Many forms of flu: one vaccine?

As bird flu continues to grab headlines and demand for doses of yearly flu vaccine surges beyond expectations, imagine a different scenario.

Instead of an annual flu shot, you could go anytime of the year to the doctor and get a painless nasal spray that would protect you from this year’s flu virus -- and every year after that. The most you might need would be an occasional booster.

Vaccine makers have long wished they could teach the human immune system to recognize and fight all known strains of influenza virus, not just the few that are circulating at one time. The ever-changing nature of the influenza virus has so far made that a fantasy.

Although many hurdles remain, scientists say a universal flu vaccine -- “the dream of every vaccinologist,” as noted vaccine designer Dr. Philip Russell puts it -- is closer at hand than ever.

Within at least three companies -- one British, one Israeli and one in the U.S. -- candidate universal vaccines are making their way from the lab bench toward testing. The National Institutes of Health is funding such efforts; the World Health Organization has called for more work on universal vaccines. All three companies and other groups working on this effort will be addressing the WHO in December on their progress.

“It’s such a radically different approach, so it’s going to require a lot of proof in the clinic to see if it works,” says Ashley Birkett, director of viral immunology for Acambis, a British biotechnology firm pursuing such a vaccine. “The potential is huge, but at this point it is still potential.”

Scientists are enthusiastic yet tempered in their assessment of the prospects. They question whether a universal flu vaccine will be as effective in blocking development and spread of disease as well as a yearly flu shot.

“There’s every reason in the world to look at this,” says Dr. Greg Poland, professor of medicine and infectious diseases at the Mayo Clinic. But, he adds, many viruses are tenacious survivors and transform themselves when confronted with a new vaccine. He notes that there’s preliminary evidence that the hepatitis B and pertussis viruses have evolved after adopting to vaccines.

So too might a wily virus such as influenza.

An ever-changing enemy

To understand how a universal flu vaccine would work, it is important to understand how the flu virus has plagued our species through history.

Influenza A -- the type of flu most troublesome to humankind -- is a master of disguises, constantly eluding the human immune system by subtly changing its structure. Most years, the virus camouflages itself with just a few slight changes in the proteins that stud its surface.

But sometimes it effects a costume change so dramatic that it can saunter into the respiratory system of the most robust human, completely unrecognized as a potential killer. That’s when pandemics of flu, such as the 1918 Spanish flu, which killed as many as 50 million, take hold.

Vaccine makers, armed with design and production methods little changed in half a century, struggle to keep up with this quick-change artist. Each year, international health officials huddle and make an educated guess about which of many strains will circulate most widely.

Starting with a sample of the chosen viruses, pharmaceutical companies use millions of chicken eggs to mass-produce a vaccine against the two Influenza A strains that are the greatest threat at that moment. Each year, the flu shots that result prime humans’ natural defenses to recognize and fight those strains.

It’s a time-consuming, costly and error-prone process. Flat-footed against this wily virus, humans have always been on the defensive.

A universal influenza vaccine would be different. The master of disguises would be unmasked.

Instead of being bamboozled by the flu virus’ showy costume changes, scientists would pick dowdy, less prominent parts of the virus -- the housekeeping features that don’t change year to year and are common to all strains. Presenting these pieces to the human immune system would prompt the vaccinated person to recognize and fight off any influenza virus.

Gone would be the need to guess each year’s dominant flu strains eight months ahead of flu season, the endless culturing in eggs and the need to deliver the resulting vaccine to millions within a three-month window.

At least three companies as well as others in academia and business are busily at work on that endeavor, each using a slightly different approach.

Acambis uses a protein called M2 that sits on the outside of the virus, although it’s buried beneath the other, more prominent proteins that our immune systems normally react to.

BiondVax Ltd., based in Israel, has developed a candidate vaccine based on several fragments of flu virus protein that haven’t varied in all the pandemic strains of the 20th century.

In animal studies, its universal vaccine candidate was found to confer high levels of immunity in mice genetically engineered to mimic human immune responses -- immunity that lasted for about a quarter of their lifetimes. The mice were more likely to fend off flu viruses when they were exposed. And if an infection of flu began to take hold, their immune systems were more likely to muster a robust defense against it.

Dynavax Technologies, a Berkeley-based firm, uses a protein -- called a nucleoprotein -- from the innards of the virus. When used as a supplement to an existing flu vaccine, it boosted the strength of immune responses in mice; primate tests are planned for early next year.

Gary Van Nest, the company’s vice president of preclinical research, says the vaccine would likely give some protection to people who missed their yearly flu shot or got a dose of traditional vaccine that didn’t match the circulating flu virus very well.

In each of these three cases, the chosen pieces of virus are genetically engineered to be bigger, showier or more numerous than they are on a natural flu virus -- anything to get the human immune system to notice it, brand it an invader and mount a defense against it. In some cases, these pieces are simply multiplied so they can’t be missed. In others, they are tagged with a protein the immune system is already primed to look for. Then, they are strung together, like a clutch of master keys hooked together on a key chain.

The result is that the heretofore shy viral components are “just sort of screaming out to the immune system and saying, ‘Here I am!’ ” says Acambis’ Birkett.

Since these genetically engineered viral pieces are not living organisms, they need not be cultured in eggs. Instead, they can be reproduced inside another living organism, for example, a bacterium or by fermentation, a cheap and ubiquitous technology used in making diverse products including bread, wine and pharmaceuticals.

What’s more, because the viral pieces used in making a universal vaccine are not implicated in making humans sick, scientists expect that these vaccines would pose fewer risks for those who take it.

Despite the high payoff of universal vaccines, there is no mention of universal flu vaccine in the Bush administration’s 396- page, $7.1-billion plan to prepare the nation for a possible pandemic of influenza. Instead, President Bush has proposed to spend $2.8 billion to speed up the process of producing current-generation flu vaccine and another $2.5 billion to buy and stockpile doses of antiviral medication and vaccine that would protect against a specific strain of bird flu that scientists see as a plausible threat to the world.

Russell, a senior advisor to the Washington, D.C.-based Sabine Institute and a leading authority on vaccines, says that is “a missed opportunity.”

Although the NIH has funded much of the research underlying the new approaches to flu vaccine, Russell says it will take more dedicated funds and high-level support to see if a clever scientific idea can translate into an effective and economically viable vaccine.

The hunt for a universal flu vaccine long predates recent fears of a bird flu pandemic. And if such a flu virus strikes in the next few years -- a highly uncertain prospect -- it is unlikely that a universal vaccine could be of much help because as a novel vaccine it would be subject to extensive testing requirements by the Food and Drug Administration.

But in a more distant future, a safe and effective universal flu vaccine that is in wide use might blunt the power of pandemics significantly.

“I’m excited about it,” says Russell. But, he adds, “We can be as optimistic as we want. In the end, it depends on Mother Nature.”