Getting malaria on purpose

Volunteers roll up their sleeves and get infected to test an experimental drug
Photo of Molly Perry and Dr. Jim Kublin
Volunteer Molly Perry receives an injection of sporozoites — the infectious form of the malaria parasite — from Dr. Jim Kublin at the Fred Hutch-based Seattle Malaria Clinical Trials Center. Photo by Robert Hood

Molly Perry volunteered to be infected with malaria because of her mother.

All her life, she’s watched her mom deal — valiantly — with the after-effects of another infectious disease: polio. Contracted in utero in the early 1950s, it left her with one leg shorter and weaker than the other.

Her mother’s experience bequeathed Perry, 29, with a compassionate heart and a passion for healthcare that goes beyond her work as a nuclear medicine technologist. It led her to join an early-phase clinical trial testing an experimental drug that could one day be used to prevent or treat malaria. Last Thursday, she pushed up her sleeve and received an injection of sporozoites — the infectious form of the malaria parasite ordinarily introduced into human blood by a mosquito’s bite.

“I am a huge proponent of vaccines and preventive medicine,” Perry said. “This was an opportunity to be involved in something that’s a good cause. I feel like I’m doing something rather than just saying ‘I support that.’”

Curtis Parker, 30, also was motivated to support something. But in his case, it was his music. Trial participants are compensated for their considerable time investment over the 24 days of the trial. The money he stands to earn will pay for two days in the recording studio for his metal band, Witch Ripper.

Someone at the restaurant where he tends bar had participated in an earlier malaria drug trial and deemed the experience “fine,” so Parker signed up.

“Me and the other people at the bar are all broke musicians and were seeing dollar signs,” he said as a physician searched his tattooed arm for a vein. “I thought, ‘I’d subject my body to that.’”

First, safety

Perry, Parker, and six other healthy adults ranging in age from 20 to 37 are taking part in a new study conducted by the Seattle Malaria Clinical Trials Center, or MCTC, run by Fred Hutchinson Cancer Research Center and the Center for Infectious Disease Research.

Participants take either the experimental drug or a placebo, and ­neither the volunteers nor the researchers will know who took which until the trial is “unblinded” at the end of the study. ­Volunteers are then “challenged,” as the practice is called, using a strain of malaria that responds to conventional treatment and that is easy to diagnose.

Already screened and tested before being accepted for the trial, participants report each day to the Fred Hutch-based MCTC over the next two weeks for blood and other tests. (They’ve all submitted at least two back-up contacts in case they don’t report as expected.) A molecular diagnostics technique developed by a Seattle MCTC researcher will detect infections before volunteers feel symptoms. Anyone infected will be promptly treated before ever feeling sick.

To be clear, there is no risk that the volunteers can infect anyone else. Malaria is not spread through contact with infected people but through the bite of an infectious mosquito. The species of Anopheles mosquito needed to transmit the parasite isn’t found in Seattle. Besides, volunteers who become infected will be treated well before the parasite’s complex life-and-transmission cycle plays out. As an extra precaution, even those who don’t show signs of infection will be treated at the trial’s end.

Still, it’s not everyone who would volunteer to get a jab of malaria. Today marks the first day that any infections will be detectable. It also, coincidentally, is World Malaria Day — a reminder of why it matters that people participate in clinical trials like this one.

Zika makes headlines, but malaria still kills

Today’s headlines focus on the Aedes mosquito-borne Zika virus, which began roaring through Brazil last year and has been linked to severe birth defects. Malaria may be old news, but researchers who have been in the trenches for decades know the toll it still takes.

Fred Hutch’s Dr. Jim Kublin, the MCTC’s medical director, is one of them.

“As terrible and disruptive as Zika is to public health, the morbidity and mortality associated with malaria is much more severe,” he said of the disease that kills more than 400,000 people a year, most of them young children in sub-Saharan Africa, and sickens 214 million.

In the last decade, new therapies and a push to distribute insecticide-treated bed nets have more than halved the number of malaria deaths, down from 1 million.  But these gains are threatened by the twin challenges of climate change, which is expanding the Anopheles mosquito’s range, and drug resistance. It is the latter that the MCTC trial is seeking to address.

“Resistance remains a global issue, one we’ve barely been able to stay ahead of for the last 40 years,” Kublin said. “Having new drugs is a top priority.”

 Jonathan Jackson and Meghan Marquette In the lab
Sanaria Inc.'s Jonathan Jackson and Meghan Marquette came to the Seattle Malaria Clinical Trials Center to prepare infectious sporozoites for injecting into volunteers to test whether an experimental drug prevents malaria infection. Photo by Robert Hood

Direct injection replaces bug bites

The clinical trial that started last week boasts a number of firsts for the MCTC. It is the first trial since the center officially moved to the Fred Hutch campus, using a basement warren of interview and exam rooms, laboratories, and a kitchen and lounge area administered by Fred Hutch’s Prevention Center. It is the first trial of a novel antimalarial that could potentially be taken just once a week rather than daily and also might be safely used by pregnant women to protect their health and to prevent such malaria-associated outcomes as low birthweight babies.

It’s also the first time the MCTC is delivering the malaria sporozoites via direct venous inoculation, an approach developed by the U.S. biotechnology company Sanaria.

In previous trials, participants placed their arms over a cup of infected mosquitoes at the Center for Infectious Disease Research’s Human Challenge Center, one of four insectaries worldwide and the only non-military insectary in the United States for breeding malaria-carrying mosquitoes. Taking sporozoites grown in mosquitoes in the laboratory and packaging them in a form acceptable for human clinical trials is a technological breakthrough that has taken a little of the challenge out of time-sensitive “challenge” trials.

Just ask Dr. Sean Murphy, an MCTC researcher and medical director of the Human Challenge Center, what happens when mosquitoes bred for a tight-deadline trial turn out to be noninfectious.

Murphy’s claim to fame is spearheading the development of the molecular diagnostics that allow the trial researchers to detect ­and treat malaria before trial participants are symptomatic. He directs diagnostic testing for the trials and helps oversee them as an investigator and a physician.

He’s also an all-around trouble-shooter. Two years ago, the MCTC was about to commence another clinical trial of a different type of drug when researchers found out that the mosquitoes manufactured by the Seattle insectary weren’t as infectious as needed to guarantee infection. He was the one who came up with a Plan B.

The great mosquito road trip

Photo of Sean Murphy
Dr. Sean Murphy, toothbrush in hand, in Carrington, ND, 24 hours into and halfway through the 2014 Great Mosquito Road Trip. Photo courtesy of Dr. Sean Murphy

A challenge trial is highly choreographed to come together at one moment­ when the reviews and approvals are in hand, the volunteers are ready and the mosquitoes are “ripe.” Manufacturing another batch of mosquitoes would have taken eight weeks. That was not an option.

Fortunately, the researchers had arranged for colleagues at Sanaria in Rockville, Maryland, to have a backup batch on standby. Unfortunately, they didn’t have a permit to have the mosquitoes flown to Seattle.

Seeing the dismay on his fellow researchers’ faces, Murphy threw out a morale booster: “I said, ‘Worst case scenario, I will fly to DC and drive them back.’ It was a group hug situation.”

That is exactly what he did.

He and Center for Infectious Disease Research colleagues Louie Coffman and Sebastian Mikolajczak took a commercial flight to Washington D.C., rented a Lincoln Navigator and, with a stack of road-shipping permits in hand, drove 2,000 malaria-infected mosquitoes packaged in four layers of containment material and strapped into the cargo bay back to Seattle.

Listening to country music CDs calmed his nerves, Murphy said, though his taste for twang was lost on his co-pilots. Fortunately, he brought a variety of music, and he and Coffman not only agreed that Luciano Pavarotti’s rendition of Nessun Dorma was “out of this world” but joined the tenor for a middle-of-the-night sing-along.

Driving in four-hour shifts, taking turns sleeping in the back seat, the trio and their cargo made the 2,767-mile trip in 43 hours.

A rainbow greeted the Navigator as it crossed the I-90 bridge into Seattle, and the trial proceeded as planned.

Photo of Curtis Parker
Volunteer Curtis Parker Photo by Robert Hood

Do something weird — check

By the standard of the Great Mosquito Road Trip, the trial underway now has been an oasis of calm, albeit an oasis run by the clock and with checklists.

Volunteers showed up on the first day at 6:30 a.m. then stayed for a marathon 14 hours of interviews, checkups and blood tests after drinking a small bottle of liquid medicine (or placebo). Perry passed the time reading a book on 18th century code breakers. Parker had stored up three seasons worth of “Daredevil” to watch on Netflix.

On Day Zero — malaria injection day — Murphy's trouble-shooting consisted merely of figuring out why an outlet wasn’t working and dashing across campus to grab an extra container of liquid nitrogen for the Sanaria scientists to use in thawing the frozen sporozoites.

Perry snapped a cell phone selfie of her injection. Parker, who got to sleep at 2:30 a.m. after playing a gig and was back at the MCTC four hours later, struggled to stay awake.

Both professed calm, though Parker allowed as to how his mother had tried to talk him out of doing the trial.

“She was, like, I will match what they’re going to pay you not to do it,” he said.

But even though that would have paid for his studio time and spared him the time and the blood draws (which he doesn’t like), he saw advantages for sticking to his plan. For one, he didn’t want to take money from his parents. Two, for a guy who “hasn’t been to a doctor in ever,” he’s getting free checkups and blood tests. He’s also getting street cred from his friends, who told him, “That’s pretty badass that you’re willing to go through this to support your music.”

And then there’s this:

“I can check one of the life-goals boxes,” he said. “‘Do something weird.’”

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Mary Engel is a former staff writer at Fred Hutchinson Cancer Center. Previously, she covered medicine and health policy for the Los Angeles Times, where she was part of a team that won a Pulitzer Prize for Public Service. She was also a fellow at the Knight Science Journalism Program at MIT. Follow her on Twitter @Engel140.

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