Faulty gene adds the fever to a vaccine.

Fever can be a patient's best friend. At elevated body temperatures, the immune system goes into overdrive and some pathogens stop reproducing. Now, researchers studying vaccines have discovered how one virus slips into cells without firing up a fever.

"Probably, we've found the first example of a virus that blocks the induction of fever and the mechanism by which it operates," says Geoffrey L. Smith, a virologist at the University of Oxford in England.

Smith and his colleague Antonio Alcami report in the Oct. 1 Proceedings of the National Academy of Sciences their comparison of three vaccines that had been used against smallpox. In tests on mice, all three vaccines-each containing a weakened strain of the cowpox virus-stimulated antibody production.

Two proved relatively benign, producing only symptoms of a mild cold, but the third, known as the Copenhagen vaccine, also produced a fever.

The difference arose from a gene in the vaccines. When infected, cells release messenger proteins, or cytokines, to alert the immune system. A gene in the milder vaccines coded for a protein that latches onto a cytokine. This action prevented the cytokine from triggering an immune response that includes fever.

The Copenhagen vaccine had a damaged version of the gene, which let the cytokine go undeterred. When the messenger reached the pituitary gland, the body turned up the heat.

"It's a fascinating study," says Raymond M. Welsh of the University of Massachusetts Medical Center in Worcester. "This clearly shows in this case that one protein causes the fever and one gene can suppress it." To verify their findings, the virologists repaired the damaged gene and then inoculated mice with the mended Copenhagen vaccine. The mice responded with no rise in temperature.

"Take the gene out, get a fever," says Smith. "Put it back in, you don't." The researchers believe the vaccines would act in people just as they do in mice because both use the same cytokine.

"The study paves the way for asking fascinating questions about the evolution of viruses and the immune response," says biologist Rustom Antia of Emory University in Atlanta.

Antia suggests that future studies compare two colonies of mice, one inoculated with a genetically intact vaccine virus and the other with a defective, fever-causing version. If suppressing fever gives a virus an evolutionary advantage, he would expect the genetically undamaged strain to spread through a population more easily than the damaged one.

The study's authors warn that their results may point to a potential pitfall in plans to defang viruses through genetic engineering. "You can't be certain that taking a gene out of a virus is going to make it less virulent," says Smith. "It might do the opposite."