Not long after researchers completed their work with mice, guinea pigs, ferrets and monkeys, Human Subject 8, an art director for a software company in Missouri, received an injection. Four days later, her sister, a schoolteacher, became Subject 14.
Together, the sisters make up about 5 percent of the first ever clinical trial of a DNA vaccine for the novel coronavirus. How they respond to it will help determine the future of the vaccine. If it proves safe in this trial and effective in future trials, it could become not only one of the first coronavirus vaccines, but also the first DNA vaccine ever approved for commercial use against a human disease.
Hundreds of experimental vaccines for the new coronavirus are currently being developed across the world. These vaccines’ ability to advance will depend not only on science and funding, but also on the willingness of tens of thousands of healthy people to have an unproven solution injected into their bodies.
In many of these studies, the vaccine recipe isn’t the only thing on trial. Gene-based vaccines — and at least 20 coronavirus vaccines in development fall into this category — have yet to make it to market. Should one end up in doctors’ offices amid the rush to shield billions from Covid-19, it would represent a new chapter for vaccine development.
And though vaccine research has never moved this quickly — potentially meaning enhanced risks for volunteers — it has never been easier to recruit subjects, according to Dr. John E. Ervin, who is overseeing the DNA vaccine trial at the Center for Pharmaceutical Research in Kansas City, Mo., in which the sisters are involved. For the Phase 1 trial of the vaccine, which was developed by Inovio Pharmaceuticals, 90 people applied for the 20 slots in Kansas City.
“We probably could charge people to let them in and still fill it up,” he said. (In fact, the participants were paid per visit.)
The art director, Heather Wiley of Independence, Mo., said that realizing she would make around $1,000 for her participation was a bonus, not her primary motivation.
“I’m in the middle of the country trying to process 100,000 dead and how all those people died alone,” she said. Her fears for her family left her so anxious she couldn’t sleep.
While looking up vaccines, she stumbled on Dr. Ervin’s trial, which was recruiting volunteers just 20 miles from her. Two months shy of 50 and healthy, she qualified.
Step 1: A shot with computer-engineered DNA
Two weeks later, Dr. Ervin was injecting Ms. Wiley just beneath the skin of her upper arm with a transparent liquid containing the experimental vaccine.
The solution contains a computer-engineered DNA sequence, which includes genetic instructions for building the spike that makes the coronavirus so superb at entering its host’s cells. Cells are equipped to read genetic instructions; that’s just part of what they do. When these instructions arrive, the cells follow them and make the very same spike protein present on the surface of the coronavirus now wreaking havoc on the world.
The immune system responds to these spike proteins, now being manufactured by the body, and mounts a defense. These spike proteins are harmless; they are not attached to a virus. But the hope is that in the future, should a virus wearing spikes with that same genetic code attempt to invade, the immune system’s arsenal would be prepared.
Inovio researchers engineered the vaccine in just three hours, according to Kate Broderick, the company’s senior vice president for research and development. Or, rather, their computer algorithm did: On Jan. 10, when Chinese researchers released the genetic code of the novel coronavirus, the team ran the sequence through its software, which popped out a formula.
This timeline struck some in the financial sector as too good to be true. Citron Research, which advises investors on companies to bet on, called Inovio “the Covid-19 version of Theranos,” referring to the blood-testing device company that imploded as its supposedly revolutionary product was revealed to be a hoax.
“Much like Theranos, Inovio claims to have a ‘secret sauce’ that, miraculously, no pharma giant has been able to figure out,” Citron Research wrote. “This is the same ‘secret sauce’ that supposedly developed a vaccine for Covid-19 in just three hours.”
There are several reasons that vaccine scientists are skeptical that we will ever see a DNA vaccine for the coronavirus. But speed is not one of them.
“That’s the beauty of these DNA vaccines,” said Wolfgang W. Leitner, the chief of the innate immunity section at the National Institute of Allergy and Infectious Diseases. “They are simple and fast in terms of development.”
Nor are vaccine scientists concerned about the supposed “secret sauce.” In fact, it’s quite the opposite: They are skeptical precisely because the technology behind DNA vaccines has been around for decades and has been applied toward so many infectious diseases — H.I.V., the flu, malaria — yet none of the vaccines have made it to market.
They believe that this approach is capable of producing immunity. Already, DNA vaccines have been licensed for use in pigs, dogs and poultry. But the big if, according to Dr. Dennis M. Klinman, a vaccine scientist who worked at the Food and Drug Administration for 18 years, is whether one will ever be able to generate strong enough an immune response in humans.
Step 2: A series of zaps to ‘steer the DNA’
Even though Ms. Wiley had read the packet on the science of it all, the next step felt like entering uncharted territory.
Shortly after the initial injection, a nurse handed Dr. Ervin a device resembling an electric toothbrush. He pressed the head — which contains three tiny needles instead of bristles — over the raised skin on her arm, where she’d just had a shot. Then he zapped her.
“It was not painful, but it’s unlike anything I’ve ever experienced,” Ms. Wiley said.
The carefully calibrated electrical pulses “basically steer the DNA” into the cells by briefly opening up pores in their membrane, according to David B. Weiner, the director of the vaccine and immunotherapy center at the Wistar Institute and an adviser to Inovio.
Although it may sound fantastical, the technology, called electroporation, dates to the 1980s, when a similar approach was first used to make transgenic plants, according to Dr. Leitner.
Phase 1 trials are focused on safety. As a whole, DNA vaccines are known to be very safe, Dr. Klinman has written. Early fears — that they might change a person’s DNA, for example — were proved unfounded long ago.
But there is still no way to know how subjects will respond to the new formula or how the new approach to administering the vaccine will go over. When Dr. Ervin used a different electrical pulse system in an Ebola DNA vaccine trial in 2018, “Boom! They were ready to jump off the table,” he said, adding that he wished he could have paid the subjects extra. (Dr. Ervin runs trials for many biotech companies and is not involved in deciding dosages or implementation methods. His job is to follow the company’s instructions and report back, he said.)
Step 3: Wait for side effects
Ms. Wiley spent the next couple of hours after her injection watching “The King’s Speech” as researchers monitored her for an adverse response. But she felt only relief at being useful in some way.
“I’m not a health care worker; I’m not an essential worker,” she said. “But I’m healthy, so I can do this.”
Soon her sister Ellie Lilly, 46, a seventh-grade history teacher in Lee’s Summit, Mo., had enrolled as well.
Throughout a Phase 1 trial, the newest subjects receive larger doses than participants who started earlier. Ms. Lilly, who entered the trial as Subject 14 four days after her sister, learned that she would be receiving twice as many shots and zaps. Still, the pulses didn’t hurt. “It just feels strange,” she said.
By the time Ms. Lilly got home she felt exhausted and a little nauseous, she said. She told a nurse who called to check in that she wasn’t sure if that was a function of the vaccine or an emotional day. Either way, she felt well enough the following day that her husband wanted to enroll. (He was rejected.)
Four weeks after their first injections, the sisters returned for their second and final doses.
Step 4: Wait to see if it’s deemed safe, and whether it actually did anything
The first hint of whether anyone in the trial developed the coveted antibodies, which would suggest that the vaccine might be helping the immune system, won’t come until Inovio releases that data later this month. That report will include findings from both the Kansas City trial and a simultaneous trial of 20 volunteers in Pennsylvania. This data will influence whether the vaccine dies in the first stage, as most vaccines do, or whether it moves on.
The Phase 1 trial has already been expanded to include older patients at a third location. If everything goes as hoped, the F.D.A. has granted the company permission to start testing effectiveness in the community, according to Inovio.
At that point, researchers would inject thousands of people with the vaccine and thousands more with a placebo. No one would be intentionally exposed to the coronavirus, but by studying rates of infection of the two groups, the researchers could draw conclusions about the effectiveness of the vaccine.
The sisters are rooting for the Inovio vaccine. But, “even if it doesn’t work, we’re still a piece of the research,” Ms. Lilly said.
Ms. Lilly knows that the chances are low that her two experimental doses will protect her, but she can’t help hoping. Come fall, she is headed back to the classroom, where it feels inevitable that sooner or later, she too will be exposed to this tiny but powerful virus.
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