Vaccine companies around the world are racing to manufacture enough bird-flu vaccine to deal with a feared influenza pandemic. Yet it’s unclear whether this vaccine will work against a more virulent strain of avian influenza. What is clear is that if it fails, it would take months to years to create a new vaccine in sufficient quantities, giving the virus time to spread throughout the world.

That fear has reinvigorated the hunt for a more universal vaccine to protect against any flu – both a pandemic strain and the seasonal virus that spreads every winter. Although such a universal vaccine is unlikely to be ready if a pandemic strikes soon, it could provide a longer-term solution to the threat of virulent flu.

“What a major step forward [a universal vaccine] would be,” says Gregory Poland, a vaccinologist at the Mayo Clinic College of Medicine in Rochester, MN. “The promise is very definitely there.”

Existing seasonal flu vaccines are targeted to a part of the influenza virus that mutates rapidly, so they must be made fresh every year. Public health officials must guess what next year’s strain will look like, and then manufacturers can create a vaccine based on that guess.

Avian flu, the strain that public health officials fear could lead to a pandemic, presents a similar problem. Scientists have created a bird-flu vaccine based on the current circulating strain of virus. If that virus mutates, however, it’s unclear how well the current vaccine will work.

“You can’t predict what changes will happen to a virus,” says Andrew Pekosz, a virologist at the Washington University School of Medicine in St. Louis. “That’s part of the problem with flu – you can’t make a flu vaccine unless you have [the virus] in humans.”

A universal flu vaccine would eliminate that problem, thus avoiding the lag time between identifying a virulent flu strain and developing and manufacturing enough vaccine to combat it. Such a vaccine could be made year-round and stored for future pandemics. What’s more, manufacturers wouldn’t have to dump excess quantities that become obsolete as the virus mutates.

The key hurdle in creating a universal flu vaccine, biologists say, is finding a component of the virus that remains stable over time. While conventional flu vaccines target a large protein on the surface of viruses, the best targets for a universal vaccine may be smaller, more stable proteins. Under normal circumstances, these proteins tend to slip past the immune system unnoticed. So in a traditional vaccine, which contains an inactive form of the virus, these proteins elicit no immune response.

But researchers have developed ways to modify these small proteins so that they aggravate the immune system enough to make antibodies – and thus act as a vaccine.

British biotech company Acambis has focused on one such protein, called M2, whose sequence in human flu viruses has remained the same as far back as the 1918 Spanish flu. The vaccine is effective in mice against various strains of human influenza. Now the company is gearing up to run toxicity studies before starting human trials. Meanwhile, Israeli company BiondVax Pharmaceuticals has a similar strategy, using several stable proteins to boost the immune response.

Both Acambis and BiondVax plan to test their vaccines against avian viruses, which have a slightly different form of the M2 protein. If successful, the companies will speed up the development process. Both companies say their vaccines can be manufactured quickly – possibly in a matter of weeks – because they can be made using bacteria rather than grown using the traditional egg-based method.

But it’s unclear how well these vaccines will work in people. Some experts say the focus should stay with more traditional strategies, such as surveillance systems to monitor strains as they emerge and faster methods to manufacture traditional flu vaccines.

Even if development of these vaccines goes well, it will be at least several years before they are ready. Biondvax aims to begin human testing in January 2007.

Meanwhile, DNA-based vaccines might provide protection from a pandemic far sooner than a universal vaccine would be ready. Instead of administering a dressed-up protein, as Acambis and BiondVax do, or a safe form of a virus, like traditional vaccines, PowderMed, based in Oxford, UK, is developing a small chunk of DNA that encodes the viral gene for the targeted viral protein. The DNA is shot into cells on the skin, which start making the viral proteins and trigger an antibody response.

Like traditional vaccines, the DNA target sequence would need to be updated for new strains of flu. But because the vaccine is composed of DNA rather than proteins, new genes could be made in a week, says Clive Dix, PowderMed’s chief executive officer.

PowderMed has already begun testing on humans. People who have been vaccinated with this method produce the appropriate antibodies and show no safety complications, says Dix. The company is now planning a larger-scale trial, in which participants will be exposed to a flu virus.

Scientists developing any of these new vaccines say they hope to get a financial boost from invigorated interest in the industry. In early November, President Bush announced a pandemic preparedness plan that includes $2.8 billion to support the development of new vaccine technologies.

“We know there will be future pandemics,” says Ashley Birkett, director of viral immunology for Acambis. “We see this is a long-term strategy.”