But while vaccines for, say, whooping cough and polio clearly and dramatically reduced death rates from those diseases, the impact of flu vaccine has been harder to determine. Flu comes and goes with the seasons, and often it does not kill people directly, but rather contributes to death by making the body more susceptible to secondary infections like pneumonia or bronchitis. For this reason, researchers studying the impact of flu vaccination typically look at deaths from all causes during flu season, and compare the vaccinated and unvaccinated populations.
Such comparisons have shown a dramatic difference in mortality between these two groups: study after study has found that people who get a flu shot in the fall are about half as likely to die that winter—from any cause—as people who do not. Get your flu shot each year, the literature suggests, and you will dramatically reduce your chance of dying during flu season.
Yet in the view of several vaccine skeptics, this claim is suspicious on its face. Influenza causes only a small minority of all deaths in the U.S., even among senior citizens, and even after adding in the deaths to which flu might have contributed indirectly. When researchers from the National Institute of Allergy and Infectious Diseases included all deaths from illnesses that flu aggravates, like lung disease or chronic heart failure, they found that flu accounts for, at most, 10 percent of winter deaths among the elderly. So how could flu vaccine possibly reduce total deaths by half? Tom Jefferson, a physician based in Rome and the head of the Vaccines Field at the Cochrane Collaboration, a highly respected international network of researchers who appraise medical evidence, says: “For a vaccine to reduce mortality by 50 percent and up to 90 percent in some studies means it has to prevent deaths not just from influenza, but also from falls, fires, heart disease, strokes, and car accidents. That’s not a vaccine, that’s a miracle.”
The estimate of 50 percent mortality reduction is based on “cohort studies,” which compare death rates in large groups, or cohorts, of people who choose to be vaccinated, against death rates in groups who don’t. But people who choose to be vaccinated may differ in many important respects from people who go unvaccinated—and those differences can influence the chance of death during flu season. Education, lifestyle, income, and many other “confounding” factors can come into play, and as a result, cohort studies are notoriously prone to bias. When researchers crunch the numbers, they typically try to factor out variables that could bias the results, but, as Jefferson remarks, “you can adjust for the confounders you know about, not for the ones you don’t,” and researchers can’t always anticipate what factors are likely to be important to whether a patient dies from flu. There is always the chance that they might miss some critical confounder that renders their results entirely wrong.
When Lisa Jackson, a physician and senior investigator with the Group Health Research Center, in Seattle, began wondering aloud to colleagues if maybe something was amiss with the estimate of 50 percent mortality reduction for people who get flu vaccine, the response she got sounded more like doctrine than science. “People told me, ‘No good can come of [asking] this,’” she says. “‘Potentially a lot of bad could happen’ for me professionally by raising any criticism that might dissuade people from getting vaccinated, because of course, ‘We know that vaccine works.’ This was the prevailing wisdom.”
Nonetheless, in 2004, Jackson and three colleagues set out to determine whether the mortality difference between the vaccinated and the unvaccinated might be caused by a phenomenon known as the “healthy user effect.” They hypothesized that on average, people who get vaccinated are simply healthier than those who don’t, and thus less liable to die over the short term. People who don’t get vaccinated may be bedridden or otherwise too sick to go get a shot. They may also be more likely to succumb to flu or any other illness, because they are generally older and sicker. To test their thesis, Jackson and her colleagues combed through eight years of medical data on more than 72,000 people 65 and older. They looked at who got flu shots and who didn’t. Then they examined which group’s members were more likely to die of any cause when it was not flu season.
Jackson’s findings showed that outside of flu season, the baseline risk of death among people who did not get vaccinated was approximately 60 percent higher than among those who did, lending support to the hypothesis that on average, healthy people chose to get the vaccine, while the “frail elderly” didn’t or couldn’t. In fact, the healthy-user effect explained the entire benefit that other researchers were attributing to flu vaccine, suggesting that the vaccine itself might not reduce mortality at all. Jackson’s papers “are beautiful,” says Lone Simonsen, who is a professor of global health at George Washington University, in Washington, D.C., and an internationally recognized expert in influenza and vaccine epidemiology. “They are classic studies in epidemiology, they are so carefully done.”
