Studying the data from his office at Celera, Hoffman got to thinking: What if he was staring at the malaria vaccine that had eluded him for 20 years?
That March, he traveled to Keystone, Colorado, to attend a scientific conference that attracts the world’s most esteemed malaria researchers. One afternoon, he hosted a discussion on malaria-vaccine development titled “Why Is It Taking So Long?”
Standing at the podium, Hoffman asked the roomful of scientists to predict how many years it would be before an effective malaria vaccine reached the market. His heart sank as estimates stretched nearly a quarter century into the future.
Next, he presented the results of his irradiated-mosquito experiments. “What should we do now?” he asked.
“Let’s use this as a model to make a better subunit vaccine,” a researcher suggested.
“We started doing that ten years ago and we haven’t gotten very far,” Hoffman said. “What about making this into a vaccine?”
The room fell silent.
Then, one by one, scientists stepped forward to dismiss the idea. “People thought, ‘Oh, this can’t work,’ ” says Carole Long, an NIH malaria researcher who helped organize the event.
No one disputed that irradiated parasites offered protection against malaria. But getting those parasites out of the salivary glands of a dirty, bacteria-laden mosquito and into a vaccine that would be pure enough to meet Food and Drug Administration standards? And even if you could get some, how could you ever produce enough for a disease that affects more than 200 million people a year?
“The idea was so outlandish—it was like something from outer space—that no one had ever bothered to see if it was possible,” says Christopher Plowe, a malaria researcher at the University of Maryland.
Hoffman was stunned by how resoundingly the leading thinkers rejected his idea. He didn’t see any promising vaccines on the horizon. And besides, scientists have used similar tactics—weakening but not killing an infectious agent—to develop vaccines against diseases from polio to yellow fever.
When Hoffman returned to Rockville, Tom Luke, a low-ranking Navy doctor who had helped him write his irradiated-parasite paper, urged him to give it a shot. “You do realize this is your vaccine?” Luke once told Hoffman.
In August 2002, Hoffman resigned his high-paying position at Celera and set out to make an impossible vaccine. Says Hoffman: “I just came to the conclusion that somebody had to try this.”
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The work began at his house in Gaithersburg. His eldest son, Alexander, had recently moved back home after some post-college surfing in Hawaii, and the two began knocking around ideas.
The first step was to secure funding. Each morning, he and Alexander convened at the kitchen table to fill out grant applications.
The new venture needed a name. The word “malaria” comes from the Italian mal’aria, or “bad air”; the Romans believed that malarial fevers resulted from breathing the noxious vapors that rose from swamps. Hoffman called his company Sanaria, meaning “healthy air.”
Good news came in July 2003 when NIH approved a $500,000 grant, allowing Sanaria to move out of Hoffman’s kitchen into 750 square feet of converted retail space in a Rockville strip mall, next to a carpet wholesaler and a framing store. Dirt clouded the windows. “It was a dump,” says Bob Thompson, an early member of Sanaria’s team.
The space appeared so unfit for scientific research that Hoffman refused to interview prospective employees there. Instead, he met job candidates in the offices of the biotech company where his wife, Kim Lee Sim, was a molecular biologist.
“We’d say, ‘Well, our facility is down in Rockville and we are still working on getting it ready,’ ” Thompson says.
The team stocked the space with used and discarded scientific equipment. Thompson’s buddies he’d worked with at Celera gave him a deal on outdated computers and lab supplies. “I paid them $2,000, and they let me pull up in a truck and fill it,” Thompson says.
Understaffed and poorly financed, Sanaria began the painstaking effort of creating the vaccine. “You’re starting with a product that you know works—you just have to refine it and figure out how to mimic the bite of a thousand mosquitoes in a shot or a series of shots,” Alexander says. “It was an engineering problem, not a science problem.”
Their initial challenge was to breed sterile mosquitoes—free of the fungi and bacteria in which the creatures naturally reproduce. Sanaria’s researchers raised the insects in test tubes, feeding them a diet of aseptic nutrients. At first, the mosquitoes all died. Then some hatched with no wings. “We didn’t know anything,” Hoffman says. “It was like every single small step we had to solve.”
With each setback, their understanding improved. Before long, Sanaria was breeding thousands of mosquitoes a week, each perfectly sterile. The insects consumed blood that had been infected with malaria parasites. Hoffman bought a 14,000-pound gamma irradiator. (“We had to close down Rockville Pike to have it put in,” he says.) Lab technicians learned how to extract the tiny parasites out of mosquitoes’ salivary glands. Hoffman’s wife and her team discovered how to purify the parasites once they’d been removed. And a cryopreservation expert developed a way to keep the parasites alive while they were stored in vials. By 2006, the vaccine was nearly ready.
Inside the company, pressure ran high. Hoffman drove the staff to meet tight deadlines. Employees worried that Sanaria’s facilities—which now housed a gamma irradiator and millions of deadly, malaria-infected mosquitoes—might break down at any moment. Blackouts occurred regularly. Thompson once had to climb onto the roof with a blowtorch to defrost the air conditioner. “I had terrible, terrible dreams all the time about mosquitoes getting loose,” says Adam Richman, an early employee.
Meanwhile, the malaria-research establishment believed Hoffman had gone off the deep end. Tom Luke remembers sitting in the audience at a scientific conference when Hoffman took the stage to describe Sanaria’s work. As he spoke, top malaria researchers snickered: This will never work.
Hoffman found himself waking in the middle of the night, his thoughts racing. How can I scale up manufacturing without a bigger facility? What if we under-radiated the parasites? And his most urgent concern: How am I going to make payroll next month?
Hoffman was on vacation in Alaska when he finalized the negotiation with the Bill & Melinda Gates Foundation for a $29-million grant to Sanaria. Hoffman was ecstatic. Since 2005, the foundation has poured nearly $2 billion into malaria research, making it one of the field’s most influential funders. The grant did more than provide needed cash; it brought credibility to Hoffman’s endeavor.
At the foundation’s Malaria Forum in 2007, Hoffman spent nearly an hour discussing his irradiated parasites with Bill and Melinda Gates. Later that fall, Sanaria finished building a state-of-the-art manufacturing facility in Rockville.
Flattering accounts of Hoffman’s work appeared in the New York Times, Esquire, and National Geographic. But Sanaria still had to prove the vaccine worked. In the spring of 2009, the FDA allowed Sanaria to move further with testing the vaccine in human trials.