Dr. Hoffman vs. the Mosquito
A Rockville scientist has spent 30 years struggling to eradicate malaria, the deadly insect-borne disease that has outwitted generations of medical researchers. Experts have long called his vaccine a fantasy. Now he has one last chance to prove himself.
In the summer of 2012, Dr. Stephen Hoffman did everything he could to keep his mind off the experiment. He took a vacation to Malaysia with his wife and three children. He worked out for 45 minutes a day. And each morning, he walked into his Rockville office, sat down at his desk, and pretended it didn’t matter what the results of the study would look like. But as the calendar flipped to October, he found it impossible to think about anything else.
One year earlier, researchers had begun injecting Hoffman’s experimental malaria vaccine into healthy volunteers. Any day now, the National Institutes of Health might call with the results.
In years past, when the critics or the failure or the anxiety became too much, Hoffman found himself lying awake at 2 AM, his mind spinning with panic. He’d made a lot more money before he began chasing this vaccine a decade earlier, and nobody ever called him a crackpot. He had a wonderful family and all the honors a scientist could hope for. He never had to worry about a blackout at his laboratory or a grant that might not get approved or his life’s work being measured by one last experiment.
“I have said, ‘Why do I need this?’ ” Hoffman says. “And the answer is that this is a gift and a treasure to have the opportunity of making this kind of impact against the kind of odds that were presented to me. It’s an extraordinary opportunity in life. How many people get that chance?”
Now, as he waited to find out—once and for all—whether his vaccine worked, Hoffman felt the pressure of a basketball player in a playoff game. “It’s double overtime,” he says. “And you’ve got to make the last shot.”
It’s been more than 30 years since Hoffman set out to rid the world of malaria—the mosquito-borne, parasitic disease that has outwitted every scientist before him. He couldn’t have chosen a more ruthless adversary. Malarial fevers have ravaged humankind for half a million years. There’s evidence that the disease killed Alexander the Great, helped unravel the Roman Empire, and repulsed the army of Genghis Khan. Malaria parasites infected George Washington and led to a million Union casualties in the Civil War. The Centers for Disease Control and Prevention was established specifically to fight the epidemic. Even today, malaria afflicts nearly 220 million people a year—predominantly African children—and kills more than 650,000.
“It’s probably the greatest single source of human tragedy in the history of our species,” says Dr. Thomas Richie, research coordinator of the US Military Malaria Vaccine Program.
Hoffman’s quest to annihilate the parasite has come at his own peril. He has trudged through Indonesian swamps and watched children with malaria die in his arms. He has injected experimental vaccines into his body and survived a plane crash during a research trip to Kenya. He once let more than 3,000 malaria-infected mosquitoes feast on his arm.
But Hoffman’s biggest gamble came in 2002 when he quit his high-paying job to develop the malaria vaccine that everyone else considered impossible. Launching the effort from his kitchen table, Hoffman became the laughingstock of the malaria-science establishment.
“Even calling it a vaccine is a compliment,” Dr. Pierre Druilhe, a malaria expert, told the New York Times. “It has no chance of offering protection. It is like Captain Ahab in the movie trying to kill Moby Dick with his knife.”
The NIH trial in 2012 was Hoffman’s last chance to prove that he just might have found the way to eradicate the world’s most elusive killer once and for all.
• • •
The call came in around midnight. It was serious: A four-year-old girl with malaria was slipping away, fast. Hoffman jumped out of bed and raced through the tropical humidity to the single-story hospital. Inside, he found the girl alive but unresponsive; her body was cold and clammy.
It was 1984, four years after Hoffman arrived in Indonesia as a young US Navy doctor ready to save the world. Since that time, he had seen malaria snatch too many children from the lowland rainforests and beaches that surrounded him. He wasn’t about to let another one go.
As with all malaria victims, the girl’s crisis began with a tiny bug bite. When a malaria-infected mosquito pierces human skin, it shoots a handful of microscopic parasites into the bloodstream. The parasites squirm into the liver, where they quietly multiply. About a week later, a violent mob of 3 million parasites explodes back into the bloodstream, savaging red blood cells and overwhelming the immune system. The incursion triggers fevers, headaches, chills, and fatigue. In severe cases—like the young Indonesian girl’s—the disease chokes off blood flow to the brain, causing coma or death.
When Hoffman and a colleague examined the girl, they found that her blood sugar was dangerously low—a malaria-related complication that can send patients into shock. The doctors injected her with a large dose of sugar solution. Almost immediately, the girl’s condition improved; her blood pressure increased, her body warmed, and she returned to consciousness.
Walking out of the hospital, Hoffman felt like a hero. If we hadn’t been here, he thought, that girl would have died.
Hours later, he received another phone call. The girl was dead.
“We had the hubris to think that somehow we were doing something great and congratulating ourselves,” Hoffman says. “And now, three hours later, you get a wake-up call—which is truly a wake-up call—which is that you thought you were good, but this disease is tougher than you are.”
Hoffman had come to Indonesia to save patients like this young girl. During a yearlong break from Cornell University Medical College, he had traveled to Ecuador and contracted typhoid fever. For ten days he roasted in a South American hospital. The experience crystallized his commitment to fight the tropical diseases—such as dengue fever and malaria—that devastate poor communities in Latin America, Asia, and Africa.
The Navy had one of the world’s leading tropical-medicine programs. US soldiers have been battling malaria for as long as they’ve deployed to the rain-soaked regions where the parasite thrives. The parasite caused more lost person-days for Americans than bullets in 20th-century military campaigns in malaria-endemic regions. As a result, the Department of Defense has plowed hundreds of millions of dollars into the effort to protect US servicemembers from it.
In 1980, Hoffman had clipped his ponytail, pressed his new Navy whites, and arrived at his post in Indonesia. But after nearly five years of watching children die of malaria, he decided to return to the United States to search for a way to defeat it.
Hoffman reported to the Naval Medical Research Institute in Bethesda in 1984. By then, scientists believed they had finally outsmarted malaria. Researchers had identified and cloned the gene in the parasite that triggers an immune response in humans. The head of the US Agency for International Development predicted it would take just five years to convert this breakthrough into a vaccine. MALARIA VACCINE IS NEAR, U.S. HEALTH OFFICIALS SAY, a 1984 New York Times headline proclaimed.
Scientists from the Army and SmithKline Beckman—a predecessor of pharmaceutical giant GlaxoSmithKline—scrambled to develop the vaccine. Hoffman joined the team as a collaborator. (There are five different species of malaria-causing parasites. Nearly all experimental vaccines target the most deadly, Plasmodium falciparum.)
It was a thrilling time; he flew to meetings in choppers and was whisked off the tarmac in limousines. By 1986, it was ready—malaria’s first-ever “subunit” vaccine, so named because it used portions of the parasites’ proteins to stimulate protection. “We all felt like we were in the midst of history,” Hoffman says.
Scientists have never created an effective vaccine against a parasite. The great triumphs of 20th-century vaccinology—vaccines for polio, smallpox, measles, and mumps—all came over viruses.
Parasites are far more complex. The malaria parasite consists of 5,300 different genes; HIV has nine. Meanwhile, malaria parasites repeatedly change form during their multistage life cycles. “It’s like someone who comes into a Halloween party and changes their costume every couple of minutes,” says Captain Judith Epstein of the Naval Medical Research Center.
Market forces have also undercut attempts to develop a vaccine. Malaria has been all but wiped out in most Western countries since the 1950s, in part through the widespread use of DDT, and wealthy travelers have access to prophylactic drugs that aren’t always affordable to those living in malaria-endemic regions. Because victims are clustered in impoverished corners of the world, pharmaceutical companies see little financial incentive to invest in malaria research.
Hoffman was so excited about the subunit vaccine that he agreed to test it on himself. The best way to evaluate a malaria vaccine is to give it to a volunteer and then infect that person with malaria parasites. If the volunteer doesn’t develop malaria, the vaccine works.
One year after he was injected with the subunit vaccine, Hoffman walked into the Walter Reed Army Institute of Research. He was handed a one-pint, cylindrical container with a mesh screen stretched across its top. Inside, five malaria-infected mosquitoes circled.
Hoffman rolled up his sleeve and pressed the container—mesh side down—to the inside of his forearm. He felt a tickling sensation as the mosquitoes pricked his skin. Five minutes later, he removed the canister; an Army scientist examined the mosquitoes to confirm that each had sucked Hoffman’s blood. Five other volunteers did the same.
For the next several days, Hoffman and the other volunteers bit their nails and hoped the vaccine would keep them healthy. (Those who come down with the disease are given drugs to kill the parasites.) By day ten, three volunteers were sick, but Hoffman and two others felt fine. Excitement began to swell; no injected malaria vaccine had come close to 50-percent protection—and this was its very first trial. “We thought we were going to win the Nobel Prize,” Hoffman says.
He flew to San Diego that week for a scientific meeting. During his speech, he felt a wave of chills rush through him. By dinnertime, his temperature had spiked to 104 degrees and his body shook uncontrollably. A doctor examined his blood under a microscope: malaria.
The subunit vaccine had protected just one of the six volunteers.
• • •
In 1987, Hoffman became director of the Navy’s malaria-research program. His assignment: to develop a vaccine for military personnel that protected at least 80 percent of its users for at least six months.
He initially focused on making a better subunit vaccine. But after years of frustration, he concluded that a vaccine based only on one or two proteins would never provide sufficient protection. Unsure how else to proceed, he revisited the landmark studies in malaria research.
Back in the late 1960s, scientists at New York University began zapping malaria-infected mosquitoes with gamma radiation. They found that when these irradiated mosquitoes bit mice, they conferred malaria protection without causing the disease. Six years later, University of Mary-land researchers demonstrated that this same approach worked in humans. Ninety percent of volunteers who were bitten by at least 1,000 irradiated, malaria-infected mosquitoes received protection from the disease.
The process works by weakening—but not killing—the malaria parasites. Once injected into the bloodstream by mosquitoes, the irradiated parasites swim to the liver, where they induce a powerful immune response.
There was no way Hoffman was going to ask US Marines to line up for a thousand mosquito bites each. But he decided to repeat the irradiated-mosquito experiments to understand the science better.
Once again, Hoffman signed himself up for the study. In the mid 1990s, he returned to the Walter Reed Army Institute of Research to stick another pint-size container of insects against his arm. This time, the cylinder swarmed with hundreds of malaria-infected mosquitoes, each having been buzzed with a dose of radiation. The bloodthirsty insects left a circle of swollen red skin on his arm, but Hoffman didn’t stop until he had been bitten by 3,000 mosquitoes.
Weeks later, when he was infected with malaria, he didn’t get sick.
• • •
As his career progressed, Hoffman earned his place alongside the field’s top researchers. He spearheaded the effort to sequence the most dangerous malaria parasite’s genome, conducted groundbreaking studies on experimental DNA vaccines, and published nearly 400 scientific papers. He was elected to the Institute of Medicine of the National Academies—one of the highest honors a scientist can receive.
Hoffman retired from the Navy in 2001 and became a top executive at Celera Genomics, the Rockville biotech dynamo that stunned the world in 2000 when it sequenced the entire human genome.
Although he spent his days working on cancer vaccines, there was one project from his time in the military he still needed to finish. Before leaving the Navy, he had assigned his staff to help him write a scientific paper on the irradiated-parasite experiments he conducted in the 1990s. The task took longer than expected, but by 2002 it was nearly complete.
Thirteen of the 14 volunteers who had been bitten with irradiated, malaria-infected mosquitoes were protected from the disease. What’s more, the protection was long-lasting and effective against multiple strains of malaria. No other vaccine had ever come close to those results.
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.”
• • •
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.
In July 2010, Hoffman was in his office at Sanaria, preparing to leave for the day, when he received a frantic phone call about his second-eldest son. “He’s hurt, and it’s bad,” his son’s friend said.
During his summer break from college, Hoffman’s son—who he asked not be identified by name—had traveled to Indonesia for a tropical-medicine program. As he walked to the beach that morning, a motorcycle zipped past. The next thing he knew, he was on the ground with blood spurting from his skull. It’s unclear exactly what happened; Hoffman believes the motorcycle driver may have struck his son in the head with a pole.
At the emergency room, Hoffman’s son showed signs of traumatic brain injury; he was transferred to an Indonesian hospital for neurosurgery. Hoffman and his wife immediately flew to Singapore, where their son had been sent to recover from the operation. The family returned to Gaithersburg a week later. But before his son could undergo facial-reconstruction surgery, Hoffman had to drive to Bethesda for the most important meeting of his life.
Still trembling from his son’s accident, Hoffman walked into the conference room of a Bethesda hotel. There he greeted a delegation from the PATH Malaria Vaccine Initiative, the nonprofit that administered the Gates Foundation’s $29-million grant to Sanaria. PATH had called the meeting to review the data from Sanaria’s vaccine trials and determine whether its approach merited additional funding.
The trial results fell far short of expectations; Sanaria’s vaccine protected just 5 of 80 volunteers. Throughout two days of discussions, Hoffman pleaded with PATH officials to continue their support for one more trial. But PATH executives insisted that Sanaria’s vaccine hadn’t hit the thresholds to warrant another infusion of Gates Foundation money. “We set up clear go/no-go standards,” PATH director Dr. David Kaslow says. “And the ‘go’ criteria weren’t met.”
The news crushed Sanaria’s staff; even some of Hoffman’s most loyal lieutenants wavered. Says Bob Thompson: “It was kind of like, ‘Well, sometimes a great idea doesn’t quite make it because of circumstances beyond its control.’ ”
For Hoffman, the days after the PATH meeting were among the darkest since he’d begun hunting the parasite more than 30 years earlier. “Your life’s dream just went down the tubes and your son is in between two surgeries,” he says.
But despite the heartache, Hoffman refused to give up on his irradiated parasites. He believed he knew what had gone wrong in the trial.
Years earlier, NIH researchers had used monkeys to evaluate the different ways of administering Sanaria’s vaccine. Some of the monkeys received the vaccine as an injection through their skin, as you might get a flu shot. Others took the injection directly into a vein. “The way you give the vaccine had a dramatic difference,” says Dr. Robert Seder, the NIH scientist who led the studies. “If you gave it through the skin, it really didn’t work, but if you gave it intravenously—through the vein—it worked much better.”
However, Hoffman’s team didn’t have the results of that study when they designed their trial, so they injected the vaccine through volunteers’ skin. After reviewing the NIH experiments, Hoffman became convinced that the irradiated parasites would be protective if delivered intravenously.
Hoffman rallied his staff with plans for a new trial. “I knew that if I gave the right dose of these parasites in the right way, we would get protection,” Hoffman says. “The question is: How many chances do you get to do this?”
Pressure mounted further in October 2011 as GlaxoSmithKline announced that its subunit vaccine candidate—known as RTS,S—protected almost 50 percent of the African children who received it, a level well short of the 90-percent protection that vaccines must achieve but significantly higher than Sanaria had demonstrated.
Hoffman approached Dr. Anthony Fauci, director of NIH’s National Institute of Allergy and Infectious Diseases, about funding the trial.
“Rather than be the naysayer saying, ‘It’s not going to work,’ I’m saying, ‘Well, it isn’t as if you’ve got a lot of other candidates out there that really, really look good,’ ” Fauci says.
In the fall of 2011, NIH began recruiting volunteers for the trial.
• • •
The countdown began in October 2012, when the final set of 15 volunteers was exposed to malaria-infected mosquitoes. Twenty-three previous volunteers had already come down with the disease, but this group had received a higher dose of the vaccine. Officially, this final phase lasted 28 days, but malaria symptoms typically materialize 7 to 11 days after infection. Anytime during that period, an NIH researcher could call to inform Hoffman that the rest of his volunteers were sick and his dream was over. No news was good news.
Hoffman began holding his breath on day 7. By day 12, he fought a flicker of excitement. Every day that passed without word from NIH, his elation became harder to contain.
Three weeks into the final test, Hoffman was walking to a meeting in downtown DC with Sanaria staffers. Right then it hit him. He grabbed a colleague in a bear hug and together the two jumped up and down.
“It’s day 21!”
“It’s day 21!”
When he got the official word from NIH, Hoffman called an all-staff meeting in Sanaria’s conference room. Everyone, down to the janitor, stood silent with anticipation. Then Hoffman told them: Six out of six volunteers who’d received five doses of vaccine were protected, as were six out of nine volunteers who’d received four doses. The room burst into hoots and cheers.
The results became public on August 8, when they were published in the journal Science. “The trial results constitute the most important advance in malaria vaccine development since the first demonstration of protection with [irradiated parasite] immunization by mosquito bite in the ’70s,” Stefan Kappe, a malaria researcher at the Seattle Biomedical Research Institute, told Nature.com.
Although Hoffman believes his vaccine will reach the market within four years, many in the malaria community are unconvinced. He must first reproduce his results in larger studies while demonstrating that the vaccine can provide long-lasting protection against various malaria strains. Sanaria has several trials slated to begin next year.
But it’s the logistical hurdles that critics consider insurmountable. No vaccine has ever been administered through intravenous injection, a clumsy means of delivery compared with the oral or skin-injected vaccines typically deployed in mass campaigns. And many argue that malaria-endemic regions aren’t equipped to store Sanaria’s vaccine, which must be cryopreserved. “I think [the current challenges] are more daunting than what he has already faced,” NIH’s Carole Long says.
Ten years after Hoffman set out to make an impossible vaccine, he must now return to the lab and figure out how he can deliver it to the hundreds of millions of people who need it.
The skeptics don’t think he can do it.
This article appears in the October 2013 issue of The Washingtonian.