Earlier this month, when the U.S. Centers for Disease Control and Prevention revealed concerns that the country may be facing one of its worst flu seasons in nearly a decade, there was promising news, too.

This year's flu vaccine, the CDC reported, seems to be extremely well matched to the influenza strains now starting to circulate. And that could be the biggest difference between this season and the winter of a decade ago, when the vaccine was a poor match and offered almost no protection.

This year's shot may prove especially useful, but the flu vaccine is notoriously one of the least effective immunizations, in large part because it has to be reformulated, and administered again, every year. In addition, its effectiveness wanes as people age, meaning those who are among the most vulnerable to the flu - the elderly - also get the least benefit from it.

Doctors believe that recent advances both in how the vaccine is formulated and how it's delivered to patients will better protect people from the flu. In the Bay Area, scientists are working on a variety of techniques to boost the protective power of the vaccine.

But the "holy grail" of immunization has proved frustratingly evasive.

"One shot that takes care of the flu for the rest of your life - that's the holy grail," said Dr. Cornelia Dekker, medical director of the Packard Children's Hospital Vaccine Program. "But if that were an easy thing to do, my colleagues would have it by now."

The flu is thought to kill between 10,000 and 40,000 people in the United States every year, according to the CDC, and many millions more are sickened by it. It's so pervasive that for many healthy adults, the flu is synonymous with the common cold, although the diseases are very different.

A serious disease

Influenza almost always causes a fever, along with fatigue and body aches severe enough to keep most people home in bed for a few days. The very young or very old, or anyone with a weakened immune system, are more likely to become infected, and they're more likely to suffer severe symptoms that can lead to hospitalization or death.

Once infected by a certain strain, most people retain some resistance to that strain for years, if not the rest of their life. But the influenza virus is constantly shifting, sometimes even over the course of a single winter, which threatens that natural protection.

And there always lingers the danger of a flu pandemic, like the 2009 swine flu outbreak, with a new strain suddenly appearing that leaves almost everyone vulnerable.

A flu vaccine has been available since the 1950s, and in 1960 the U.S. surgeon general recommended for the first time annual immunization for older adults, defined as anyone over age 64, along with pregnant women and people with certain medical conditions that weakened their immune system.

In 2010, more than 50 years after the first flu vaccine was introduced, those recommendations expanded to include all people over 6 months of age. Slightly more than one-third of Americans have been vaccinated this year, according to the CDC.

The vaccine is about 60 to 90 percent effective in preventing the flu, and least effective in people over age 64. At least one study released by the National Institutes of Health in 2007 found that the vaccine was less than 30 percent effective in people over age 70.

Diminishing returns

Studies also have shown that for most people, their immune response to the vaccine - meaning how well the vaccine primes their body to fight off the flu - starts falling off in their mid-30s. A Stanford report published last year found that in the elderly, the vaccine produces antibodies that are just as strong as in younger people, but in significantly smaller amounts.

Meanwhile, in almost everyone the vaccine's effects fade after just a few months, which is part of the reason - in addition to the shifting strains in circulation - that people need to be immunized every year.

"It seems like over a very short period of time we lose that immunity," said Dr. Randy Bergen, clinical lead for Kaiser Permanente's Northern California Flu Vaccine Program. "Our bodies aren't able to translate (the vaccine response) into a deeper memory in our immune system."

The modern vaccine provides protection by exposing people to tiny bits from three strains of influenza virus, which triggers the body's immune system to start developing antibodies that will fight those specific strains. Then, if someone is later exposed to one or more of those strains, their body will be primed to fight off the virus immediately, before the person ever feels sick.

What makes the vaccine less effective than doctors would like is the mechanism by which it triggers antibody production. The vaccine includes fragments of a protein called hemagglutinin, which is found on the surface of the influenza virus. The antibodies recognize that specific protein and attack the virus it's attached to.

The ideal solution

Because of the protein's location - at the very tip of the virus - it's an easy target for antibodies. But hemagglutinin changes from one strain of influenza to the next. Ideally, scientists said, they'll someday be able to identify a protein in the virus that is constant across all strains of influenza and also easily accessible to antibodies.

That search has been a major focus of flu vaccine research in the past decade, but so far it hasn't turned up a viable target.

"The goal is to find a region of the influenza germ that can't change, and develop a vaccine against that conserved region," Bergen said. "The problem is that pretty much all of those regions that we've found so far are buried in the virus. Even if we were able to make an antibody for that region, the virus would have replicated before the antibody could get in there and attack."

Until scientists develop a way to immunize people against all strains of influenza, a need persists to increase the effectiveness of the vaccine currently available.

In just the last year, two new flu vaccine mechanisms became available: an intradermal shot that is injected close to the surface of the skin, and a high-dose vaccine that may improve the immune response in older people. Next year, a vaccine is coming out that includes four strains of influenza instead of the usual three.

But those improvements are relatively subtle and fall far short of the larger goals of making a powerful immunization that provides protection to the vast majority of people for a wide variety of strains, and won't need to be re-administered every flu season.

Other options

Among the more popular fields of study for improving vaccine effectiveness is chemical adjuvants. For reasons that aren't entirely clear, adding adjuvants to the vaccine seems to provide an extra boost to the immune system, helping it produce more antibodies.

Adjuvants are widely used in Europe and other parts of the world, but they're not approved for use with the flu vaccine in the United States, mostly because the nation has never had a supply problem with the vaccine. But there's also a negative perception of adjuvants among many Americans who worry they may not be safe, although no studies have backed up those concerns, vaccine experts said.

In addition to adjuvants, scientists are looking at something called DNA vaccines, which include DNA that instruct the body to make the hemagglutinin protein itself, instead of having it inserted pre-made.

The idea is that the so-called homemade protein will inspire the body to produce not only antibodies to target that protein, but also increase the body's production of other immune cells that aren't flu-specific. In other words, the DNA vaccines, in theory, will help the body mount a stronger, more expansive immune response to the flu.

Dekker is conducting a clinical trial at Stanford of the DNA vaccine, with hopes of enrolling up to 100 patients before the end of the year.

For now, most doctors and scientists recommend that everyone get an annual flu shot, even if the effectiveness isn't ideal. Although the best protection may remain the simplest, public health experts say: aggressive hand-washing.

That was Johan Andreasson's preferred means of protection from the flu until this year, when he decided to sign up for Dekker's DNA vaccine trial. He'd never had a flu shot before, partly because he thinks he's only had the flu once in his life, but he's a convert now.

"There's really no downside to it. It's generally safe, and you don't only contribute to your own immunity, but you also help people around you by not transmitting it," Andreasson said. "From a global health perspective, it's better if everyone just does it.

"Then again, I haven't done it any time before this year," he said with a laugh. "I guess it's easy to be moralizing after the fact."

Clinical trial

Stanford is seeking volunteers for a clinical trial of a new flu vaccine. For more information, or to enroll in the trial, call (650) 498-7284 or go to vaccines.stanford.edu. The deadline to sign up is Dec. 17.
