The Imaginations of Unreasonable Men

by Bill Shore

  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.2 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.3

  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:For a vaccine like RTS,S, which delays but does not necessarily prevent infection or clinical malaria, time-to-event analysis is needed. Nevertheless, because we are not certain whether time-to-event or proportional analysis will ultimately predict the long-term effect of the vaccine and because of the complexities of assessing a partly protective vaccine, I believe that it would be helpful for the authors to state the results of both types of analyses in future publications.4

  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.

  A GATHERING OF MALARIA ROYALTY

  For the Sana
ria 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.”5

  To demonstrate the fragility of the chain of discovery, in which happenstance is everything, Ruth Nussenzweig told me how she had come to make her contribution. She had met Victor, her husband and collaborator, at the entrance exams for medical school in Brazil about sixty years ago. She was originally from Austria:Both my parents were physicians but we were chased from Vienna because we were Jews.

  My initial research was on Trypanosoma cruzi [a parasite that causes another neglected disease, known as Chagas’ disease for the doctor who discovered it in 1909]. We found that if we added gentian violet—a dye—to the blood, the cruzi was killed. This is my cruzi story.

  We came to the U.S., went back to Brazil and then returned here. They needed an immunoparasitologist in the Department of Preventive Medicine. I became an assistant professor, then associate, then full professor, and then the first woman chair of a department at the medical school, and for many years I was the only woman chair.

  I started to work on malaria in mice. For a long time it was just me and no one else. The dogma at the time was that malaria did not induce immunity, so that there could be no vaccine. This is not true. There is partial protection. People became less ill as they became older.

  When I asked her if anyone had tried this before, she said:As always, someone preceded me, it was years before, with bird malaria. Birds had been exposed to ultraviolet light. I tried irradiation. I played around with it. It needed a high degree of radiation. Intravenously with mice because you can do that with mice. You couldn’t miss the result. There were no parasites in the blood.

  Years later I immunized monkeys. There was a good deal of protection but not full protection. I was called to Walter Reed by Phil Russell.6 He asked: “How would you go about immunizing humans?”

  Then something funny happened. I couldn’t participate in the study on humans because they were done on volunteers in prison and women were not allowed in. So the study was published by a man, a colleague right here. I was naïve. I accepted this.

  Though it was other researchers who documented that the same concept would work with humans, it has always been Ruth Nussenzweig who was credited with proving that the irradiated parasites could act as an immunity-triggering vaccine. She and Steve Hoffman would see each other at conferences. In 2008 her life’s work was recognized with the award of the Albert B. Sabin Gold Medal for her pioneering efforts. Whichever of the many competing malaria vaccines eventually succeeds, it will owe its genesis to her.

  So it was symbolic and right that Dr. Nussenzweig should have guided the audience through a PowerPoint presentation of the vaccine’s history, offering an occasional touch of nostalgia when asking, “Steve, you remember this?” “They say you cannot do better than nature. Well, one can, and Steve is succeeding,” she said, almost echoing Jay Keasling’s words. When she was finished she was given the day’s only standing ovation.

  Steve Hoffman wore a dark suit and blue striped tie, and the relaxed glow of someone whose day had come at last. He served as host, master of ceremonies, audiovisual technician, speaker, and object of admiration and acclaim. He introduced Anthony Fauci as “the most respected physician scientist in the world,” and Fauci, winner of the Presidential Medal of Freedom for his work on HIV/AIDS, returned the compliment, acknowledging it as “an historic day” and explaining that he’d first met Steve in the late 1980s and had found him to be “a doer of the highest magnitude.” He recalled sitting next to him at a dinner when they agreed it would take a Manhattan Project approach to address malaria. He said Hoffman had “the insight, talent, energy and drive to take a vision and follow it.”

  For the past few years he and Hoffman had met every six months. Praising the vaccine for being built on a well-founded scientific concept, Fauci said that “the big hurdle to overcome is the technical challenges, whether it could be produced in sufficient quantities and meet regulatory hurdles.”

  When Regina Rabinovich of the Gates Foundation spoke after Fauci, she explained that the foundation had searched for the infectious diseases whose toll represented the greatest inequality and the greatest disparity. She shared the foundation’s introspection on the issues of “‘Are we being ambitious enough?’ ‘What do we want to achieve 20 to 30 years from now?’” and said, “The answer to those questions probably means having to develop different tools.”

  Jeff Sachs, director of the Earth Institute at Columbia University and advocate for the Millennium Development goals to fight poverty in the developing world, was complimentary of Hoffman but argued that “bed nets are the tool we have now” and said he couldn’t believe “how hard it is to get rich people to give a small amount of money for bed nets.” Kent Campbell, the program director for the PATH Malaria Control and Evaluation Partnership in Africa (MACEPA), made the po
int that it was possible to actually change the epidemiology of malaria by going rapidly instead of incrementally.

  Hoffman used his time at the podium to share the credit with his team, and to acknowledge the role of Ruth Nussenzweig and an early coauthor named Tom Luke, but principally to emphasize that what everyone had thought was impossible had instead turned out to be possible because of bioengineering and applied biology. Radiating infected mosquitoes weakens the parasite that resides in the mosquito’s salivary glands enough that the attenuated parasite will trigger natural immunity without actually making one sick. The challenge is in then dissecting the salivary glands and harvesting enough of the sporozoites to equal 1,000 bites of a mosquito, which is nature’s threshold for conferring immunity over time.

  He gave the vaccine battle plan’s time line, explaining that three days after it is in the liver the parasite is 3 to 5 microns in size, a micron being one-millionth of a meter. But if they have been irradiated, they stop growing, which advances the goal of ensuring that no parasite gets out of the liver and into the bloodstream.

  Aseptic mosquitoes go from eggs to larvae to pupae in nine days in a flask. By day fourteen they are ready to feed on infected blood. After feeding, they sit for sixteen more days before being irradiated, dissected, and put in a vile.