Here's the Skinny on Painless Vaccines.

Parents with a child needing vaccinations might one day pick up shampoo from the pharmacy rather than drag the kid to a physician for a painful shot. This futuristic scenario stems from the unexpected finding in mice that a novel kind of vaccine, a simple solution containing DNA, works when applied directly to skin--as long as the skin has hair on it.

If the new result holds up, DNA-loaded skin patches or shampoos could replace injectable vaccines, lowering medical costs and making immunization more practical in developing countries. Some scientists are skeptical of the new work, reported in the September NATURE BIOTECHNOLOGY, but others express optimism.

"This is a very preliminary report, but it's an exciting, logical progression towards the idea of much simpler and more effective vaccines," comments Stephen A. Johnston of the University of Texas Southwestern Medical Center at Dallas, who pioneered research on DNA vaccines.

Such vaccines have been called the third revolution in vaccine science. The first came more than a century ago, when scientists found that injections of a dead or weakened pathogen can confer protection against the disease it causes. In the second revolution, scientists over the past 2 decades have found that they can immunize people with just a single protein from a pathogen.

DNA vaccines now extend and simplify the latter strategy: Scientists inject the gene for the immune-stimulating protein rather than the protein itself. Some of the body's cells then take up the gene and make the protein. Although researchers still aren't sure why, a DNA vaccine often stimulates more effective immunity than the corresponding protein inoculation.

Investigators normally inject DNA vaccines into muscle or the blood. The assumption that such vaccines require injection, in fact, led to the latest findings. Hongran Fan and her coworkers at the Veteran Affairs Palo Alto (Calif.) Health Care System and Stanford University School of Medicine planned to demonstrate the effectiveness of intramuscular gene injections by comparing them with simply dripping a DNA vaccine solution onto the skin of mice.

They noticed, however, that skin cells also absorbed the gene in the dripped DNA vaccine. Curiously, this didn't work on a strain of hairless mice. "We finally realized we were seeing gene transfer, and it was dependent upon hair," says Paul A. Khavari, a colleague of Fan's.

Subsequent experiments showed that cells within hair follicles take up and make protein from the DNA-vaccine gene, the team reports. This triggers an immune response in which the mice make antibodies and immune cells specific for the gene's protein. Facing a constant onslaught from infectious microbes, the skin has evolved means to efficiently generate an immune response, the researchers speculate.

Khavari and his colleagues have not yet shown that a skin application of a DNA vaccine protects animals from a virus or bacterium. In fact, in a test using a gene from the hepatitis B virus, the immune response was about one-third as strong as that produced by a commercial injected-protein vaccine. "We're looking at ways to boost the immune response," Khavari says.

While a California biotech firm called Maxygen has licensed the rights to Khavari's DNA-vaccine approach, some researchers remain skeptical. "Many people have had problems reproducing their findings," says De-chu Tang of the University of Alabama at Birmingham.

Tang says his group has shown that infecting skin with a cold virus carrying the gene for a flu-virus protein protects mice against influenza. However, merely applying the gene for that protein to the skin doesn't stimulate immunity, he says. Other genes may more effectively arouse the immune system, Tang admits.