Researchers Race to Boost Supply of Bird Flu Vaccine

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 is 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 E. 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 6.5 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 as likely 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.