The Imaginations of Unreasonable Men

by Bill Shore

  Unlike Steve Hoffman, who sees tourism and the military creating a market that would help pay for his vaccine, or Jay Keasling, who is allowing synthetic fuel development interests to subsidize his development of bioengineered artemisinin, Alonso does not talk much about market mechanisms. Just the opposite, actually. In 2008 Alonso told a reporter for GlobalPost, “It’s pretty simple . . . If the head [of a pharmaceutical company] gets up this morning and announces that they’re going to invest $1 billion [in a malaria vaccine], by lunchtime . . . the stock would have plummeted and the guy would be out. Who is going to buy a malaria vaccine?”6

  In fact, Alonso is unabashed in his rejection of the social-marketing approach. “This is something we simply must do,” he told me, referring to the project of making malaria nets and vaccines available to all who need them. “At what point will we treat immunization the way we treat utilities? The government sees the public health benefit of getting clean water to you. How will it be different for a malaria vaccine? We must see that it will take fifty to one hundred years to achieve this and be willing to make that commitment,” he said, calling to mind the cathedral builders in this city that is home to the world’s most famous unfinished cathedral, Gaudi’s Sagrada Familia, 150 years under construction and still lacking a finished roof.

  But what if political will is lacking? What if it is just not in the cards politically? Wouldn’t you want to find market mechanisms that could be put to use to achieve at least some of your objectives? I asked Alonso these questions. “That would be okay,” Alonso conceded reluctantly. But he believes the market would not be able to accomplish the task as resolutely or as completely.

  The debate is emblematic of the continuing evolution of the nonprofit sector. The same issues underpin so many of the developments taking place today. If it feels like the nonprofit sector is in the midst of turbulent transformation, especially in the United States, it is because the demands placed upon it have moved it ever closer to the fault line that has defined American politics since at least World War II, a fault line dividing those who believe it is government’s responsibility to improve the lives of individuals, and to help to care for those who cannot care for themselves, and those who believe such tasks should be left to the individuals themselves, their families, and their communities, aided by whatever incentives the market sees to join that effort. Few issues, outside of religion, evoke such deeply held beliefs.

  Whether it is Gates’s creative capitalism philosophy or Alonso’s that prevails, the debate is likely irrelevant to the African mother of a four-year-old girl convulsing from the fevers and chills of severe malaria. She is less political than pragmatic, wanting only whatever will work to save her child. Saving her, and millions like her, requires society to continue to struggle to find a balance between political solutions and market solutions, and not to exclude either completely. For that essential underlying reason, Gates, despite his belief in creative capitalism, has poured enormous philanthropic resources into Alonso’s work. Gates and Alonso are not letting the politics of the market divide them from the task at hand: eradication.

  CHAPTER 10

  MOMENT OF TRUTH

  Army medical researchers reported today a major breakthrough in the fight against malaria, next to the Viet Cong[,] the most savage enemy American troops face in Vietnam.

  A spokesman for the Surgeon General’s office said diaminodiphenylsulfone (DDS), a drug long used in treating leprosy, was found in Vietnam field tests to cut in half the number of men who are stricken by malaria. . . .

  . . . The Army considers the malaria problem urgent enough that necessary final approval from the Food and Drug Administration was arranged in a telephone call.

  —Associated Press, June 23, 1966

  IMAGINE CHECKING INTO A HOTEL for a week-long stay on a sunny spring morning. After the receptionist at the front desk greets you, checks you in, and offers a key to the mini-bar, you go to your room, unpack your suitcase, and open the curtains to check the view. You change into comfortable, loose-fitting clothes. But instead of heading off to a conference or to the fitness center, you walk down the hall to a room and knock on a door, which is opened by a military official. He directs you in and toward a chair. Once you are seated, he awkwardly straps a cylindrical white box onto your arm. The box is swarming with mosquitoes. They not only take bite after bite of the tender skin on your forearm, but have been bred to inject into your bloodstream, along with their saliva, malaria parasites of the species Plasmodium falciparum , the same parasites that kill 1 million children and sicken another 300 million people worldwide every year.

  This is what it means to be “challenged” in a clinical trial for the volunteers who meet the strict criteria for participation, and were previously inoculated with an experimental malaria vaccine candidate. The hotel is filled with such volunteers, as well as doctors and nurses who take blood samples from them once a day and perform exams. Anyone presenting with evidence of malaria, measured in numbers of parasites per microliter of blood—can be treated at once with powerful antimalarial drugs, even before symptoms set in, so that the parasites are permanently cleared from their bloodstream. It is standard procedure and perfectly safe. Since no vaccine to prevent malaria has ever been fully effective, though, it is a procedure that has been necessary to follow time and time again to return challenged volunteers to good health.

  On Tuesday, May 26, 2009, Steve Hoffman began Phase I of just such a clinical trial in Maryland on the vaccine he had dedicated much of his life to developing. For more than a year, Hoffman had been telling anyone who would listen that “trials will start in the next month or so.” But like the horizon, the date always seemed to recede as he moved closer to it. There was always some complication or delay, most of them probably fully anticipated by Hoffman in the first place. But he understood that dangling the imminence of clinical trials, like dangling a carrot in front of a horse, would keep things moving. The nature of science and experimentation is, in part, making it up as you go, and like a successful TV talk-show host, Hoffman knew that among his most useful injunctions were “stay tuned” and “coming up next. . . . ”

  The start of the trial was as much personal triumph as professional milestone. It was a day that the vast majority of experts in the malaria field thought would never come. Some had said so publicly, while others had snickered privately. Many simply ignored Hoffman, focusing their energies instead on more conventional approaches that were farther along than his. In the press release that Sanaria and the PATH Malaria Vaccine Initiative put out on April 23, 2009, Myron M. Levine, director of the University of Maryland School of Medicine’s Center for Vaccine Development—one of the locations for the trials—noted that Hoffman’s vaccine was based on studies from the 1970s “that were never translated into vaccine development effort because the task was considered to be impossible.”1

  But Hoffman had persevered, undeterred, if not unfazed. He had reached this day thanks to a combination of paradoxical conditions: personal financial sacrifice that cost him more than a few nights’ sleep, until earning generous philanthropic support that restored his peace of mind; a devoted following of true believers committed to disproving the skeptics, who vastly outnumbered them; and a brilliant wife and partner who kept a low profile but whose own discoveries had made key stages of his work possible.

  During that last week of May and the beginning of June, the team initiated inoculations of 104 people via four injections at two sites. One was Levine’s Center for Vaccine Development; the other was the Clinical Trials Center at the National Naval Medical Center in Bethesda, Maryland. In September the two sites began the “hotel challenge.” The verdict on the trial would take six months to compile. If research determined that the vaccine was safe, Hoffman could proceed with further phases of testing and trials to assess effectiveness. There would be a need for additional large sums of money, but no one is better than Hoffman when it comes to parlaying small victories into a larger narrative that in
spires further support.

  By coincidence, or perhaps not, on the same day that Steve Hoffman’s vaccine began clinical trials in Maryland, his principal competitor, GlaxoSmithKline, was commencing more advanced trials 8,700 miles away in a small town called Bagamayo, a once important trading port and now a center for sailboat construction on the east central coast of Tanzania. Five infants between the ages of five and seventeen months were being inoculated with GSK’s RTS,S vaccine.

  RTS,S was advanced enough to be launching Phase III of its clinical trial, the largest ever of a malaria vaccine. The five infants were the first of 16,000 kids in seven African nations in a trial that would last seventeen months. Half would get RTS,S, and half a placebo. All would be given insecticide-treated bed nets. They would then be clinically monitored for two years.2

  When Phase III is over, RTS,S will either be crowned as the great new hope for the African continent, and rushed into production at GSK’s Rixensart, Belgium, manufacturing facility, or it will go back to the lab for refinement. Perhaps both. RTS,S is widely expected to be the vaccine that is first to market, but not the final word. It appears to only provide protection to about half of those vaccinated. Critics, including Hoffman, argue that it doesn’t prevent infection so much as delay its onset. Even so, that may be enough to allow small children to survive until their own natural immunities kick in to make them less vulnerable. They would still contract malaria, but the hope is that it would be less debilitating.

  RTS,S is, to date, the only malaria vaccine candidate, out of more than seventy that have fallen short, to get as far as Phase III trials. As such, the launch in Bagamayo, a town of only 30,000, got extensive media attention, internationally as well as in Hoffman’s own backyard, and especially in the science and medical trade press. American, European, and African newspapers and websites were filled with reports of this unprecedented undertaking. The coverage threatened to swamp Steve Hoffman’s efforts.

  RTS,S, the kind of high-tech, subunit recombinant DNA vaccine in vogue today, has an “adjuvant” designed to boost its effectiveness (in this case a surface antigen of the hepatitis B virus). Hoffman’s vaccine is a throwback to the earliest days of vaccine development: a vaccine composed wholly of the very parasite (weakened but still strong enough to trigger the immune system) that one intends to destroy, similar in premise to the vaccines for the smallpox and polio viruses.

  The automated manufacture of RTS,S is capable of being scaled up in mass quantities at GSK’s sophisticated production facilities. Hoffman’s vaccine requires the labor-intensive costs of lab technicians doing precision piecework, the equivalent of a shoe manufacturer like Timberland making expensive hand-sewn boots in the Dominican Republic when many of its competitors use technologically advanced factories in China.

  If either vaccine proves successful—and leads to the eradication of malaria—it would be only the second time in human history that a disease has been wiped out. The first was the elimination of smallpox in 1979. Even polio, for which a vaccine was discovered in 1952, was diagnosed 1,300 times in 2007 and poses the threat of resurgence.3

  Getting to the RTS,S trials had taken GSK decades and cost tens of millions of dollars, with the team behind the project enduring dozens of conferences, writing dozens more peer-reviewed papers, and going through all the requisite disappointing experiments, regulatory approvals, and more. Getting through the trials may be even harder.

  Just a few days after the RTS,S inoculations began, the Toronto Globe and Mail described the test as a task “that pits hundreds of scientists, doctors and field workers against floods, famine and corruption that corrode the very core of health infrastructure and breeds deep public distrust.”4

  In Kilifi, Kenya, the skepticism of tribal chiefs and mothers was so deep that it took more than six months to recruit just four hundred volunteers. Daunting logistical issues compounded the challenge: The Globe and Mail reported that, “As the long rains set in, trucks wallowed and got stuck in thigh-deep mud, everything from samples in need of refrigeration to sick children had to be moved across dozens of kilometres by motorbike or on foot. Field workers in rubber boots struggled to access homesteads, some of them mere islands in a sea of mud.”5

  This is what the makers of RTS,S are dealing with today. It’s what Hoffman hopes he gets far enough to deal with tomorrow.

  ONE STEP FORWARD AND ONE STEP BACK

  The milestone of clinical vaccine trials finally achieved by Hoffman as well as RTS,S is especially timely in light of new and alarming reports of growing resistance to the one drug that until now has been the most effective and reliable method for treating malaria, artemisinin. It is a development that could also drastically undermine the impact Jay Keasling seeks to have by using synthetic biology to inexpensively increase supply.

  The emerging resistance to artemisinin is partly due to the complexity of the parasite and the unstoppable nature of its ability to evolve. But it is also the direct result of greed, for which there is no drug or vaccine.

  In early 2009 the World Health Organization (WHO) announced the discovery of malaria parasites along the Thai-Cambodia border that were proving resistant to commonly used derivatives of artemisinin called artesunate and arthemeter.

  Prior to this there had been a hugely optimistic surge of interest, research, and spending on combination therapies using artemisinin. Chinese companies developed numerous forms of artemisinin and combined it with another antimalarial drug called lumefatrine so that the parasites would be less likely to develop resistance. China’s own malaria caseload went from 2 million in 1980 to 90,000 in 1990. Colonel Peter Weina, who, as chief of the pharmacology department at Walter Reed Army Institute of Research from 2002 to 2009 had led the U.S. Army’s effort to develop a drug against the most severe form of malaria, went so far as to admit that, “there was an assumption and there was a hope and there was a prayer that resistance to artemisinin would never happen.”6

  History teaches that we should have known better. Resistance to malaria medicines has always been a question of when, not if. In previous decades malaria had become resistant to once potent drugs like chloroquine in the 1960s and mefloquine by the 1990s. A category of drugs known as SPs (for sulfadoxine pyrimethamine) was introduced in 1977 with a 100 percent success rate. Though it remains widely effective in Africa, within five years SPs were effective in only 10 percent of patients in some areas of Southeast Asia.

  Wishful thinking held that artemisinin might be the exception. But the new discoveries are showing that artemisinin, which once cleared parasites from the blood in two days, is taking three or even five days in a large number of those infected, the first sign of growing resistance.

  The Chinese sold the rights to the drug to Novartis in 1994. Novartis sold it at $44 a course to Western travelers but agreed to sell it to the World Health Organization at $2 a course. Even at that price it was ten to twenty times more expensive than previous drugs, such as chloroquine, and USAID and CDC officials considered it too expensive for Africa. Then, an underground market developed. Underground markets, by definition, are unregulated. As a result bad things happen.

  One of those bad things was counterfeit drugs. Paul Newton, head of the Wellcome Trust Southeast Asian unit in Laos, concluded that tablets with low doses of artesunate—insufficient to kill the parasites, but enough to lead to resistance—were the main source of the growing problem. Pills with only small quantities of the active ingredient, instead of the full amount, are dangerous because they wipe out only the weakest parasites, enabling the hardiest to survive and multiply. When a malaria victim infected with resistant parasites is then bitten by another mosquito, and that mosquito bites another human, the resistant parasites have a chance to thrive and multiply some more. And on and on it goes, like a breeding plan for more and more drug-resistant parasites. After a while, the genuine drugs will no longer work.

  The pirated drugs are often sold in packaging indistinguishable from the real medicine and contain sma
ll amounts of active antimalarial substances in order to pass quality-control tests. Studies have found that between one-third and one-half of artesunate tablets across Southeast Asia were counterfeits. The criminal trade in these cheap imitations was made attractive by the relatively high cost of the real drug—about $2 for a course of treatment, or up to $10 in the private sector. A course of chloroquine, by contrast, costs only 10 cents.

  Another contributing factor was the widespread availability in the region of high-quality artesunate tablets from China and Vietnam. The artesunate in these tablets was present as a single ingredient, rather than in a combination of ingredients, which also gave the parasite a better chance of developing resistance.

  In addition, because of the relatively high cost of the drugs, poor people were often not completing their courses—they stopped taking the tablets when they felt better, giving any resistant parasites a chance to survive and proliferate.

  In 2008, the International Criminal Police Organization (Interpol) arrested twenty-seven people in raids across Asia and seized 16 million counterfeit pills worth at least $7 million. The global market for fake pharmaceuticals is estimated to be $75 billion. As Paul Newton of Wellcome Trust has pointed out, the crime really involves more than just making cheap drugs: “If you make a medicine that contains no active ingredient for a disease you know can be fatal,” he said, “at best that is manslaughter and at worst it is murder.”7

  The crime is even greater when one considers all the consequences. On one level, selling the pirated drug could easily cause one person to die—the person who took that drug and as a result did not get better. But on another level, selling the pirated drug contributes potentially to the death of millions, since the imitations are causing the real artemisinin drugs to become ineffective. “Twice in the past, South East Asia has made a gift, unwittingly, of drug resistant parasites to the rest of the world, in particular to Africa,” according to Nick Day, director of the Mahidol-Oxford Tropical Medicine Research Unit. “If the same thing happens again . . . that will have devastating consequences for malaria control.”8