The Imaginations of Unreasonable Men

by Bill Shore

  Virtually all malaria researchers would concur with Day on that point. “If we lose the artemisinins at this stage, just now when we dare to mention the word ‘eradication’ again, it would be a disaster for malaria control,” said Dr. Arjen Dondorp, lead author of a study about artemisinin resistance in Cambodia. “It would cause millions of deaths, without exaggeration.”9

  There is yet another level of danger arising from these circumstances, with the consequences going far beyond even losing the benefits of a once-effective medicine, as serious as that would be. The greater problem is that the parasite could come back stronger than ever. Partial victory against malaria could ultimately be worse than total failure.

  History offers one such example that traumatized the malaria community for nearly half a century. In 1955, the World Health Organization believed that malaria could be eliminated within ten years, thanks to the introduction of chloroquine in the 1940s and the discovery of DDT, the most effective insecticide in history, in 1939. Today we are more aware of the dangers of DDT than its benefits, but in 1948 the chemist who created it, Paul Müller, won the Nobel Prize in medicine for doing so.

  WHO spent more than a billion dollars in its campaign against malaria, and the disease was wiped out in much of the Caribbean and South Pacific. Malaria cases in Sri Lanka dropped from 2.8 million in 1946 to a total of 17 in 1963. Likewise, in India there were 75 million cases in 1951 and only 50,000 in 1961.

  But in the deep tropics, the disease remained untouched, and the program largely bypassed sub-Saharan Africa. Overuse of DDT by farmers (not by malaria fighters) led Rachel Carson, who is widely considered the founder of the environmental movement, to document its abuse in her book Silent Spring, and as a result of her revelations, much of the world outlawed it for agricultural use. DDT became politically incorrect and difficult to procure. The political will for financing malaria eradication eventually began to fade, and resistance to chloroquine created epidemics of malaria even more difficult to treat. The disease came roaring back in India and Sri Lanka. Today the toll from malaria is almost twice what it was a generation ago.

  So when a leading drug such as artemisinin, once considered infallible, begins to falter, attention shifts to other approaches. One result has been to look to vaccines as a promising alternative to drugs. Hence the intense competition among leaders in the race to a vaccine, like Steve Hoffman and GSK. But there is also competition from advocates of other strategies for defeating malaria.

  Just as different branches of the armed services employ different weapons and tactics to achieve the same goal, the malaria community has always been divided into different branches to wage its war, and each branch vigorously champions its own particular capabilities and worldview. Vaccine developers believe that prevention would be the most effective and economical method of combating malaria. Without a vaccine, they argue, we will be trapped in a perpetual cycle, spending massive amounts of money and energy on treatments that the parasite will eventually be able to resist.

  Those who develop drugs to treat the disease think a vaccine would be great but quickly point out that there has never been one for malaria, or for any other parasitic disease. So the old debate begins again: Do we encourage palliative treatment today that falls short of eradication, or support a total cure that is years (and millions of deaths) away from universal application, if indeed it works?

  And there are those in the malaria community who believe that resistance to both drugs and vaccines is just a matter of time and that we should focus on the only thing that has ever really worked: “vector control,” that is, using bed nets and insecticide sprays as the weapons of choice. Thus we would try to get rid of the malaria parasite by getting rid of the mosquitoes that house, transport, and deliver it. But even this option is not exempt from evolution’s toll. At the Fifth Multilateral Initiative on Malaria, held in Kenya in October 2009, it was reported that mosquitoes were adapting to bed nets by changing their feeding habits. Instead of trying to feed at night, when people were safely beneath their nets, the mosquitoes were getting their meals earlier in the evening when people were still out in the open. At the same time, there is evidence of the mosquito developing resistance to the pyrethrum-based insecticides used to treat the nets.

  Practitioners within any one branch tend to be consumed by developments in their own field and not especially knowledgeable about the others. They can be uninterested at best, and dismissive at worst. Steve Hoffman and Jay Keasling devote to each other, at most, a glimmer of recognition—and less than a glimmer of enthusiasm. Or maybe it is simply a matter of staying focused on what one does best. As Hoffman told me of Keasling’s work: “I admire what he’s done, but I leave his job to him and he leaves mine to me.” In each branch of the malaria war, there are many who believe their own approach embodies the best mix of compassion, realism, and effectiveness, and therefore occupies the moral high ground.

  New discoveries, technological advances, and policy shifts regularly reset the playing field, temporarily boosting one approach over another and causing tidal shifts in the flow of resources, money, and manpower from one branch to another. Over time, however, it has become apparent that the malaria parasite is too complex and evasive to succumb to the attacks of one branch alone. All are necessary.

  “All” gets very expensive, very quickly. Even more, it creates a challenge: the need for scientists to coordinate with each other and work together. The various branches of our military forces have rarely been successful any other way. The various branches of the malaria community have rarely even tried.

  CAREFULLY CHOREOGRAPHED CLINICAL TRIALS

  I first heard about Judith Epstein, a U.S. Navy commander, from Steve Hoffman when he told me about the editorial she’d written in 2007 for the medical journal The Lancet, “What Will a Partly Protective Malaria Vaccine Mean to Mothers in Africa?,” which raised some of the same questions that Hoffman has asked about the RTS,S vaccine. The kind of humanistic themes she brought out are rare in scientific journal articles written by military personnel. Epstein argued for a vaccine that went beyond the partial effectiveness of RTS,S, even though the military—at least the army—was deeply invested in it.10

  Epstein works at the Naval Medical Research Center, which is located near the imposing Bethesda Naval Hospital. As principal investigator at the Navy’s Center for Clinical Trials, Epstein was responsible for conducting and assessing the Phase I trials in 2009 of Steve Hoffman’s vaccine. She will yield the first official evaluation of the safety and efficacy of the vaccine Hoffman has worked on for all these years, determining whether the more than $60 million that foundations and government agencies have already invested in Hoffman’s effort will be followed by investments of even greater magnitude.11 The trials are not “make-or-break” so much as potentially “break.” It is only the first of numerous trials, but there is no Phase II without getting past Phase I.

  I wanted to get to know Epstein, partly because a doctor who goes into tropical medicine sets himself or herself apart from 99 percent of the rest of the medical community. The difference goes beyond being smart, or altruistic, though the doctors who make this choice often are both. It has more to do with having made different choices about how to lead one’s life, choices that isolate one from the mainstream in medicine and that result in a way of being that is, by nature, rather solitary. I wanted to know more about the quality of character that enables people like Hoffman and Epstein to make such choices, and I thought Judy Epstein might help me understand this. She did not disappoint.

  I drove out to NMRC—known as “Namric” in military parlance—on a Monday morning and waited to clear a checkpoint manned by a squad of five or six military police. I was directed to pull in behind a line of cars parked on the helipad, which was marked by an enormous white cross in front of the naval hospital. Behind it lay a naval base that looked more like a rural college campus, with old buildings, leafy paths, and the stately residences of admirals instead of the offic
es of a college president and dean. Epstein pulled up, rolled down her window, and told me to follow her. As we went through the checkpoint, where she returned the salute of a military police officer, and proceeded to the grounds of the Naval Medical Research Center, I noticed how carefully and thoroughly she obeyed speed limits, stop signs, and traffic directions. Though fifty-four and an officer for nearly ten years, Judy still acted as if she were new to the navy, too new to take casually the numerous rules and regulations that are second nature to military life.

  Epstein would be easy to underestimate. She’s small and slim, and she walks with a brittle gait because of an old back injury. When she got out of her van, I was surprised to find her in uniform: khakis, well-shined black patent leather dress shoes, and a black sweater with three gold stripes on each shoulder. As she got out of the car, she fitted a khaki garrison cap over a thick knot of black hair pinned up on the top of her head. Her demeanor was serious. Though she was friendly and open, I don’t think I ever saw her smile.

  We headed over to Building 141, the headquarters for the Center for Clinical Trials. An old whitewashed building from the 1940s or 1950s, it contained offices, conference rooms, and examining rooms. Epstein, who had an office in the back, introduced me to several other investigators, including a nurse and a doctor. The corridors were quiet. Some of the staff was in another building, busy copying 20,000 pages needed for an Institutional Review Board.

  Judy came late to the malaria community—and even to science and medicine. Her father was a doctor, her mother a painter whose first husband was Will Barnet, an artist best known for his enigmatic portraits of women and girls. Notwithstanding childhood dreams of being a marine biologist or working on the Hope hospital ship, she left college after one year for ballet and joined the company of legendary choreographer Agnes de Mille. When the revival of Oklahoma opened at the Palace Theater on Broadway on December 13, 1979, she was in the cast.

  It was the combination of her own back injury and de Mille’s stroke that led Judy to leave dancing and become de Mille’s caretaker. She grew more interested in health issues and considered becoming a physical therapist. At the age of twenty-eight she returned to Columbia University and “kind of locked myself away for three to four years.” After graduating she took another year off because her father was battling colon cancer, and from there it was off to Harvard Medical School.

  Interested in both parasitology and pediatrics, Epstein did a residency at Children’s Hospital in Philadelphia and was then awarded a four-year research grant. In 1998, the last year of her fellowship, an adviser recommended that she join the navy, and she was given a billet in the dengue program. “Then I saw Steve Hoffman’s papers and asked to meet him,” she told me. “As soon as I met him I said, ‘I have to work for him.’” She found a way to work with him instead, as principal investigator running the clinical trials that began in September 2009.

  TRIALS AND TRIBULATIONS

  The trial had two critical phases: the immunization, and the challenge. The threshold question for immunization was not the efficacy of the vaccine, but its safety. Would there be “breakthrough infections”? That is, might the vaccine be so strong that it not only triggers the immune system but goes so far as to make sick the person one is attempting to immunize?

  Hoffman’s wife, Kim Lee, oversaw the immunizations each day. At 6:00 A.M., she’d start the process of extracting the vaccine from the liquid nitrogen and then diluting it. It would be injected intradermally or subcutaneously, and then the volunteers would be observed for thirty minutes. There were four cohorts of about twenty people each.

  Although every aspect of a clinical trial is planned out with great care, the human factor can play havoc with any effort to even approach choreography. Trials use volunteers, and though carefully screened, volunteers can still be unpredictable. For example, one man came down with fever, chills, and joint and muscle pains, which could have been a reaction to the vaccine that would stop the trial. But ten days of intensive diagnostic efforts showed that it was instead Lyme disease. Low, medium, and high doses are administered, the high doses twice, and many things can go wrong. But two weeks later, Hoffman told me that “the headline is ‘no breakthroughs’”—in other words, no infections.

  But then Steve explained how, the day before they were to challenge the third group—“the day I’d been waiting for for seven years”—hegot a call from Tom Richie at NIH, who said, “We’ve got a problem.” All of the volunteers were fine but the Institutional Review Board had suspended the trial. . . . While no one had become sick or been harmed in any way, there were some issues around dosage that did not satisfy our standard of clinical practice, and so the trial was suspended. The IRB’s first responsibility is to the volunteers and we all get that. It didn’t matter that the vaccine worked or that no one got sick. The cost to us would potentially run to millions of dollars. This work is not for the faint of heart.

  When I asked Hoffman how typical it was that a mistake like this would happen, he explained that, “of the 1,000 things that could result in a vaccine trial being suspended, this is one that I would never have imagined or seen coming.”

  In early 2010 Hoffman tried again, but by May he had more disappointing news to share: “There’s a lot we don’t know about how the mosquito delivers the parasites when it bites. In any case, what we learned is that our dose was way too low, more than tenfold too low. But that’s what you do in a Phase I.”

  The results were illuminating, but a potential problem in terms of future funding: “We gave 80 volunteers one dose, 66 volunteers four doses, and 17 volunteers 6 doses,” Hoffman told me:There were no breakthrough infections. It was safe and well tolerated. And that in itself is incredibly important. We then challenged them with bites from five infected mosquitoes three weeks after their last dose. But when we challenged group 1 there was no protection. In group 2 there were 2 of 16 protected. Group 3 could not be challenged. In a fourth group there was no protection. . . . One explanation was that we were not using enough parasites. Our senior advisers said we should be happy because we had proved what a Phase I sets out to prove, which is that the vaccine is safe.

  Sanaria’s main funder, the PATH Malaria Vaccine Initiative, he explained, “said we hadn’t met their go-no go criteria and that, at least in the short run, there would be no more funds, despite the fact that more than $50 million had already been invested in this approach. . . . They wanted the clinical trials to show not only safety but effectiveness. So did I! But often that’s not how science works. That’s not what the first phase of clinical trials is for.”

  After all the years of preparing for that moment, all of the lab results, all of the papers, conferences, and collaborations, when it came to administering the vaccine Hoffman was left to make an educated guess. Trying intradermal and subcutaneous injections was a huge “maybe,” and when the trial results finally came back, nature had answered “maybe not.”

  “This trial was what I’d been waiting for and working toward for almost a decade,” Steve told me:I was devastated. It left me really morose—like stay-under-the-covers-and-read-trashy-novels-for-a-month morose. I thought, “I’m sixty-one, what the hell do I need this for? Maybe I should go practice family medicine in some small town in Idaho or Maine.” It’s what I used to do and I loved it, so I’d be okay with that. My dream of creating the vaccine that would eradicate malaria is over. I’m just another guy working in a lab somewhere trying to make a difference. And I’m okay with that too. That’s reality.

  After about two weeks, Hoffman finally pulled himself together and went to New York to see Ruth Nussenzweig. It was like journeying to Delphi to touch base with the oracle. “You know what she said?” he asked me. “She said, ‘So you’re no magician.’ And she’s right. I’m no magician. That’s life. Who was I to think that on the first try I’d have the vaccine? That it would be easy for me and for me alone. In my head, I knew that you can’t get that from Phase I. Still, I’d hoped.”
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  He also went to see Tony Fauci at NIH, who said, “You must keep going!” And then he got a call from his son Seth at Cornell, who said, “Dad, it would be totally immoral and unethical to stop now, no matter how disappointed you are.”

  “Look. Bed nets aren’t going to solve this problem,” Steve said to me. People were dying, including Americans. He cited a Stanford student who had been traveling in Ghana, an American traveling in India, and a Seabee (a member of the Construction Battalion, or CB) from the U.S. Navy, all of whom had contracted malaria in recent months and died. “If I see you on the first or second day that you’ve been infected I can cure you for sure,” Steve said. “The medicines work.” But there are many who do not receive treatment until it is too late, if at all. At this point Hoffman pulled out a recent Lancet editorial arguing that a vaccine is the only thing that has ever been effective in eliminating a disease.12

  Hoffman had raised $63 million and spent almost all of it. Current funds would keep him going for another twelve months. “So now I’ve got to make the case again that we’ve got a business plan and economics that make sense for investors. So I don’t have to keep begging for money only from foundations,” he said. “There is actually a multibilliondollar market for travelers and the military. And a vaccine can be a lot cheaper than taking Malerone (the current antimalarial of choice) for extended periods.”

  Some people are as energized by defeat as by victory. Their competitive juices flow stronger when they’ve picked themselves up off the mat than before they were knocked down. Depending on how long they were down and out, whether they crawled away or were carried, or walked off on their own power, they may be wiser as well. I could sense that Hoffman had bounced back, was undeterred, but I wasn’t prepared for what he said next: “So we’re going to go forward and do a trial in which the vaccine is administered intravenously. Probably in about four months if we can raise the millions we need. If you can draw blood from someone, as doctors do in offices around the world every day, you can immunize them through an IV inoculation. There is no difference. We’re going to prove that the vaccine works and we’re going to prove that people can be immunized with IV’s.”