How their bodies react will determine whether this clinical trial — one of the first — proceeds to the next stage in a long and complicated process. Its target is Zika, a virus that since 2015 has spread with a vengeance to 58 countries, infecting hundreds of thousands of pregnant women and putting their babies at risk of birth defects.
In Bethesda, volunteer Andrea Vaught is a researcher who is earning a master’s degree in public health. Being part of a clinical trial appeals to her inner geek.
In Baltimore, volunteer Crystal Woodley is grateful for the $1,100 compensation, given her recent layoff from a night-shift warehouse job.
And in Atlanta, volunteer Virginia Bliss is motivated by love and gratitude for her 10-year-old daughter.
“My daughter is perfect in almost every way, and I’m very blessed,” said Bliss, who works at a primate research center. “I wouldn’t want something to happen to someone during pregnancy that’s so far beyond their control. I can only imagine how heartbreaking that would be.”
The trio is at the heart of an effort by scientists worldwide. At least six vaccine candidates are in the development pipeline in the United States, with drug companies and government institutions collaborating to accelerate the process.
There is special urgency with all this work. Zika has confounded the medical community with its unpredictability, and virtually every week, research provides disturbing new data about its damaging potential in the unborn, infants and even adults. The World Health Organization now considers Zika "a significant and enduring public health challenge."
Yet vaccines usually take at least a decade to develop because so much of the effort is trial-and-error.
“When you are dealing with something that is going to require a response in a human body, which has so many variables . . . person to person,” said Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, “the chances for lack of precision and for something to go wrong is much greater.”
Vaught, Woodley and Bliss are part of a trial led by NIAID. It may be the furthest along — having had no trouble attracting participants, particularly among women — and about 80 people have received multiple injections since August of the clear, colorless test preparation. By design, no participants are pregnant.
If things keep going smoothly with this safety testing, researchers hope to move to Phase 2 in February. That would involve trying the experimental vaccine in 2,400 to 5,000 volunteers in places where the virus is spreading to see whether it prevents infection.
One way to speed up the overall development of a Zika vaccine would be to conduct a separate trial with a vaccine that contains live virus, something the current formulation does not contain. A decision could come later this month, and scientists know that recruiting for such a controversial trial would be much more difficult.
Any such volunteers would be on the front lines of the Zika fight, just as Vaught, Woodley and Bliss are.
On a cold, blustery morning, Vaught arrived at Building 10 — the Clinical Center — on the National Institutes of Health campus in Bethesda, for her second vaccine injection. From there, the 25-year-old would head to work at Georgetown University’s Center for Global Health Science and Security, where she helps countries develop surveillance systems to prevent outbreaks.
“With everything going on in the world, I know I can sometimes feel powerless to do something,” she said. “This is a small way to contribute to the development of a vaccine. I’m a young, healthy person, and that’s a privilege that I can contribute in this way.”
She hasn’t had much of a reaction to the shots. After her first in September, she felt a little tired. But she wasn’t sure whether to blame the vaccine or her schedule as a full-time research assistant and part-time student at George Washington University.
Before every injection, she provides a urine sample to make sure she’s not pregnant, has her vital signs checked and then gets her blood taken so her body’s immune response can be assessed. All participants receive the same dose — four milligrams of a small, circular piece of DNA, called a plasmid, in one milliliter of saline. It must be individually prepared each time.
Phlebotomist Catina Boyd jokingly calls Vaught her “problem child” because her veins are so tiny that drawing blood takes finesse. Boyd makes the tourniquet extra tight and hands Vaught a plush toy — in the shape of an NIH bus — that she’ll squeeze to make her veins pop and keep the blood flowing.
“Squeeze and hold the bus,” Boyd tells her.
New technology allowed NIAID researchers to engineer the plasmid so it contains genes coded for proteins of the Zika virus. When injected, a person’s cells read the genes and make those Zika proteins, which in turn trick the body into mounting a defense with antibodies and T cells.
Such DNA vaccines don’t have infectious material, so researchers say they can’t cause a person to become infected with Zika; previous trials for other diseases have established their safety, but DNA vaccines haven’t yet made it to market for human use. When people call to ask about volunteering, “that’s one of the first conversations we have when they inquire,” said Julie Ledgerwood, the trial’s primary investigator. Everyone is reassured: “There’s no Zika virus. You can’t get Zika from the vaccine.”
All participants, who must be between 18 and 35 years old and “pristinely healthy,” in Ledgerwood’s words, receive two to three injections and commit to as many as 18 follow-up visits over two years. After each shot, they record their temperature and any fever, arm pain, redness or tenderness, nausea or headache. They return on a specific schedule to have more blood taken so researchers can monitor their health and immune response.
Zika's high profile has attracted a far greater response than usual from potential volunteers — with so many inquiries that Ledgerwood ended up with names to tap for future Zika studies. Many of the people selected are women, perhaps because of Zika's far greater consequences for pregnant women and their babies. "People want to do this because it matters," she said.
Being a first-time participant has given Vaught a different perspective on her graduate classes’ textbook discussions about designing clinical trials and effective sample sizes.
“It is actual people you are testing something on, and sometimes we can forget that,” she said.
Woodley was running late for her second shot in downtown Baltimore. Her ride didn’t show. She didn’t have time to wait for a bus. She took a taxi, arriving at the vaccine clinic at the University of Maryland School of Medicine at 10:50 a.m., almost an hour past her appointment time.
As soon as she walked in, Ginny Cummings, the no-nonsense study coordinator, picked up the telephone to notify the pharmacists to start preparing her dose.
“Let the mixing begin,” she says.
Woodley took part several years ago in a malaria trial at the medical school, a study that required her to be in the hospital for nearly two weeks. Volunteers had their vitals recorded every three hours.
“We had to drink something that had malaria in it, and they would collect our stool every day,” she said. Some people became ill, but not Woodley. “I think I had the placebo,” she said.
The experience piqued her interest, and she agreed to be contacted about future trials. The timing on this one worked well because she’d been laid off in April. She also welcomed the compensation, which depends on a volunteer’s number of visits and the time needed to reach a facility.
A doctor went over a checklist to make sure Woodley, 33, could still receive her shot. Still in good health? No recent vaccinations? No blood products? Check, check, check.
By then, another clinic staffer had returned with her dose. Minutes later, in a spot right above the “RIP Daddy” tattoo on her left arm, Woodley received her injection. Like every participant, she had to stay put for 30 minutes and be monitored for any adverse reactions. There were none.
Just before noon, she walked outside, waited in a light drizzle for her bus and rode the No. 23 home to Catonsville.
“I really like what they’re doing,” Woodley said of the researchers, some of whom she knows from her previous trial. “It’s to help people and prevent them from getting this disease.”
Investigators say volunteers haven’t reported any significant pain or unusual side effects. But interim data suggest their immune response “is lower than we would have expected,” Fauci said. He describes it as “adequate, but not great.” That’s the unpredictability of vaccine development: A substance that looks promising when used in mice and monkeys may not hold up in humans.
Researchers have begun testing a variation of the DNA-based vaccine, which in monkeys generated a much stronger response than the original formulation. They began injecting it into a new group of 45 volunteers last month, again to watch for safety and immune reaction. “Already, it looks better,” Fauci said.
As a result, that second candidate will likely progress to field testing in February. Sites are being prepared from the Gulf Coast states and Puerto Rico to South America.
Even in the best-case scenarios, though, scientists won’t know whether any of the candidates produces an effective Zika vaccine until at least early 2018. And it could take years more before one is commercially available.
One step could significantly speed up the process: injecting healthy, nonpregnant volunteers with live Zika virus. While rare, that kind of “human challenge trial” would give researchers a much better understanding of how the virus causes disease and which prospective vaccines would be most effective in preventing infection.
Yet the risks are numerous. Female participants could become pregnant inadvertently. The full spectrum of Zika infection is not known, especially its longer-term risks. A recent mouse study, for example, showed the virus’s surprise effect on male fertility — including lower testosterone levels, sperm counts and, in some animals, dramatically shrunken testicles.
In December, the NIAID and the Walter Reed Army Institute of Research convened a group of independent experts to discuss how such a trial might be conducted safely and ethically. A recommendation is expected in January.
In Atlanta, Bliss insists she would sign up. As a longtime volunteer, one who started as a young mother a decade ago, she’s familiar with the routine of clinical trials and what’s expected of her. The money earned has been helpful, she says, but participating also spurred an interest in science and biology.
“I really love being part of the process,” said Bliss, 33, a histologist at Emory University’s Yerkes National Primate Research Center, which conducts biomedical and behavioral studies.
She feels strongly that human subjects have an obligation to take part in research. She participated most recently in a clinical trial for an Ebola vaccine.
“I got pretty sick” with what felt like the flu, she said. “That was definitely the most physical symptoms I had with a vaccine.”
But not so for Zika. She has had very little reaction to the two doses she has received at Emory’s Hope Clinic, part of the Emory Vaccine Center. Her third shot is slated for February.
Bliss has talked to her daughter about her clinical trials and even tried to persuade friends to participate. But most people are reluctant.
“They just hear names like Ebola and Zika and they get freaked,” she said. “People don’t understand vaccines well enough.”
Because Bliss does not plan to have more children, she says she would eagerly volunteer for another Zika trial — even if that meant becoming infected with live virus.
“I would absolutely sign up,” she said. She knows it takes years to develop a safe and effective vaccine, but her hope is that by the time her daughter “is ready to have kids, Zika would have been eradicated. I believe there’s a distinct possibility of doing that if we’re all working together.”