The influenza vaccine, which has been strongly recommended for people over 65 for more than four decades, is losing its reputation as an effective way to ward off the virus in the elderly.
A growing number of immunologists and epidemiologists say the vaccine probably does not work very well for people over 70, the group that accounts for three-fourths of all flu deaths.
The latest blow was a study in The Lancet in August that called into question much of the statistical evidence for the vaccine's effectiveness.
The authors said previous studies had measured the wrong thing: not any actual protection against the flu virus but a fundamental difference between the kinds of people who get vaccines and those who do not.
This contention is far from universally accepted. And even skeptics say that until more effective measures are found, older people should continue to be vaccinated, because some protection against the flu is better than none.
Still, the Lancet article has reignited a longstanding debate over claims that the vaccine prevents thousands of hospitalizations and deaths in older people.
"The whole notion of who needs the vaccine and why is changing before our eyes," said Peter Doshi, a doctoral candidate at MIT who published a paper on the historical impact of influenza in May in The American Journal of Public Health.
The Lancet paper, by Michael L. Jackson and colleagues at the Group Health Center for Health Studies in Seattle, was based on an analysis of medical charts of thousands of elderly members of an HMO.
The study found that people who were healthy and conscientious about staying well were the most likely to get an annual flu shot. Those who are frail may have trouble bathing or dressing on their own and are less likely to get to their doctor's office or a clinic to receive the vaccine. They are also more likely to be closer to death.
Dr. David K. Shay of the Centers for Disease Control and Prevention, a co-author of a commentary that accompanied Jackson's study, agreed that these measures of health and frailty "were not incorporated into early estimations of the vaccine's effectiveness" and could well have skewed the findings.
Not everyone is sold on the significance of the Lancet study. "I think this is another study that provides interesting findings and raises questions," said Dr. Kristin Nichol, chief of medicine at the Veterans Affairs hospital in Minneapolis. "I don't think we know yet what the final word is on influenza vaccinations in the elderly.
"I really feel, and I feel very strongly about this, that the public health message should be that vaccines are effective," she added. "I don't think that science is necessarily best hashed out in the media."
Dozens of studies since 1960 have supported the view that the vaccine is a powerful protector of the elderly, cutting their risk of dying in winter from any cause by almost 50 percent and reducing the risk of hospitalization by nearly 30 percent.
Those findings came from observational studies, in which scientists make inferences about the effect of a treatment on a population by comparing what happens to a group that has the treatment with what happens to an apparently similar group that does not.
There has been only one large study that compared the flu vaccine with a placebo for two random groups of older people in which neither the patients nor the scientists knew which group was receiving which injection. It came to a different conclusion from the observational studies.
Conducted by Dutch researchers and published in 1994 in The Journal of the American Medical Association, it found that in those 60 to 69, the vaccine prevented influenza about 57 percent of the time. In those over 70, the vaccine prevented the flu just 23 percent of the time, though the estimate is imprecise because the study was not designed to look at this age group.
But the influenza vaccine was never put through more placebo-controlled trials, which are considered the gold standard in medical evidence. "I think the evidence base we have leaned on is not valid," said Dr. Lone Simonsen, an epidemiologist and visiting professor at the George Washington University School of Public Health and Health Services in Washington who was not connected with the Lancet study.
In 2005, Simonsen, who was then at the National Institute of Allergy and Infectious Diseases in Bethesda, Md., published a paper in The Archives of Internal Medicine that found something odd: Even though the percentage of older people who got an annual flu shot more than tripled from 1980 to 2001, there was no corresponding drop in the death rate.
That paper included one of the first estimates of how many deaths are actually caused by the flu a number hard to pin down because doctors seldom confirm flu in their patients with lab tests. Using a statistical model and the best available data, Simonsen found that influenza probably causes just 5 percent to 10 percent of all winter deaths in the elderly. But earlier studies had found that the flu vaccine cut an elderly person's risk of dying by 50 percent.
"You don't have to do a whole lot of math to realize that doesn't add up," said Dr. Lisa A. Jackson of the Group Health Center for Health Studies in Seattle, who has also studied the effectiveness of the flu vaccine in the elderly.
Jackson at first tried to tease out underlying differences between vaccinated and unvaccinated elderly people by using medical codes a numerical shorthand that doctors use to classify and record what is wrong with their patients. She and other researchers reasoned that patients with codes for cancer or heart disease, for example, might be very sick, thus skewing the results. When they adjusted for those codes, however, the differences between the vaccinated and unvaccinated groups became even more pronounced. The vaccine looked even more protective.
It was Michael L. Jackson's thesis project, at the University of Washington, that revealed the flaw in using the codes to differentiate patients.
For the project, Jackson (no relation to Lisa Jackson) and three other researchers spent almost three years reading medical charts and examining X-rays. They discovered that health-conscious people were more likely to get medical codes for things like heart disease and cancer simply because they went to the doctor more often. But when Jackson adjusted for measures of frailty things like lung function, whether people needed help bathing or dressing, and what kinds of medications they took he found that vaccination had little effect on older people's risk for pneumonia, the most dangerous complication of the flu.
That finding has a biological basis. Vaccines work by priming the immune system to recognize and respond to incoming threats. Because the immune system slows down with age, older adults do not respond as well to vaccines as younger adults.
A recent study by Dr. Wilbur H. Chen and colleagues at the Center for Vaccine Development at the University of Maryland School of Medicine found that elderly participants needed four times the amount of antigens given in a standard dose of the flu vaccine to have the same kind of immune response as healthy adults under 40. They presented their findings in May at the Annual Conference on Vaccine Research in Baltimore.
Despite these findings, Shay said the CDC had no plans to change its vaccine recommendations, though he added that the agency had financed studies to look for more effective influenza vaccines for the elderly.
Simonsen, the epidemiologist at George Washington, said the new research made common-sense infection-control measures like avoiding other sick people and frequent hand-washing more important than ever. Still, she added, "the vaccine is still important. Thirty percent protection is better than zero percent."