A dose of DNA to fight influenza virus.

Nearly every year, the influenza virus reinvents itself in order to outwit our immune systems and cause the familiar fevers, sniffles, and muscle aches of the flu. And nearly every year, in response, virus detectives around the world pool their sleuthing skills to predict which three influenza strains will predominate during the upcoming flu season.

For the past 30 years, manufacturers have used this epidemiological knowledge to fashion vaccines that produce antibodies against the virus' ever-changing outer coat. Unfortunately, these vaccines may remain effective for only one flu season.

Now, a vaccine made from DNA could change all that.

Using a piece of DNA that carries instructions for the manufacture of a protein on the virus' outer coat, as well as one from its inner depths, researchers from Merck Research Laboratories in West Point, Pa., have created a vaccine that "offers better protection against a new variant of influenza," says senior scientist Margaret A. Liu. The finding could lead to longer-lasting, more protective vaccines.

Normally, influenza vaccines work by stimulating an immune response to the proteins on the outer coat of the virus. The prospect of creating a vaccine solely from a piece of DNA first arose in 1990, when researchers inserted circular pieces of DNA, known as plasmids, into the muscles of mice. The genes in the plasmids turned on, directing the muscle cells to create the proteins encoded by the genes.

In 1993, the Merck researchers showed that a plasmid containing the gene for the internal nucleoprotein (NP) of influenza evoked an immune response to a different strain of the influenza virus in mice.

"The internal nucleoprotein is an attractive target for a vaccine because it is a very conserved [common] portion of the virus," says Liu. Influenza must adapt itself in order to infect mice. The Merck team chose to test the procedure in ferrets because these animals fall victim to the same influenza strains as humans. The researchers created a DNA vaccine that included genes for the outer hemagglutinin (HA) protein as well as the inner NP of the Hawaiian and Beijing strains.

By using ferrets, the researchers could test their DNA vaccine directly against the standard vaccine used during the 1992--93 flu season.

But the influenza of 1992--93 presented an unusual twist. Late in the season, a new strain of virus--one to which sufferers of the first version had no immunity--arrived in the United States from Asia. The new strain, known as Georgia, was "very virulent and resulted in a fair number of deaths," says Liu. The researchers exposed the ferrets to the Georgia strain. As they report in the June Nature Medicine, the DNA vaccine protected the animals against infection, whereas the standard vaccine did not.

Liu says scientists don't know how the DNA vaccine gets into an animal's cells, but once there, the plasmid instructs cells to produce the viral proteins. By reacting to the external protein produced, the immune system creates antibodies capable of blocking the virus from infecting other cells. However, by manufacturing internal proteins common to many different strains, the cells recruit a different portion of the immune system to destroy already infected cells. Using the common proteins, the researchers hope to protect against most strains. "This way, if we guess wrong, people may still be protected," says Liu.

Dominick Iacuzio of the National Institute of Allergy and Infectious Diseases in Bethesda, Md., finds the vaccine's ability to recognize many strains of influenza important to its success. "This is a very promising new way of vaccination," he says, despite the preliminary nature of Liu's work.

Liu agrees that DNA vaccines are still a long way from general use. Before clinical trials can begin, the Food and Drug Administration must approve DNA for use as a vaccine. Until then, researchers must rely on detective work and luck.