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  Microbiologist Richard Compans is developing a secret weapon—a genetically engineered virus replica that can be used as a vaccine against avian flu.
     “We have produced a non-infectious recombinant particle that contains both the core proteins and the exterior surface proteins of the avian influenza virus, but it lacks the viral genetic material,” explains Compans, chair of the Emory School of Medicine’s Department of Microbiology and Immunology. “We think that such a vaccine could be produced faster and under much safer conditions than traditional flu vaccines and that it could be more closely tailored to emerging new strains of flu.”
     While other experimental avian flu vaccines have successfully produced an immune response in people, it was often too low to prevent infection. Building on his previous work on a VLP against HIV, Compans also plans to incorporate adjuvants—additional molecules—into the vaccine to enhance its ability to induce protective immunity. "We are calling this a chimeric VLP vaccine, because we’re inserting new molecules to enhance the potency of the vaccine," Compans says. He believes he can develop a VLP vaccine that will activate immune responses, including both neutralizing antibodies as well as long-term antibodies and cell-mediated immunity.
     VLPs copy the structure of authentic viruses but are not infectious, making them safer to produce than vaccines using live, but weakened, organisms. They are recognized by the immune system as the "real" virus upon immunization, causing the body to produce antibodies, but not causing illness. When a person is exposed to the real thing, the immune system releases antibodies to protect against infection. The influenza VLPs contain multiple copies of the major influenza surface protein, the hemagglutinin (HA) protein, which binds to cell surfaces. Antibodies to the HA protein are responsible for blocking infection by the virus.
     Emory and Georgia Tech collaborators have already developed an influenza VLP that has been tested in mice exposed to a mouse-adapted strain of flu. The next step is to develop a VLP that specifically resembles H5N1 (the current avian flu strain) and test it in poultry exposed to the live virus. The VLP should be ready to test in about a year.
Hitting a moving target
Even before avian flu emerged as a possible pandemic threat, concerns were mounting about the cumbersome process required to produce the traditional flu vaccine. Each year, public health officials gather data on the strains that are circulating in people to determine which three strains are likely to cause the most serious illness during the peak flu season. Once these strains are chosen, the viruses are injected into fertilized hen’s eggs. The viruses must then grow inside chicken embryos before the eggs can be broken open and the virus harvested. It then must be purified and chemically treated to produce enough killed-virus vaccine to inoculate most of the population.
     Because up to six months may lapse between the time the strains are chosen and when a vaccine is available, sometimes a strain not included in the vaccine turns out to be the season’s most prevalent virus. When this happens, the vaccine is less effective.
     And with avian flu, scientists learned early on that traditional vaccine production technology wouldn’t work at all. "It’s a highly pathogenic avian virus, so when it’s injected into the eggs it rapidly kills the embryo and then the virus can’t grow," Compans says. The VLP technology will address this problem. Because VLPs can be produced in cell cultures, without the long process of growing live virus in chicken eggs, newly identi-fied circula-ting strains can be rapidly incorporated into the vaccine. And because the VLPs are not infectious themselves, there is much lower risk to vaccine production workers, and more sites should be able to produce the vaccine.
     "Right now, there is potential risk because you have people working with live virus to inoculate the eggs," Compans says. "Only a few sites have facilities that can provide an appropriate protected environment. This results in limited production capacity as well as greater risk to workers."
Feeling no pain
Emory and Georgia Tech are working not just on a new vaccine but also a new way to administer it. Compans’s lab has partnered with Tech’s Center for Drug Design, Development, and Delivery to work on a transdermal flu vaccine patch. Tech researchers have developed microscopic needles that can be coated with a drug or vaccine and then placed on the skin to inject the medication painlessly. The microneedles—100 to 1000 micrometers thinner than the width of a human hair—allow the drug to be injected, which is more effective than cutaneous absorption. But the needles are too small to stimulate nerve endings and result in pain, says Mark Prausnitz, director of Tech’s center.
     The center became interested in working on microneedle applications in vaccines because of the skin’s unique immune capabilities, says Prausnitz. "We have found that there is something about the immune response in the skin that permits us to use lower dosages than we would if the vaccine were delivered the usual way."
     The technology is well suited to vaccine administration. Vaccine patches could be stored and transported much more easily than current vaccine supplies. They likely would not require refrigeration and could be stored for longer times under less expensive conditions. And a patch would give the public health system many more options to protect people, especially in the event of a pandemic, Compans says.
     "First, a painless vaccine will be much more acceptable and we might see improved rates of vaccination," he says. "And whereas the current vaccine must be administered by trained health care providers, a patch could be self-administered—people could apply it to themselves. Some day, you might be able to get your annual flu vaccine in an envelope in the mail."


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