The Imaginations of Unreasonable Men (18 page)

Steve suggested we ride together to the building that would house the new lab. We got in his nine-year-old Jaguar to drive out to Rockville’s Biotech Corridor, just fifteen minutes away. On the highway, to my surprise, the car jolted and sputtered, and Steve visibly struggled to keep it moving, pumping the gas pedal, gripping the jerking steering wheel with both hands. It was not what I had expected from a polished and shiny Jaguar. It seemed just a matter of time before we would be stranded along the side of the road. But Steve never made mention of it. He kept up his monologue about a BBC film that had been made about malaria vaccines, as if I thereby might not notice, as if the only thing that could bring the vehicle to a halt was acknowledging its shortcomings. It was not a bad metaphor for Sanaria’s journey so far—an impressive-looking operation that seemed at times to be lurching from start to stutter to almost stop, with a driver who kept his eyes straight ahead, powered by confidence, faith, or the simple conviction that there was nowhere else he’d rather be going.

Sanaria would have several floors of the building that also housed a few other companies, but it seemed all but abandoned as we toured it. We never saw another human being. This space was previously a lab for another biotech company, and the lab benches and tables were still there, waiting to be torn out. It was at least ten times the space he’d had to work with hitherto, with room for eight dissectors. There were individual offices and large, enclosed areas for manufacturing, including the autoclave, which would sterilize equipment via high-pressured steam; the 14,000-pound
irradiation machine; and the insectary. The life sciences supply company Fisher Scientific would store the finished product. It was a professionally designed facility, equipped for the purpose: “The lawyers and advisers really didn’t want us making the vaccine at the other place,” Hoffman said. “They just didn’t think it would look right given the way that stuff was all thrown together.” He would later admit about Sanaria’s first facility: “We couldn’t control the temperature. We couldn’t control the air. We had floods. One time during one of those manufacturing campaigns it got to be 104 degrees outside and the air conditioner froze to the roof. So Bob Thompson, our director of operations, was up there with a blowtorch trying to unfreeze it.”

There was a rags-to-riches, born-in-a-log-cabin aspect to Steve’s experience that he seemed to have already concluded would be an important part of Sanaria’s legend. He relished the makeshift quality of Sanaria’s original lab, how little money they’d had when they’d started, the image of sitting at the kitchen table with his son, writing the business plan together. The vaccine and the storyline were both being developed by Hoffman, and in tandem.

They eventually moved into the new facility in August 2007. Steve planned to do some trial production runs after that to get the kinks out and start manufacturing in January 2008. Once the trials went well and the process was approved, Hoffman hoped to build an identical plant somewhere in Asia, probably India, and then a plant five times as large in Africa.

It was a breakneck pace, without a lot of time to spare. Nevertheless, Steve expected to keep Sanaria in the limelight as well. He had agreed to speak at a forum at Harvard’s School of Public Health that would also include Jay Keasling and a representative from GlaxoSmithKline to talk about RTS,S. Steve also wanted to take a team of six from Sanaria to London for another such forum in September, this one hosted by the Royal Society of Medicine. I asked him how much he told audiences like that about how Sanaria managed to do what it did. “I don’t tell them anything,” Steve said. “I simply explain the results that we are getting.”

The tests in Africa were to be in Ghana and Mozambique. Steve had worked in Ghana before, and both countries had established vaccination sites. “In fact,” he said, “Pedro Alonso, who is a friend, told me that he will do the trial, because even though he is doing RTS,S, he is not convinced it is going to be as effective in the long term as Sanaria’s. The RTS,S folks wrote a paper whose purpose was to communicate that our strategy wouldn’t work. Imagine doing that. I really don’t think of myself as competitive. As a scientist you want to see something work even if it is something developed by someone else. I mean you always have delusions of grandeur and you’d like it to be yours, but . . . ” He left the sentence unfinished, and began again: “Ours is the only vaccine whose purpose is to prevent infection. The other vaccines slow the spread of infection in the body.”

Hoffman had been thinking, too, about how this vaccine would actually get into the arms of African children if
it made it through clinical trials. He was envisaging a distribution system that would bring business to Africa. And instead of relying on some government program or nongovernmental organization, he would create it himself: “Usually something like that is done through the World Health Organization, but I think by using liquid nitrogen, we can keep the vaccine potent for at least two months and have a roundhouse operation that sends it out. It could create jobs.” Like so many other aspects of Hoffman’s venture, this had never been done before.

I asked Hoffman about a new report that Marcelo Jacobs-Lorena and his colleagues had just published about the creation of genetically modified mosquitoes that could not pass on malaria. The strategy would mean releasing thousands of genetically modified malaria-resistant mosquitoes into the wild on the conviction that they would breed and become dominant, and therefore no longer transmit the parasite. The report had received front-page coverage in
The Guardian
.
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Hoffman was skeptical. “The concept is such a stretch,” he said. “But the media takes it and reprints it at face value without asking any questions. I’ll tell you what is going on there. Donors put $200 million into the Hopkins School of Public Health and another $100 million into malaria there. So they have to have something to show them.” He concedes that “Marcelo is a lovely guy.” But he explained that “they are creating transgenic mosquitoes to have fewer parasites. I’m doing just the opposite. I’m creating transgenic mosquitoes to have more. Initially they
came to us to get their parasites. We were growing them and they weren’t.”

I asked if he planned on writing any more papers. “I haven’t written a paper since 2002,” he responded, “and I’d written 350 in the ten years before that. But it’s not necessary now to get the money.”

Steve was still competitive, but he was no longer feeling unappreciated. There was more of a bounce in his step, and less of a grudge in his voice. The grants were enabling him to pursue his dream, and they were also a form of validation. Like an athlete who had never lost confidence in his own abilities, but still celebrated when signed by a major league team, Hoffman was now inside the clubhouse. He was being invited to speak at international conferences, and he was being listened to. It was a very different time from the days when Diane Griffin, the head of the Johns Hopkins Malaria Research Institute, had giggled about “that crazy thing Steve Hoffman is doing.”

The feasibility of Hoffman’s vaccine hinged on being able to obtain sufficient quantities of sporozoites from a process once thought to be so tedious, laborious, and fraught with technical complications as to be entirely unrealistic. Insects taken from the field have a few thousand sporozoites. Labs that raise mosquitoes from eggs to larvae to pupae to adults and feed them on parasite-infected blood get about 15,000 to 20,000 sporozoites per mosquito. Hoffman had figured out how to get more than 70,000 or even 80,000. His vaccine was the end product of a rigorous set of proprietary
processes and procedures specifically designed to overcome those challenges.

Hoffman had recently returned from a Keystone Symposium in Alpbach, Austria, where he’d given the opening address to a three-day conference on all aspects of malaria, including vaccine development. On the way, he’d stopped in Geneva to make the case to the World Health Organization about recommending a standard for measuring the effectiveness of vaccines. GlaxoSmithKline was using a “time to event” analysis rather than a proportional analysis for measuring the efficacy of RTS,S. What they were really measuring was how long their vaccine delayed vaccinated participants from getting malaria, not the degree to which it prevented infection. One of Hoffman’s issues with RTS,S had always been how the results of the clinical trials were reported.

Many public health officials preferred the proportional analysis, which was based on the proportion of vaccinated participants versus “control” participants who did not become infected with the disease during a specifically defined period. So, for example, in the children in Mozambique from ages one to four, RTS,S reported vaccine efficacy was 45 percent for delaying a first infection over the first six months. With the proportional analysis approach for the same data, the vaccine efficacy against acquiring an infection by age six months was 11 percent.
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This was a critical issue in Hoffman’s David and Goliath competition with GlaxoSmithKline, which hopes to manufacture RTS,S as the world’s first commercial malaria vaccine.
Steve recounted for me the flaws in the process with an air of exasperation fueled by moral outrage, and, despite his assertion to the contrary, a fierce competitive nature. “Pedro Alonso is very charming and articulate and a wonderful guy, and when he talks about the results of their trials everyone nods and goes along. But anyone who really knows anything about vaccines knows that RTS,S is not preventing malaria.”

Judith Epstein, a commander in the navy’s vaccine research division who would eventually be responsible for conducting the clinical trials of the Sanaria vaccine, had written an article in
The Lancet
critical of Alonso’s methodology. It was pointedly entitled, “What Will a Partly Protective Malaria Vaccine Mean to the Mothers in Africa?” In it she concluded:

What Epstein seemed to be saying was that a vaccine that delayed infection but didn’t prevent it would be good, but it would not be good enough.

For the Sanaria ribbon-cutting ceremony on October 26, 2007, a large meeting room was packed with several hundred people. They represented the wide diversity of interests and opinions that have always existed, sometimes divisively so, when it comes to solving the plague of malaria. There were American scientists and European doctors, African diplomats and U.S. military personnel, the latter in dress uniforms bedecked with medals and ribbons. Some were advocates of vaccines. Others had devoted careers to bed nets, insecticides, antimalarial drugs, or the creation of public health infrastructures. Not even the vaccine advocates were all convinced that Hoffman’s vaccine was the way to go.

It was politically astute of Hoffman to showcase icons from previous eras and to place his own work in the context of all the other efforts, as if to soften the break that his effort represented with what had come before. By subtly but visibly putting Sanaria on a continuum, he took the edge off of just how audacious his idea was—without diluting the audacity itself.

The attendance of some amounted to a hedging of bets. Past the midpoint of careers that careened between glimpses of glory and repeated near misses, and after decades of experiments, trials, travel, hearings, field clinics, and late-night edits of papers for scientific journals, who could take the chance of not being in the room when something as potentially
historic as the first lab and strategic plan for manufacturing a live, attenuated malaria vaccine was unveiled, even if suspecting the odds of ultimate success were slim? Tropical medicine in general, and vaccine development in particular, made gamblers of doctors, researchers, and grantmakers.

The day’s agenda included the obligatory elected officials, from U.S. Senator Benjamin Cardin down to the local congressman and county executive. Their interest in Sanaria seemed more parochially confined to the impact of its growth on Montgomery County’s employment statistics, and to making sure their constituents knew of their role in securing the initial Small Business Innovation and Research grants that started Sanaria on its way.

But the malaria community’s royalty was also attendant. Dr. Regina Rabinovich from the Gates Foundation represented the crown. At the lunch break, suitors circled around her, hoping for a brief audience. The princes included Dr. Anthony Fauci, the director of the Institute of Allergies and Infectious Diseases at the National Institutes of Health (NIH); Dr. Christian Loucq from the PATH Malaria Vaccine Initiative; and Dr. Louis Miller, the chief of the Malaria Vaccine Development Branch of NIH, who began working on malaria in 1965, eight presidential administrations ago.

If there was a queen mum it was Ruth Nussenzweig, who back in 1967 first demonstrated the effectiveness in mice of the vaccine that Hoffman has overcome technical challenges to manufacture. Stooped by age, their hair gray, and holding hands, Ruth and Victor Nussenzweig wore name
tags that were unnecessary for all but a handful in attendance. I asked her if she had ever anticipated this day would come. “Never,” she said quietly but emphatically, in her Austrian accent. “I never did.” Throughout the remainder of the day, virtually every speaker made a point of paying homage to her work, “not so much for anything she’s done lately,” as science writer Merrill Goozner later put it in his blog, “but for having carried the torch through the long, dark night.”
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