thwart it with medicine must play an endless game of catch-up -- making fresh vaccine every year to match the viral strains most likely to circulate in the next flu season.
“The problem with the influenza vaccine is influenza itself,” says Dr. Edwin Kilbourne, retired emeritus professor of microbiology and immunology at New York Medical College and a veteran flu researcher.
It is also a problem of economics. Because making flu vaccine isn’t lucrative, very few companies in the world manufacture it.
But the headaches of today are also tied to history and the early creation of the vaccine.
If the flu shot had been developed a little bit later (in the 1950s, say, like the polio vaccine) its manufacture would not remain enmeshed in early 20th century technology. It wouldn’t depend on the ready supply of millions and millions of freshly fertilized chicken eggs trucked en masse from farms to pharmaceutical plants -- one egg, on average, for every vaccine shot into an arm.
“We’re clearly stuck in an antiquated way of doing things,” says Dr. Peter Gross, chair of the department of internal medicine at Hackensack University Medical Center in New Jersey.
Dependence on eggs renders vaccine production slower, less flexible and more vulnerable than it could be.
Now medical experts are calling for change, and pharmaceutical companies and academics are investigating new technologies. Chief among them: growing the vaccine in two-story-high fermenting vessels filled with cells from African green monkeys, dog kidneys, human tissues or insects.
The perceived need is driven by the ever-present threat of a worldwide flu pandemic that would exact a far greater toll on human life than experienced in a normal flu season.
But cost and uncertainty are involved in abandoning the familiar conga lines of eggs for as yet unproven methods. “To switch suddenly from eggs to cell culture, there is a risk inherent in that,” said Linda Lambert, chief of the respiratory diseases branch at the National Institute of Allergy and Infectious Diseases in Bethesda, Md.
“Instead, we need to diversify so we’re less vulnerable. Right now, we’re in an ‘all our eggs in one basket’ sort of scenario.”
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Scientists challenged
Influenza is an impressive killer. Its effect varies year by year, but on average the Centers for Disease Control and Prevention estimates it causes 36,000 deaths in the United States and hospitalizes more than 200,000 people. The reason the death toll looks large is because catching the flu is so common. Each year, 5% to 20% of the populace comes down with it.
Generally, the experience is nasty but no big deal. High-risk groups, such as very young children, the elderly and people with certain chronic medical conditions, are far more prone to be hospitalized and, in the case of the elderly, to die.
Sadly, many of the highest-risk people miss their annual shots. Only two of three adults older than 65 are vaccinated, and the rate of hospitalization is far lower than that in other high-risk groups, such as younger adults with chronic medical conditions. The hospitalization rate is just 12% in pregnant women.
It has been tricky for scientists to figure out how good the vaccine is at warding off flu and reducing its nastiest complications. The bottom line: It depends on who you are and what year it is.
Research conducted during the last half-century suggests that -- in the best years -- for healthy children and adults younger than 65 the vaccine seems to offer 70% to 90% protection against flu.
The results are not as good for people older than 65, probably because their immune systems are less able to mount healthy antibody responses against the dead virus that’s present in the vaccine. A 1995 analysis of 20 studies of elderly patients found that respiratory illness was reduced 56%, pneumonia by 53% and death by 68%. Some scientists say those numbers are overestimates.
Protection is weaker still in the oldest people and for elderly residents of nursing homes (the frailest folks who need protection most), reducing the rate of respiratory illnesses by 30% to 40%.
But it does seem to take the edge off those illnesses, making it significantly less likely that patients will die.
These numbers hold true when the vaccine is well-matched to the strain of influenzas currently circulating. But this doesn’t always happen, because the virus is constantly accumulating small changes, or “drifts,” and scientists can’t always keep pace with it.
Every few decades, a far larger change -- a “shift” -- occurs when genetic material from some animal flu strain gets mixed up with that of a human strain.
The viruses that arise from a shift are so foreign that they can easily swat off human immune defenses, infecting more people than usual and causing more deaths and more hospitalizations as they sweep across the world. The 1918 killer flu was a shift, as was the 1957 Asian flu, which killed 70,000 Americans.
Drift and shift mean that every year, vaccine-making must be meticulously planned many months ahead of schedule. (It is well underway for next season.)
Year-round, data and samples of flu cultures taken around the world pour into labs at the World Health Organization and the Centers for Disease Control and Prevention. They are chemically typed so that scientists know what strain they are. In February and March, an advisory board decides which strains are most likely to hit the U.S. nine months later.
Three strains are selected each year to make the vaccine. One is a type of flu known as influenza B. Two are influenza A’s, the type of flu that infectious disease experts worry most about because it can cause pandemics. For the 2005-06 flu season, the two A’s chosen were A/New Caledonia/20/99 (H1N1)-like and a new strain, A/California/7/2004 (H3N2)-like -- awkwardly named for where and when they were found and their biochemical nature.
Months before the CDC makes its final decision, vaccine manufacturers take an educated guess and start ramping up production; that’s the only way to ensure enough vaccine will be ready when needed.
Trucks filled with freshly fertilized eggs from carefully scheduled chicken flocks trundle into the vaccine plant. The eggs are loaded onto conveyer belts, then jabbed with needles containing one of the three viruses.
The eggs bask in the warm rooms for several days. Then they are loaded once again onto conveyer belts, their tops slashed open with blades and the whites, teeming with virus, collected. The billions of particles of virus are killed and purified, tested and finally pooled with the other two chosen virus particles to make the final vaccine.
Scientists at the CDC say that most years they get a good match -- but not always. For instance, in 1997, a strain of flu named A/Sydney showed up in June, too late to be put in the vaccine.
And in 2003, the advisory committee knew in February that a strain known as Fujian should be included -- but they couldn’t find any of the virus growing in eggs, which are the only approved source.
A less closely related virus was included, and it offered much less protection.
Vaccine researchers made an important discovery after a pandemic Asian flu swept the world in 1957 and an older vaccine proved useless. A newly made vaccine -- prepared directly from the Asian flu virus -- was very effective.
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Looking for stability
Gradually, it was dawning on scientists that the only way they would keep pace with influenza was to constantly keep tabs on the flu viruses circulating among people and then update the vaccine each year.
Some scientists hope they can stop the carousel one day -- if they can only come up with an evergreen vaccine that can be stockpiled.
The trick would be to select a part of the influenza virus that hardly changes, and use that to create a vaccine. Several academics and a Berkeley-based pharmaceutical company, Dynavax Technologies Corp., are exploring whether this could boost the efficiency of the current vaccine among the elderly -- or possibly even negate the need for annual updates.
“Some people say this is never going to happen -- that this is not possible with the flu,” NIH’s Lambert says. “But it’s definitely worth pursuing.... The payoff would be tremendous.”
If an evergreen vaccine turns out to be the stuff of science fiction, other approaches could make vaccine production faster and more flexible. One technology, known in the trade as “reverse genetics,” allows scientists to use gene splicing to quickly create a virus that grows vigorously in eggs and has the right immune properties for the preparation of vaccine.
Such a method might shave weeks off the production process, but -- more importantly -- could mean the difference between getting the correct virus for a vaccine or not.
This could be especially important in the battle against the troubling bird flu sweeping through Southeast Asian chicken flocks. That virus could not be grown on eggs -- because it killed them. Thus, no vaccine could even be made for testing until reverse genetics was used to make a less lethal strain.
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Specter of bird flu
Easing reliance on eggs is another key goal. Growing viruses in big vats of cells (as is done for polio and other vaccines) means eliminating the hassle of carefully scheduling egg deliveries -- and offers the possibility of making changes later in the season. Several companies based in the Netherlands, Austria and the United States are pursuing the cell culture strategy.
But it will take years before a cell culture vaccine makes its way to the United States.
Perhaps the most pressing reason to move away from eggs is the specter of bird flu. If another global pandemic occurs, we would be vulnerable indeed if the egg-laying flocks needed to make a vaccine against it were killed -- by the very same flu that threatens us.
In 2003, the Netherlands had a small taste of the kind of confusion that could ensue, says Bram Palache, global medical affairs director for influenza vaccines at Solvay Pharmaceuticals in the Netherlands.
During the height of a less-serious bird flu outbreak, the country’s Ministry of Agriculture banned the movement of poultry and poultry products to halt the spread of the pestilence.
Only an 11th-hour intervention by the Ministry of Health allowed the company to get the shipments of eggs it needed to make the human vaccine for the next flu season.
