By David Brown
Washington Post Staff Writer
Saturday, February 11, 2006 2:45 PM
Medical researchers bracing for a global influenza epidemic are in frantic search of a way to perform a loaves-and-fishes miracle with the world's skimpy annual production of flu vaccine.
That production -- about 300 million flu shots a year -- cannot be increased quickly or easily, no matter how dire the circumstances. If the supply is going to protect more than a tiny fraction of the world's 6.8 billion people, some way has to be found to stretch it.
Nearly all the experts believe that a vaccine is the only tool capable of stopping a flu pandemic. They also agree the world is closer today to that potentially calamitous event than it has been in decades.
In the last six months, the H5N1 strain of "bird flu" that first caused human deaths in Hong Kong in 1997 has moved across Central Asia into Eastern Europe and Africa. Just in the last month, it has appeared in three new places: Iraq, Cyprus and Nigeria. Of the 150 confirmed human victims worldwide, 85 have died. All the virus needs to trigger a pandemic is the capacity to spread easily among humans.
To prepare for that -- to try to work the miracle -- biologists have turned to "adjuvants," substances added to conventional vaccines to increase their potency.
Adjuvants make small doses of vaccine act big. They focus the immune system's attention on the "antigen" -- the substance that stimulates the protective effect. Some adjuvants even broaden immunity and make it longer-lasting. Scientists do not know exactly how adjuvants do all this. But they do know they make it possible to dilute a vaccine with no loss of effect.
"The global demand for pandemic vaccines will be immense," said David S. Fedson, a physician, epidemiologist and former consultant to the World Health Organization. The only way to meet the demand, he believes, "is to use an adjuvant."
To pharmaceutical companies, these peculiar substances are hot properties.
"We are in possession of one of the key ingredients of a potential solution to the pandemic threat," said Howard Pien, president of Chiron Corp. The California biotech firm has an adjuvant, an emulsion called MF59 whose main constituent is shark-liver oil. It is already in use in a flu vaccine in Europe.
"We believe that the adjuvant may become the holy grail of vaccines," Chrystyna Bedrij, an analyst with Griffin Securities, wrote in November in a review of avian flu-related business.
Since their discovery in 1925, adjuvants have been mostly curiosities -- occasionally useful, occasionally dangerous. It now appears they will make or break a pandemic flu vaccine. Nineteen clinical trials of pandemic flu shots -- against H5N1 and three other types of avian influenza -- are scheduled to be run this year. Seventeen of the vaccines will contain an adjuvant.
But it probably will be an uphill battle. The only study completed of an H5N1 vaccine made in the manner of a traditional flu shot found that adding an adjuvant did not help much. The reason might lie as much with the virus as with the adjuvant. There is growing evidence that H5N1 is inherently less stimulating to the immune system than other influenza strains -- yet another dangerous trait it possesses.
Many adjuvants mimic parts of viruses or bacteria known to trigger important steps in the complicated process by which the immune system rebuffs a microbial invader and then stores the information to allow a more rapid defense if the same invader returns.
The best-known adjuvant, however, is low-tech and does not look like anything made by microbes. It's a group of stable, easily dissolved aluminum salts known collectively as "alum." The vaccine antigen apparently sticks to the salt.
"Just by keeping the antigen from floating away, [the adjuvant] improves the immune response," said John Treanor, a researcher at the University of Rochester.
At the fancy end of the spectrum are "archaeosomes" -- microscopic envelopes packed with antigen that essentially function as artificial viruses. Devised by two researchers at the Canadian government's Institute for Biological Sciences, archaeosome technology has been licensed to a drug company in India.
Adjuvants that mimic biological structures stimulate broader immunity than alum. But the fear is they might work too well, triggering an out-of-control response.
A nasal-spray flu vaccine introduced in Switzerland in 2000 using a toxin from the bacterium Escherichia coli as an adjuvant was pulled from the market when users developed a rare form of facial paralysis called Bell's palsy at a rate 20 times higher than non-users. The cause is not certain, but the adjuvant is the leading suspect.
Nevertheless, the need to put an adjuvant in a pandemic flu shot is clear from the harsh arithmetic of global vaccine supply.
Seasonal flu shots contain three different strains of virus. In the face of a pandemic, companies would devote all their efforts to growing only the pandemic strain. That means existing production could turn out about 900 million pandemic flu shots.
However, a study last year of an H5N1 vaccine -- without adjuvant -- showed that a person needs two doses of a shot with six times the amount of virus in the standard flu shot in order to be protected. That means the world could make pandemic flu shots for only about 75 million of the world's 6.8 billion people -- a meaninglessly small amount.
In December, the French vaccine maker Sanofi Pasteur announced that its experimental H5N1 vaccine containing an alum adjuvant did a little better. Two shots containing 30 micrograms of virus -- twice the amount used for each virus strain in the seasonal flu shot -- were protective. But even that would be of little use in a pandemic whose toll in an unprepared world has been estimated to be as low as 2 million and as high as 100 million dead.
In 1999, Chiron found that an experimental avian flu vaccine given with the company's shark-oil adjuvant MF59 provided protection at a dose as low as 7.5 micrograms in two shots. The vaccine also seemed to provide some protection against descendants of the original virus whose genetic identity has "drifted" through mutation.
That unexpected finding has led some experts to argue that an H5N1 strain should be added to the annual flu shot now in the hope it might provide at least partial protection against a future pandemic.
The problem with that strategy is that vaccines with MF59 are not yet approved for use in the United States. Even if they get approved, the Chiron adjuvant is patented and would undoubtedly raise the price of shots considerably.
But alum adjuvants -- which are cheap, unpatented and FDA-approved -- might yet prove useful.
A team of German researchers two years ago tested a vaccine containing alum and a flu strain in which the virus was "whole killed" -- chemically inactivated but not broken into pieces. With as little as 1.9 micrograms, that vaccine provided protection in 80 percent of people.
The problem with that solution is that the dozen companies making 90 percent of the world's flu shots all use virus that has been broken up by chemical detergents -- a treatment that makes the injection less painful than a whole-killed vaccine but also less stimulating to the immune system.
To capture the advantage of a whole-killed vaccine, the vaccine makers would have to change their manufacturing methods, and whether they are willing to do that is a big unanswered question.