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.”
JUST AFTER 6 P.M. on a warm Friday evening in July, Dr. David Newman is only minutes into a 10-hour shift in the emergency room of New York City’s St. Luke’s Hospital, and already he has assumed responsibility for 11 patients. The young Italian tourist sitting on the bed in front of the doctor has meningitis, and through an interpreter, Newman tells him he almost certainly has the viral form of the disease, which will do nothing more than make him feel ill for a few days. There is a tiny chance, says Newman, that the illness is caused by a bacterium, which can be deadly, but he is almost positive that’s not what the tourist has. He says to his patient, “I can’t tell you with 100 percent certainty that you don’t have it, but if you do, you’ll begin to feel worse and you’ll need to come back.” The tourist, on learning that he might be infected with a potentially lethal disease, looks down at his feet and confesses that he is much more worried about another illness: swine flu. Newman smiles patiently. “It would be nice if you had swine flu,” he says. “Compared to bacterial meningitis, swine flu is safe.”
Late last spring, as headlines and airwaves warned of a possible pandemic, patients like Newman’s began clogging emergency rooms across the country, a sneezing, coughing, infectious tide of humanity more worried than truly sick, but whose mere presence in the emergency room has endangered the lives of others. “Studies show that when there is ER crowding, mortality goes up, because patients who need immediate attention don’t get it,” says Newman, the director of clinical research in the Department of Emergency Medicine at the hospital, which is affiliated with Columbia University. In an average year the ER at St. Luke’s, a sprawling 1,076-bed hospital on 113th Street, takes in 110,000 patients, some 300 a day. At the height of the summer swine flu outbreak, that number doubled. The vast majority of panicky patients who came in the door at St. Luke’s and other emergency departments didn’t actually have the virus, and of those who did, most were not sick enough to need hospitalization. Even so, says Newman, when patients with even mild flu symptoms show up in the hospital, they vastly increase the spread of the virus, simply because they inevitably sneeze and cough in rooms that are jammed with other people.
Many of the worried sick come to St. Luke’s and other hospitals in search of antiviral drugs. The CDC recommends the use of two drugs against H1N1: oseltamivir and zanamivir, better known by their brand names, Tamiflu and Relenza, which together form the second pillar of the government’s anti-pandemic-flu strategy. Public-health officials at the state and local levels are also recommending the drugs. Guidelines issued by the New York City Department of Health, says Newman, “encourage us to give a prescription to just about every patient with the sniffles,” a practice that some experts worry will quickly lead to resistant strains of the virus.
Indeed, that’s already happening. Daniel Janies, an associate professor of biomedical informatics at Ohio State University, tracks the genetic mutations that allow flu virus to develop resistance to drugs. Flu can become resistant to Tamiflu in a matter of days, he says. Handing out the drug early in the pandemic, when H1N1 poses only a minimal threat to the vast majority of patients, strikes him as “shortsighted.” Indeed, samples of resistant H1N1 were cropping up by midsummer, increasing the likelihood that come late fall, many people will be infected with a resistant strain of swine flu. Alarmed at that prospect, the World Health Organization issued an alert on August 21, recommending that Tamiflu and Relenza be used only in severe cases and in patients who are at high risk of serious complications. By mid-August, two U.S. swine flu patients had developed Tamiflu-resistant strains.
The U.S. first began stockpiling Tamiflu and Relenza back in 2005, in the wake of concern that an outbreak in Southeast Asia of bird flu, a far more deadly form of the disease, might go global. On November 1, 2005, President George W.Bush pronounced pandemic flu a “danger to our homeland,” and he asked Congress to approve legislation that included $1billion for the production and stockpiling of antivirals. This was after Congress had already approved $1.8billion to stockpile Tamiflu for the military, a decision that was made during the tenure of Defense Secretary Donald Rumsfeld. (Before joining the Bush Cabinet, Rumsfeld was chairman for four years of Gilead Sciences, the company that holds the patent on Tamiflu, and he held millions of dollars’ worth of stock in the company. According to Roll Call, an online newspaper covering events on Capitol Hill, Rumsfeld says he recused himself from all government decisions involving Tamiflu. Gilead’s stock price rose more than 50 percent in 2005, when the government’s plan was announced.)
As with vaccines, the scientific evidence for Tamiflu and Relenza is thin at best. In its general-information section, the CDC’s Web site tells readers that antiviral drugs can “make you feel better faster.” True, but not by much. On average, Tamiflu (which accounts for 85 to 90 percent of the flu antiviral-drug market) cuts the duration of flu symptoms by 24hours in otherwise healthy people. In exchange for a slightly shorter bout of illness, as many as one in five people taking Tamiflu will experience nausea and vomiting. About one in five children will have neuropsychiatric side effects, possibly including anxiety and suicidal behavior. In Japan, where Tamiflu is liberally prescribed, the drug may have been responsible for 50 deaths from cardiopulmonary arrest, from 2001 to 2007, according to Rokuro Hama, the chair of the Japan Institute of Pharmacovigilance.
Such side effects might be worth risking if the antivirals prevented serious complications of flu, such as pneumonia, hospitalization, and death. Roche Laboratories, the company licensed to manufacture and market Tamiflu, says its drug does just that. In two September2006 press releases, the company announced, “Tamiflu significantly reduces the risk of death from influenza: New data shows treatment was associated with more than a two third reduction in deaths,” and “Children with influenza [are] 53 percent less likely to contract pneumonia when treated with Tamiflu.” Once again cohort studies (the same kind of potentially biased research that led to the conclusion that flu vaccine cuts mortality by 50 percent) are behind these claims. Tamiflu costs $10 a pill. It is possible that people who take it are more likely to be insured and affluent, or at least middle-class, than those who do not, and a large body of evidence shows that the well-off nearly always fare better than the poor when stricken with an infectious disease, including flu. In both 2003 and 2009, reviews of randomized placebo-controlled studies found that the study populations simply weren’t large enough to answer the question: Does Tamiflu prevent pneumonia?
As late as this August, the company’s own Web site contained the following statement, which was written under the direction of the FDA: “Tamiflu has not been proven to have a positive impact on the potential consequences (such as hospitalizations, mortality, or economic impact) of seasonal, avian, or pandemic influenza.” An FDA spokesperson said recently that the agency is unaware of any data submitted by Roche that would support the claims in the company’s September 2006 news release about the drug’s reducing flu deaths.
WHY, THEN, HAS the federal government stockpiled millions of doses of antivirals, at a cost of several billion dollars? And why are physicians being encouraged to hand out prescriptions to large numbers of people, without sound evidence that the drugs will help? The short answer may be that public-health officials feel they must offer something, and these drugs are the only possible remedies at hand. “I have to agree with the critics the antiviral question is not cut-and-dried,” says Fauci. “But [these drugs are] the best we have.” The CDC’s Nancy Cox also acknowledges that the science is not as sound as she might like, but the government still recommends their use. And as with vaccines, she considers additional randomized placebo-controlled trials of the antiviral drugs to be “unethical” and thus out of the question.
This is the curious state of debate about the government’s two main weapons in the fight against pandemic flu. At first, government officials declare that both vaccines and drugs are effective. When faced with contrary evidence, the adherents acknowledge that the science is not as crisp as they might wish. Then, in response to calls for placebo-controlled trials, which would provide clear results one way or the other, the proponents say such studies would deprive patients of vaccines and drugs that have already been deemed effective. “We can’t just let people die,” says Cox.
Students of U.S. medical history will find this circular logic familiar: it is a long-recurring theme in American medicine, and one that has, on occasion, had deadly consequences. In 1925, Sinclair Lewis caricatured a medical culture that allowed belief—and profits—to distort science in his Pulitzer Prize–winning book, Arrowsmith. Based on the lives of the real-life microbiologists Paul de Kruif and Jacques Loeb, Lewis tells the story of Martin Arrowsmith, a physician who invents a new vaccine during a deadly outbreak of bubonic plague. But his efforts to test the vaccine’s efficacy are frustrated by an angry community that desperately wants to believe the vaccine works, and a profit-hungry institute that rushes the vaccine into use prematurely—forever preempting the proper studies that are needed.
The annals of medicine are littered with treatments and tests that became medical doctrine on the slimmest of evidence, and were then declared sacrosanct and beyond scientific investigation. In the 1980s and ’90s, for example, cancer specialists were convinced that high-dose chemotherapy followed by a bone-marrow transplant was the best hope for women with advanced breast cancer, and many refused to enroll their patients in randomized clinical trials that were designed to test transplants against the standard—and far less toxic—therapy. The trials, they said, were unethical, because they knew transplants worked. When the studies were concluded, in 1999 and 2000, it turned out that bone-marrow transplants were killing patients. Another recent example involves drugs related to the analgesic lidocaine. In the 1970s, doctors noticed that the drugs seemed to make the heart beat rhythmically, and they began prescribing them to patients suffering from irregular heartbeats, assuming that restoring a proper rhythm would reduce the patient’s risk of dying. Prominent cardiologists for years opposed clinical trials of the drugs, saying it would be medical malpractice to withhold them from patients in a control group. The drugs were widely used for two decades, until a government-sponsored study showed in 1989 that patients who were prescribed the medicine were three and a half times as likely to die as those given a placebo.
Demonstrating the efficacy (or lack thereof) of vaccine and antivirals during flu season would not be hard to do, given the proper resources. Take a group of people who are at risk of getting the flu, and randomly assign half to get vaccine and the other half a dummy shot. Then count the people in each group who come down with flu, suffer serious illness, or die. (A similarly designed trial would suffice for the antivirals.) It might sound coldhearted, but it is the only way to know for certain whether, and for whom, current remedies actually work. It would also be useful to know whether vaccinating healthy people—who can mount an immune response on their own—protects the more vulnerable people around them. For example, immunizing nursing-home staff and healthy children is thought to reduce the spread of flu to the elderly and the immune-compromised. Pinning down the effectiveness of this strategy would be a bit more complex, but not impossible.
IN THE ABSENCE of such evidence, we are left with two possibilities. One is that flu vaccine is in fact highly beneficial, or at least helpful. Solid evidence to that effect would encourage more citizens—and particularly more health professionals—to get their shots and prevent the flu’s spread. As it stands, more than 50 percent of health-care workers say they do not intend to get vaccinated for swine flu and don’t routinely get their shots for seasonal flu, in part because many of them doubt the vaccines’ efficacy. The other possibility, of course, is that we’re relying heavily on vaccines and antivirals that simply don’t work, or don’t work as well as we believe. And as a result, we may be neglecting other, proven measures that could minimize the death rate during pandemics.
“Vaccines give us a false sense of security,” says Sumit Majumdar. “When you have a strategy that [everybody thinks] reduces death by 50 percent, it’s pretty hard to invest resources to come up with better remedies.” For instance, health departments in every state are responsible for submitting plans to the CDC for educating the public, in the event of a serious pandemic, about hand-washing and “social distancing” (voluntary quarantines, school closings, and even enforcement of mandatory quarantines to keep infected people in their homes). Putting these plans into action will require considerable coordination among government officials, the media, and health-care workers—and widespread buy-in from the public. Yet little discussion has appeared in the press to help people understand the measures they can take to best protect themselves during a flu outbreak—other than vaccination and antivirals.
“Launched early enough and continued long enough, social distancing can blunt the impact of a pandemic,” says Howard Markel, a pediatrician and historian of medicine at the University of Michigan. Washing hands diligently, avoiding public places during an outbreak, and having a supply of canned goods and water on hand are sound defenses, he says. Such steps could be highly effective in helping to slow the spread of the virus. In Mexico, for instance, where the first swine flu cases were identified in March, the government launched an aggressive program to get people to wash their hands and exhorted those who were sick to stay home and effectively quarantine themselves. In the United Kingdom, the national health department is promoting a “buddy” program, encouraging citizens to find a friend or neighbor willing to deliver food and medicine so people who fall ill can stay home.
In the U.S., by contrast, our reliance on vaccination may have the opposite effect: breeding feelings of invulnerability, and leading some people to ignore simple measures like better-than-normal hygiene, staying away from those who are sick, and staying home when they feel ill. Likewise, our encouragement of early treatment with antiviral drugs will likely lead many people to show up at the hospital at first sniffle. “There’s no worse place to go than the hospital during flu season,” says Majumdar. Those who don’t have the flu are more likely to catch it there, and those who do will spread it around, he says. “But we don’t tell people this.”
All of which leaves open the question of what people should do when faced with a decision about whether to get themselves and their families vaccinated. There is little immediate danger from getting a seasonal flu shot, aside from a sore arm and mild flu-like symptoms. The safety of the swine flu vaccine remains to be seen. In the absence of better evidence, vaccines and antivirals must be viewed as only partial and uncertain defenses against the flu. And they may be mere talismans. By being afraid to do the proper studies now, we may be condemning ourselves to using treatments based on illusion and faith rather than sound science.
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