Health November 2009

Does the Vaccine Matter?

Whether this season’s swine flu turns out to be deadly or mild, most experts agree that it’s only a matter of time before we’re hit by a truly devastating flu pandemic—one that might kill more people worldwide than have died of the plague and aids combined. In the U.S., the main lines of defense are pharmaceutical—vaccines and antiviral drugs to limit the spread of flu and prevent people from dying from it. Yet now some flu experts are challenging the medical orthodoxy and arguing that for those most in need of protection, flu shots and antiviral drugs may provide little to none. So where does that leave us if a bad pandemic strikes?

The history of flu vaccination suggests other reasons to doubt claims that it dramatically reduces mortality. In 2004, for example, vaccine production fell behind, causing a 40 percent drop in immunization rates. Yet mortality did not rise. In addition, vaccine “mismatches” occurred in 1968 and 1997: in both years, the vaccine that had been produced in the summer protected against one set of viruses, but come winter, a different set was circulating. In effect, nobody was vaccinated. Yet death rates from all causes, including flu and the various illnesses it can exacerbate, did not budge. Sumit Majumdar, a physician and researcher at the University of Alberta, in Canada, offers another historical observation: rising rates of vaccination of the elderly over the past two decades have not coincided with a lower overall mortality rate. In 1989, only 15 percent of people over age 65 in the U.S. and Canada were vaccinated against flu. Today, more than 65 percent are immunized. Yet death rates among the elderly during flu season have increased rather than decreased.

Vaccine proponents call Majumdar’s last observation an “ecological fallacy,” because he fails, in their view, to consider changes in the larger environment that could have boosted death rates over the years—even as rising vaccination rates were doing their part to keep mortality in check. The proponents suggest, for instance, that influenza viruses may have become more contagious over time, and thus are infecting greater numbers of elderly people, including some who have been vaccinated. Or maybe the viruses are becoming more lethal. Or maybe the elderly have less immunity to flu than they once did because, say, their diets have changed.

Or maybe vaccine just doesn’t prevent deaths in the elderly. Of course, that’s the one possibility that vaccine adherents won’t consider. Nancy Cox, the CDC’s influenza division chief, says flatly, “The flu vaccine is the best way to protect against flu.” Anthony Fauci, a physician and the director of the National Institute of Allergy and Infectious Diseases at the NIH, where much of the basic science of flu vaccine has been worked out, says, “I have no doubt that it is effective in conferring some degree of protection. To say otherwise is a minority view.”

Majumdar says, “We keep coming up against the belief that we’ve reduced mortality by 50 percent,” and when researchers poke holes in the evidence, “people pound the pulpit.”

The most vocal—and undoubtedly most vexing—critic of the gospel of flu vaccine is the Cochrane Collaboration’s Jefferson, who’s also an epidemiologist trained at the famed London School of Tropical Hygiene, and who, in Lisa Jackson’s view, makes other skeptics seem “moderate by comparison.” Among his fellow flu researchers, Jefferson’s outspokenness has made him something of a pariah. At a 2007 meeting on pandemic preparedness at a hotel in Bethesda, Maryland, Jefferson, who’d been invited to speak at the conference, was not greeted by any of the colleagues milling about the lobby. He ate his meals in the hotel restaurant alone, surrounded by scientists chatting amiably at other tables. He shrugs off such treatment. As a medical officer working for the United Nations in 1992, during the siege of Sarajevo, he and other peacekeepers were captured and held for more than a month by militiamen brandishing AK-47s and reeking of alcohol. Professional shunning seems trivial by comparison, he says.

“Tom Jefferson has taken a lot of heat just for saying, ‘Here’s the evidence: it’s not very good,’” says Majumdar. “The reaction has been so dogmatic and even hysterical that you’d think he was advocating stealing babies.” Yet while other flu researchers may not like what Jefferson has to say, they cannot ignore the fact that he knows the flu-vaccine literature better than anyone else on the planet. He leads an international team of researchers who have combed through hundreds of flu-vaccine studies. The vast majority of the studies were deeply flawed, says Jefferson. “Rubbish is not a scientific term, but I think it’s the term that applies.” Only four studies were properly designed to pin down the effectiveness of flu vaccine, he says, and two of those showed that it might be effective in certain groups of patients, such as school-age children with no underlying health issues like asthma. The other two showed equivocal results or no benefit.

Flu researchers have been fooled into thinking vaccine is more effective than the data suggest, in part, says Jefferson, by the imprecision of the statistics. The only way to know if someone has the flu—as opposed to influenza-like illness—is by putting a Q-tip into the patient’s throat or nose and running a test, which simply isn’t done that often. Likewise, nobody really has a handle on how many of the deaths that are blamed on flu were actually caused by a flu virus, because few are confirmed by a laboratory. “I used to be a family physician,” says Jefferson. “I’ve never seen a patient come to my office with H1N1 written on his forehead. When an old person dies of respiratory failure after an influenza-like illness, they nearly always get coded as influenza.”

There’s one other way flu researchers may be fooled into thinking flu vaccine is effective, Jefferson says. All vaccines work by delivering a dose of killed or weakened virus or bacteria, which provokes the immune system into producing antibodies. When the person is subsequently exposed to the real thing, the body is already prepared to repel the bug completely or to get rid of it after a mild illness. Flu researchers often use antibody response as a way of gauging the effectiveness of vaccine, on the assumption that levels of antibodies in the blood of people who have been vaccinated are a good predictor—although an imperfect one—of how well they can ward off the infection.

There’s some merit to this reasoning. Unfortunately, the very people who most need protection from the flu also have immune systems that are least likely to respond to vaccine. Studies show that young, healthy people mount a glorious immune response to seasonal flu vaccine, and their response reduces their chances of getting the flu and may lessen the severity of symptoms if they do get it. But they aren’t the people who die from seasonal flu. By contrast, the elderly, particularly those over age70, don’t have a good immune response to vaccine—and they’re the ones who account for most flu deaths. (Infants with severe disabilities, such as leukemia and congenital lung disease, and people who are immune-compromised—from AIDS, or diabetes, or cancer treatment—make up the rest. As of August8, only 36 deaths from swine flu had been confirmed among children in the U.S., and the overwhelming majority of those children had multiple, severe health disorders.)

In Jefferson’s view, this raises a troubling conundrum: Is vaccine necessary for those in whom it is effective, namely the young and healthy? Conversely, is it effective in those for whom it seems to be necessary, namely the old, the very young, and the infirm? These questions have led to the most controversial aspect of Jefferson’s work: his call for placebo-controlled trials, studies that would randomly give half the test subjects vaccine and the other half a dummy shot, or placebo. Only such large, well-constructed, randomized trials can show with any precision how effective vaccine really is, and for whom.

In the flu-vaccine world, Jefferson’s call for placebo-controlled studies is considered so radical that even some of his fellow skeptics oppose it. Majumdar, the Ottawa researcher, says he believes that evidence of a benefit among children is established and that public-health officials should try to protect seniors by immunizing children, health-care workers, and other people around them, and thus reduce the spread of the flu. Lone Simonsen explains the prevailing view: “It is considered unethical to do trials in populations that are recommended to have vaccine,” a stance that is shared by everybody from the CDC’s Nancy Cox to Anthony Fauci at the NIH. They feel strongly that vaccine has been shown to be effective and that a sham vaccine would put test subjects at unnecessary risk of getting a serious case of the flu. In a phone interview, Fauci at first voiced the opinion that a placebo trial in the elderly might be acceptable, but he called back later to retract his comment, saying that such a trial “would be unethical.” Jefferson finds this view almost exactly backward: “What do you do when you have uncertainty? You test,” he says. “We have built huge, population-based policies on the flimsiest of scientific evidence. The most unethical thing to do is to carry on business as usual.”

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