Vaccine stretch: smaller dose packs punch against flu.

A fraction of the standard dose of flu vaccine grants people immunity to influenza if injected into the skin rather than into the muscle of the upper arm, the usual target. That's the conclusion of two studies to appear in the Nov. 25 New England Journal of Medicine but released early because of their public health implications.

The technique will not be approved in time to solve this year's vaccine shortage, but it could mitigate future shortages and might also provide a new way to pump up immunity against flu in the elderly.

Injecting vaccines into a thin layer of skin requires more skill than injecting them into relatively thick muscle tissue, which is why muscle injections are standard for most immunizations. But from an immunological point of view, skin is a more attractive target because it brims with immune cells, whereas muscle is almost devoid of them.

Researchers at the Gaithersburg, Md.-based Iomai Corp. conducted one of the new studies, which included 100 men and women between the ages of 18 and 40. Half of them received one-fifth the normal dose of last year's flu vaccine injected into the skin of the upper arm; the other half got the full dose injected into muscle. Despite the reduced dose, the skin-injection volunteers developed blood concentrations of influenza antibody that were as high as or higher than those of the muscle-injection volunteers.

"It's quite a dramatic finding" says Iomai researcher Gregory M. Glenn, who coauthored the study.

The second study, led by Robert B. Belshe of St. Louis University and sponsored by GlaxoSmithKline, was similar to the Iomai study but gave the skin-injection volunteers two-fifths the normal dose. Unlike the Iomai study, it included two age groups: 130 volunteers between 18 and 60 and 108 volunteers over 60.

For the younger group, the findings agreed with those of the Iomai study. In the over-60 group, the low-dose skin injections matched the effectiveness of muscle injections for two of three influenza strains tested but were less effective for the third.

"I wouldn't call it a lot less, but it was less," says Donald J. Kennedy of St. Louis University, who contributed to the study.

Representatives from both research teams say that the technique probably won't be approved for widespread use until its effectiveness has been demonstrated in larger trials.

Anthony S. Fauci, director of the National Institute of Allergy and Infectious Diseases in Bethesda, Md., wrote a guest editorial accompanying the two reports. He says that the studies are important in their potential to solve two important problems: how to meet a sudden surge in demand for vaccine doses in the event of a flu pandemic and how to get more protection for the elderly. He suspects that a larger dose, perhaps 60 to 100 percent of the standard dose, injected into the skin of elderly patients would give them more protection than does the standard dose injected into muscle.

Improving the immune response of the elderly is "the major unmet need in influenza vaccination," according to Glenn, who notes that only 30 to 50 percent of elder people who get vaccinated in the normal way for flu develop protective immunity. "Even a modest improvement in the [potency of the] flu vaccine in that population would have a big impact on morbidity and mortality of the flu," he says.