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The future of vaccination

AFP - Getty Images
A medic injects a volunteer with a flu vaccine in Moscow. A new study
indicates that vaccination against one flu strain could boost immunity
against other strains - suggesting a strategy to fight future pandemics.

As officials around the world worry about a potential swine flu pandemic, three newly released studies hint at the next generation of flu fighters - including a "pre-pandemic" vaccine that could last for years, a universal vaccine that could battle a wide variety of flu strains, and a painless patch for flu vaccines.

It may be years before these innovations make their appearance in your doctor's office or pharmacy - but the current alarm over swine flu could accelerate the development process, said Robert Liddington, professor and director of the Infectious Disease Program at the Burnham Institute for Medical Research.

"If a serious pandemic did start to arrive, then a lot of these processes would be expedited," he told me today.

Pre-pandemic planning
One of the factors complicating the public-health response to the swine flu outbreak in Mexico and elsewhere is the fact that the standard seasonal flu vaccines offer no immunity. It generally takes up to six months to manufacture a vaccine that's effective against a particular flu strain, researchers point out in a study released today by the Proceedings of the National Academy of Sciences.

By the time a tailor-made vaccine becomes widely available, the first wave of a flu pandemic may have already run its course, said Iain Stephenson, an infectious-disease expert at Britain's Leicester Royal Infirmary and the University of Leicester.

Stephenson and his colleagues considered a different scenario, in which people are vaccinated with a flu strain that's close to one that could cause a pandemic later. They focused on avian flu (a.k.a. bird flu) rather than swine flu.

It turned out that people who were vaccinated against one strain of avian flu several years ago had more immunity against a different strain than people who didn't get an earlier flu shot. The best results were achieved when the previously vaccinated subjects were given a second booster shot. Their virus-fighting response reached a peak just seven days after the booster, compared with a six-week time frame for vaccine virgins who received two shots.

"This study is the first to show an effective pre-pandemic vaccine approach," Stephenson said in a news release. "This means that we could vaccinate people potentially many years before a pandemic, to generate memory cells that are long-lasting and can be rapidly boosted by a single dose of vaccine when needed."

The benefits vs. risks for pre-pandemic vaccination have been under discussion for years, and in fact a pre-pandemic vaccine for avian flu (called Prepandrix) was approved for use in Europe last year. Just last week, a U.S. special envoy suggested in Tokyo that medical personnel might be given a pre-pandemic flu vaccine.

But there are risks, to be sure. For some people, getting vaccinated could bring harmful side effects, as demonstrated during the swine flu debacle of 1976. And you'd have to anticipate what general kind of flu strain would spark a future pandemic. If you vaccinated people against an H5N1 avian-flu outbreak, the effort might have been useless against the current H1N1 swine-flu strain.

That's why it's so attractive to look for a universal vaccine that could take on a wide variety of flu strains.

Search for a universal vaccine
Researchers have made several advances on the universal-vaccine front over the past few weeks. Just today, a team at Saint Louis University reported positive results using a vaccine that was made with proteins from several strains of influenza A and B viruses.

"This is a significant first step in developing a universal vaccine to protect against pandemic influenza," Robert Belshe, director of the Saint Louis Center for Vaccine Development, said in a news release. The findings were presented at the National Foundation for Infectious Diseases' Conference on Vaccine Research in Baltimore.

The combination vaccine - known as Bivalent Influenza Peptide Conjugate Vaccine, or BIPCV - was administered to 377 healthy adults in three doses over six months. Belshe said that the low-dose vaccine was well-tolerated and safe, and seemingly effective as well. The vaccine sparked an immune response that was similar to levels associated with protecting flu-infected animals from serious disease and death. However, more testing is needed, Belshe said.

Liddington was involved in another study aimed at developing a universal vaccine, although he prefers to call it a "universal therapeutic." The antibody-based treatment targets a part of the flu virus that is found in many strains, rather than the part that varies from strain to strain.

In the study, published online Feb. 22 in the journal Nature Structural and Molecular Biology, researchers reported finding 10 antibodies that were effective against a wide spectrum of influenza A viruses - including the H5N1 avian flu and even the particular strain of H1N1 "Spanish flu" that caused so much trouble in 1918.

That result suggests that a concoction of the antibodies could serve as a blanket virus-killer. "The virus should be essentially unable to escape through mutation," Liddington said, "because we hit it in its 'Achilles' heel.'"

Here's another analogy: The research team's leader, Wayne Marasco of Boston's Dana-Farber Cancer Institute and Harvard Medical School, compares your typical flu virus to a lollipop. Most vaccines stimulate the immune system to produce antibodies that target the virus' "globular head" - that is, the lollipop's candy top. One vaccine targets red lollipops. Another goes after green ones, or yellow ones. Every time the virus changes its genetic "color," a new vaccine has to be created to stimulate production of a new antibody.

"That big globular head acts as a decoy," Marasco told me.

In contrast, the antibodies identified by Marasco's team target the "stick" of the lollipop, which doesn't change. In science-speak, this part of the virus is highly conserved. "The 'stick' is always white," Marasco said, and thus remains vulnerable even when the virus mutates (that is, when the lollipop candy changes color).

The virus-killer could take the form of an antibody-based medication administered after infection. But the real trick would be to develop a vaccine that stimulates the body's own immune system to go after the stick rather than the candy. "The bottom line is that we need to really evaluate this, and find a way to induce an immune response to the highly conserved area," Marasco said.

The research team is now gearing up for human clinical trials, and Marasco estimated that it might take three to five years to open up a path toward a universal, one-time-only vaccine.

In the meantime, Liddington doesn't advise holding back on getting your flu shot. "I think it still makes sense to get vaccinated every year," he said.

Creating a painless vaccine patch
That annual flu shot might be a little easier to handle if it weren't for the needle - and another study in the Proceedings of the National Academy of Sciences suggests you could eventually get your vaccination in the form of a painless patch.

For years, researchers at Emory University and Georgia Tech have been working on a system that involves putting flu vaccine on a skin patch containing microneedles the size of hairs. The patch would be applied to the skin, just like a nicotine patch or a contraceptive patch, and in a matter of minutes you'd soak up enough of the vaccine to protect yourself against infection.

The latest study showed that when mice were given the microneedle treatment, they produced the same level of immune response seen in mice that were given intramuscular, hypodermic immunizations. And when the mice were later infected with a high dose of flu virus, all of the vaccinated mice survived, while all of the unvaccinated mice died.

Gary Meek / Georgia Tech
An array of microneedles was coated with flu vaccine and applied onto mouse skin to test a technique that could lead to low-cost vaccine patches.

"Our findings show that microneedle patches are just as effective at protecting against influenza as conventional hypodermic immunizations," Emory's Richard Compans, one of the paper's senior authors, said in a news release. "In addition, vaccine delivery into the skin is desirable because of the skin's rich immune network."

Nowadays, flu vaccines have to be administered by health professionals, as a shot or as a nasal spray - and not everyone can get the nasal spray. More animal studies will have to be run before the microneedles are tested on humans, but if they work as hoped, getting your annual flu vaccine could become a cheap, do-it-yourself job.

"These micron-scaled needles can be mass-produced using low-cost methods for distribution to doctors' offices, pharmacies and, possibly, people's homes," Georgia Tech's Mark Prausnitz, another co-author of the study, said in the news release.

Update for 2:50 p.m. ET April 28: In a follow-up phone call, Prausnitz noted that the microneedle technique is being tested with other medications as well - including a hormone treatment for osteoporosis that is being developed by California-based Zosano Pharma.

Tests of the flu vaccine will proceed first with ferrets, which provide a better model than mice for flu susceptibility. Human clinical trials are likely to begin next year, and if all goes well, the patches should become available in the three- to five-year time frame, Prausnitz said.

One issue to be resolved is to make sure the dry vaccine used on the microneedle patches is as effective as the wet vaccine used in conventional intradermal vaccines, he said. Another issue would be to make sure the system is as foolproof as possible. "Can we design a system so well that if we hand it off to somebody, it will be done right?" he asked.

Flu vaccine patches will likely turn up first in the doctor's office, but the longer-range goal is to make the system so easy to use that the patches can be sent through the mail and applied directly by the patient. That could boost vaccination rates in areas that are underserved by trained medical personnel - for example, rural Mexico, which is thought to be where the current swine-flu outbreak began.

Emory microbiologist Ioanna Skountzou, another member of the research team, said the microneedles are so small "they do not cause any irritation to the skin." Eventually, the tiny metal prongs would likely be replaced by even tinier hairs of polymer that could dissolve right in the skin.

"The skin is the best think I can think of for vaccine delivery, and drug delivery in general," she told me.

Another benefit of the technology is that you might be able to get the same protective effect from a smaller amount of antigen, Skountzou said. That would ease the burden on drug-makers, allowing more people to get a low-cost, painless "flu shot" more quickly.