A molecular model of anthrax lethal factor, one of three anthrax toxin proteins. (Illustration by Martin McCarthy)
Needle and threat
The road to safe, reliable bioweapon vaccines for children is fraught with ethical peril. On campus last fall, experts began to plot it out.
On October 2, 2001, a 63-year-old Florida man who worked at a media company in Boca Raton arrived at a local hospital with a fever and what health officials later described as an “altered mental status.” He was given antibiotics but died three days later. An autopsy revealed that the cause was anthrax. Anthrax is a bacterium that most often infects animals, both domestic and wild, and people who live or work around animals. Cases in the United States are rare. Occasionally, workers are exposed to anthrax from animal hides. Anthrax is not contagious, but in some forms it is extremely deadly. When inhaled by humans, anthrax spores lead to death about 75 percent of the time. Four more people died that autumn after inhaling anthrax spores that appeared to have arrived in the mail. The investigation was closed in 2010, two years after the FBI’s chief suspect committed suicide, but the attacks thrust bioterrorism into the national consciousness. They inspired new government efforts to find ways to protect the American people—and persistent criticism that the government was not doing enough. In its 2010 report card, the Commission on the Prevention of Weapons of Mass Destruction Proliferation and Terrorism, a congressionally appointed group that has been among the loudest in sounding the bioterrorism alarm, gave the US government an F in developing medical countermeasures, noting “the lack of US capability to rapidly recognize, respond, and recover from a biological attack.” In the past two years, federal efforts to prepare for such an attack have raised ethical concerns about how to protect children. In case of an attack, the Department of Health and Human Services has plans to distribute an anthrax vaccine that provides protection against the deadly bacteria. Millions of doses are already stockpiled. The vaccine has been approved for use by adults—it has already been given to more than a million members of the armed forces—but has never been tested on children. Now the government is considering testing the anthrax vaccine on a small group of children in the hope that, should an attack occur, doctors, public-health officials, and parents will know that the vaccine is safe and effective for children. But the proposal has raised the concerns of ethicists who question whether the risks posed by such research would meet decades-old guidelines, some of them unclear and open to interpretation, for safeguarding the subjects of medical research. Such concerns are heightened when subjects are unlikely ever to need the vaccine that is being tested on them and when subjects cannot consent. “There are two goods,” says Daniel Sulmasy, the Kilbride-Clinton professor of medicine and ethics in the medical and divinity schools and a member of the Presidential Commission for the Study of Bioethical Issues. “One of them is to help children and protect them from these kinds of harms, which can only go forward through research. The other is to protect children from the possibility of being exploited by research. In both cases we want to protect children. The question is how to balance the two.” This dilemma was confronted at the University of Chicago in early November, where the commission gathered for its third public meeting about trials of biological countermeasures on children. It is, in many ways, the ultimate exercise in applied ethics. In October 2011, the National Biodefense Science Board recommended that the government go ahead with the trials—but only after seeking guidance on whether such research was ethical. Kathleen Sebelius, secretary of the Department of Health and Human Services, asked the commission to make a recommendation, not only for testing anthrax vaccine, but also for other methods of treating children who may be at risk from bioterrorist attacks or naturally occurring epidemics. It’s a tall order. National advisory committees on bioethics have existed for almost 40 years and have exerted a profound influence on federal policy. Under George W. Bush, the President’s Council on Bioethics, whose members included University of Chicago professors Leon Kass, U-High’54, SB’58, MD’62, and Janet Rowley, U-High’42, PhB’45, SB’46, MD’48, took up highly controversial issues, including the ethics of research on embryonic stem cells. Under Barack Obama, the commission has steered clear of beginning-of-life controversies. It has instead tackled problems such as privacy and genomic research, synthetic biology and new technology, and the ethics of research into sexually transmitted disease in Guatemala by the US Public Health Service in the 1940s. This anthrax testing issue, said Sulmasy, who is also associate director of the University’s MacLean Center for Clinical Medical Ethics, is especially “thorny and ambiguous.”   The problem came into sharp focus in 2011 when federal, state, and local officials tested what would happen if terrorists released airborne anthrax in San Francisco, a metropolitan area of 7.6 million people. The results of the exercise, called Dark Zephyr, alarmed them. According to the National Biodefense Science Board, “The health effects of the hypothetical attack overwhelmed hospital resources over a large area, and produced many cases of disease and many deaths, including children.” Officials were especially shaken by the degree of vulnerability of children. At the bioethics commission’s first meeting on the subject last May, member Alexander Garza, chief medical officer in the Department of Homeland Security, spoke about Dark Zephyr. When the question arose of how to protect children after the simulated attack, he said, “there was no answer, which for us as decision makers in the US government, is not a good answer.” What makes anthrax so worrisome to the government is that it is relatively easy to obtain, weaponize, and deploy. Spores can travel hundreds of miles in the air and remain dormant in the soil for years. An anthrax weapon requires little advanced equipment or knowledge. “Any country with basic health care or a basic pharmaceutical industry has the expertise to produce anthrax,” according to The Encyclopedia of Infectious Diseases. If the spores were spread over a populated area, the government says, the results would be devastating. Anthrax is treatable, but only through a grueling 60-day course of antibiotics. And because the spores can linger for months or even years and are easily stirred up again into the air, antibiotics offer only partial protection. People at risk of exposure need the protection of a vaccine. One vaccine has been available since the 1950s. Since 1998 it has been administered to American soldiers. According to the Centers for Disease Control and Prevention, there is no evidence that the anthrax vaccine causes long-term health problems in adults. Its side effects are familiar to anyone who has received a flu shot: a sore arm and maybe temporary fatigue and headaches. In fewer than one in 100,000 cases, the vaccine produces a severe allergic reaction. A vaccine would only be used in the event of an attack. But as of now, there’s no way of knowing whether the vaccine would be effective for children, or at what doses. Nor is it known whether the vaccine would be safe, although experience with adults suggests that it would be. Answering these questions requires research.   Modern ethical thinking on the protection of research subjects dates to the Nuremberg trials. A response to the experiments of Nazi doctors, the Nuremberg Code sought to prevent testing on research subjects without their voluntary consent. In the 1970s, the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research established principles that still guide biomedical research. Three stand out above all: respect for persons; beneficence, or promoting the good of others; and justice, or ensuring that the risks and benefits of research are apportioned fairly. Medical research on children is also addressed in federal regulations. But the regulations on this subject are spare and sometimes confusing. They speak of following “ethical principles” without identifying those principles, and use ambiguous terms—for example, “a minor increase over minimal risk”—without defining them. In the Divinity School’s vaulted third-floor lecture hall last November, the commissioners parsed those regulations like Talmudic scholars, trying to discover their meaning. The commission has traditionally met in Washington, but under its new chair, Amy Gutmann, president of the University of Pennsylvania, it has taken its meetings on the road. “It is important to make it clear we’re not an inside-the-beltway commission,” she said. The thirteen people on the commission come from diverse backgrounds, including the military, academia, and government. Several are doctors and public-health officials; two are university presidents. Members include professional bioethicists like Sulmasy, lawyers, and activists. Lonnie Ali, wife of Muhammad Ali, is an advocate for victims of Parkinson’s disease. Over two days, the commission heard from experts in public health, homeland security, medicine, and research ethics as they grappled with what current guidelines might mean in the context of anthrax and other biological weapons. Federal regulations “are completely unhelpful when it comes to actually figuring out what questions to ask and how to approach them,” complained John Arras, a professor of philosophy and biomedical ethics at the University of Virginia. Still, the commission was determined not to try to supplant the regulations but to build an ethical framework that might expand and clarify them. One point on which the regulations are clear: they recognize two fundamentally different kinds of research. In one, the subjects are likely to benefit from the research. Many vaccines fall into this category, such as those for common illnesses like the flu. But in some circumstances the law does allow children to participate in research that is unlikely to benefit them. In such cases the research must be “of vital importance” and expose children to only a “minor increase over minimal risk.” At the commission’s first meeting on anthrax in May, several experts told the commission they would not recommend testing an anthrax vaccine on children now—at least not until more was known about the risks involved. One of them, David DeGrazia, AB’83, a professor of philosophy at George Washington University, urged commissioners to avoid the temptation to simply weigh the risks to child research subjects against the potential benefits to millions of children who might be helped by the research. “I continue to resist the image of rights as something just to be balanced against goals,” he said. But members had also heard powerful appeals to do more to protect children from potentially devastating attacks and epidemics. “I think that we have an obligation to keep America’s children safe,” said Michael Anderson, a pediatrics professor at Case Western Reserve University, medical officer of the National Disaster Medical System in the Department of Health and Human Services, and representative of the American Academy of Pediatrics. “What’s concerning to me about the hypothetical ‘God forbid’ scenario … is, yeah, we’ll give out vaccine and antibiotics based upon what we know. We don’t know anything. What dose do we give to a six-year-old? Is it 1/70th per kilo? Is it 1/18th per year?” These two contrasting positions were revisited in many forms at Swift Hall as commission members looked for ways to reconcile them. They expressed concern for the need to encourage more medical research on children and worried lest they be overly protective. The challenge was twofold. First, to decide what amount of risk might be allowed in biomedical research in which the children being tested would not benefit from the research. The second was to determine what circumstances might justify such testing—under what conditions would it be ethical to ask parents to place their child at some risk? Through long and sometimes technical discussions, the commissioners kept circling back to these two fundamental questions. Sonja Rasmussen, deputy director of the Influenza Coordination Unit at the Centers for Disease Control and Prevention, suggested a reason for testing the anthrax vaccine on children now. In the case of an attack somewhere in the United States, she said, “I think it would be really hard to convince people to give their children a vaccine that you can say had never been tested in children at all.”   Alan Fleischman, a clinical professor of pediatrics at Yeshiva University’s Albert Einstein College of Medicine, traced the history of ethical thinking about research on children, then outlined a set of principles under which research might proceed—including a slightly higher threshold of risk, what he called “a little more than a minor increase of minimal risk.” “I might move that line just a little bit,” he said, “if I really thought that there would be thousands of children dead because of an attack in New York City. But I wouldn’t move it all the way to a likelihood of death in the trial or the likelihood of disability. ... I certainly would allow for the potential for some pain, a potential for some redness, a potential for significant swelling, potential for the child not going to school for a few days. ... And, we always know that with proteins we may have a specific child who has a specific reaction to the protein, and, therefore, I would want to set up the trial so that pediatricians and nurses were with those children.” Behind much of November’s debate lay important philosophical issues. At one point the philosophers on the commission, including Sulmasy, led a discussion of Kant’s ethical imperative to treat persons as ends, not means, and what implications that directive might have for injecting children with an anthrax vaccine. Indeed, commissioners had tentatively included a statement of that principle in the masthead of the recommendations they were developing. But several worried that focusing too much on individual rights would slight other ethical principles that might motivate a parent to allow a child to participate in a trial. Various communitarian principles might do so, they suggested: patriotism, altruism, and community solidarity, for example. Bruce Lockwood, the deputy director of emergency management in Hartford, Connecticut, told commissioners that, in his view, first responders would be willing to allow their children to take part in anthrax research. Beyond the central philosophical questions, other difficulties arose. Federal regulations allow the nontherapeutic testing of children when knowledge is of “vital importance.” But what are matters of vital importance? And who decides? Commissioners were also concerned that researchers recruit subjects for an anthrax vaccine study fairly and not take advantage of the poor or other disadvantaged groups; that they test older children first and only gradually shift their focus to younger children; and that they allow children—not just parents—the right to assent or withhold their assent. In part the commission was confronting not just new circumstances posed by weapons of terror but a decades-long reluctance of medical researchers to test any new medicines on children. May Faith Marshall, director of the program of biomedical ethics and a professor in the schools of medicine and nursing at the University of Virginia, told the commission that the majority of the medicines doctors prescribe to children were not tested on children, including commonly used drugs like Ritalin and albuterol. “We need to begin thinking in a new way,” said Georges Benjamin, executive director of the American Public Health Association. “We have historically left children behind, even in our current research approach, and I think that we need to stop doing that.” Several commission members wanted to know what would happen with a vaccine intended for children. How would it be distributed and administered? Suzet McKinney, deputy commissioner of public-health preparedness and emergency response at the Chicago Department of Public Health, gave sobering testimony on the resistance in low-income African American and Hispanic neighborhoods to vaccination campaigns for meningococcal disease and the H1N1 flu virus. These groups, she said, often view vaccination efforts with “high levels of false perception about government intent and consequentially, mistrust.” During the discussion later, several commission members argued for education and community engagement as a part of any ethical framework for testing and deploying vaccines. Some of the uncertainties surrounding the anthrax vaccine, the commission noted, are less ethical than epistemological—some basic facts aren’t known to them. What, for example, is the real risk of an anthrax attack? “Homeland Security knows but it’s not sharing anything with us,” Arras said later. “It’s kind of a shot in the dark there.” Garza, a former battalion surgeon who commanded special attention for the practical perspective he offered, said the risk of an attack is difficult to quantify; the likelihood is low, but the potential for harm is enormous. Moreover, he said, such threats are by their nature unpredictable. He noted during a break that the H1N1 pandemic had caught officials by surprise; they were expecting an epidemic of avian flu. “Not everything is going to work out the way you expect it,” he said, “and you have to be prepared for that.” The commission expects to finish its work in January and send its recommendations to Sebelius. Judging from this meeting, it will not attempt a definite yes or no on the question of whether to test the anthrax vaccine on children, but will leave that decision to officials in the government and experts convened to evaluate a specific research protocol. The commission will try to offer those officials and experts more detailed guidance than is yet available on how they ought to make the decision: what sort of questions they should ask, what they need to know, and on what principles they should stand. The deliberations resume January 14 in Miami. For now, the central question remains unresolved. “The main issues that remain are the main issues,” said Arras. “Are we prepared to give the green light to research on children with no benefit to them, when risk is more than a minimum? It’s a classic bioethics dilemma.” By vaccinating children for anthrax, he said, we could do “a lot of good, but we could do harm by giving the wrong dose, either too strong a dose or too weak a dose. There’s a strong moral case for doing research.” But what amount of risk, and how much uncertainty, should be tolerated? Finding answers to these and other questions is not only a philosophical and practical problem for the commission. It is also a test of how ethical principles framed decades ago and codified, however imperfectly, in American law can be made to serve challenges not imagined by those who crafted them. “We’re kind of in no man’s land here,” Arras said. In this age, that may go for all of us. “The American public doesn’t want to tolerate much risk,” John Parker, chair of the National Biodefense Science Board, told the commission in May. “But as we look to the future, I think … we’re going to have to engage not only ourselves but the American public and others into measured risk. And they’ve got to get used to that.”