In January, after the COVID-19 vaccines began rolling out across the country, experts quickly began to notice problems. In many places, the process for distributing the vaccines was haphazard; essential workers and others who should have had early access didn’t get it, and others who shouldn’t get it did. The delays caused by this confusion led to an unthinkable outcome: some of the medicines began to spoil and were thrown out, unused.
The cause of that spoilage was limitations in what scientists call “the cold chain,” a set of temperature requirements that have to be maintained during delivery and storage if medicines are to remain safe and effective. The cold chain presents challenges for most vaccines and special difficulties for some of those designed to combat COVID-19.
The vaccine created by pharmaceutical giant Pfizer, for instance, needs to be stored at about minus 94 degrees Fahrenheit. It must remain frozen along its entire route, from the lab to the hospital’s expensive, ultracold freezer (if the hospital can afford one), and even then can expire in a matter of months. These strict requirements make it expensive and challenging to get the vaccine to remote or poor communities in places such as the Panhandle.
Dr. Maria Croyle, a researcher at the University of Texas at Austin’s College of Pharmacy, may have a solution. She and her team have come up with an innovative way of configuring a vaccine: turning it into a thin, peelable film that could be preserved without refrigeration for much longer than conventional vaccines and be taken by mouth rather than injected, in many cases obviating the need for a medical professional to administer it.
The technology could transform the way many vaccines are stored, distributed, and administered, making the entire process simpler and less expensive—and reducing the chances that doses are thrown out unused. But there’s a catch: Croyle’s film almost certainly won’t be approved in time to speed the pace of COVID-19 vaccinations this year.
In 2005 Croyle received a phone call from Dr. Heinz Feldmann, a virologist who was working for Canada’s Public Health Agency. Feldmann is one of the world’s leading experts on Ebola, the viral hemorrhagic fever that was first identified in 1976 and kills approximately half of those infected with it. Feldmann was hoping that the Ebola vaccine he was working on could be stored and transported without the need for uninterrupted refrigeration, which is difficult to guarantee in central and western Africa, Ebola’s epicenter. He also wanted a vaccine that could be administered without needles, which would mean it could be given without the assistance of medical professionals.
Croyle, who had arrived at UT five years earlier, after stints at Merck Research Laboratories and the University of Pennsylvania, had developed a reputation as an innovator in drug formulation and delivery, having created methods for preserving viruses that could be used to treat intestinal diseases. “Heinz knew someone that I had done research with and knew my specific skill set,” she said. “At the time, most first responders to Ebola didn’t understand what pharmacists could do to help them.” Croyle, who had never worked on anything related to Ebola, spent a month at the National Microbiology Laboratory, in Winnipeg, Canada, to learn about the disease.
After she returned to UT, Croyle and her team spent nearly ten years screening 4,500 to 5,000 combinations of ingredients that would allow them to stabilize a live virus. “Even students in the lab thought we were crazy,” she said.
Early on, the team focused on synthesizing an artificial form of amber, the translucent resin from trees that can preserve organic material for eons. Through years of what Croyle describes as a lot of trial and error, her team came up with a thin film matrix made of sugar and salt that’s viscous like amber in its liquid state and lightweight and peelable like fruit leather in its solid state (but not sticky or stretchy). And unlike liquid vaccines, which last perhaps a year when refrigerated, Croyle’s thin-film version of a vaccine can be preserved without refrigeration for three years.
By 2013 Croyle and her team were ready to test the technology on animals. Because they hadn’t figured out the appropriate dosage for a vaccine that would be given by mouth, the first experiment, which attempted to immunize monkeys against Ebola, used the thin film for packaging and storage and then reconstituted it as a nasal spray. “We were having difficulty making small films that we could handle that would also easily fit in the mouths of rodents and primates,” Croyle said.
Some vaccines need to be freeze-dried to stay stable; if doses sit unprotected on a FedEx truck too long in the middle of a Houston summer, their potency can be compromised.
According to a report that Croyle and her collaborators published in 2014, a single dose successfully immunized all nine monkeys against Ebola for at least six months. This research seemed to come at the right time; in 2014 there was a major Ebola outbreak in the West African countries of Guinea, Liberia, and Sierra Leone that would last several years.
But the film wasn’t used during that outbreak. At the time, Croyle said, there were other vaccines further along in the pipeline than the one they were testing with the thin film, making it difficult for her innovation to get much attention. Pharmaceutical companies that would be needed to partner on production for large-scale clinical trials have been hesitant to collaborate on a new storage and delivery technology, since injections are a proven method. But Croyle says that the need for an easy-to-deliver vaccine remains urgent. An Ebola outbreak last year in the Democratic Republic of the Congo killed 55 people, hot on the heels of outbreaks in that country during each of the previous three years. The disease is not going away.
In the years following their initial breakthrough, Croyle and her team continued working on the technology, which is versatile enough that it can be easily adapted to vaccines for other diseases. In the March 4, 2020, issue of Science Advances she reported that her team had figured out how to administer the small pieces of film by mouth to mice. The thin film was placed under the tongues or in the upper cheek pouches of a group of mice, and all had the same antibody response as those that received a normal flu vaccine.
Even before that latest breakthrough, it was clear to Croyle that a film vaccine was commercially viable. In 2013 she began working with UT’s Office of Technology Commercialization, which helps inventors take their innovations to market. “We were looking for a company to license the technology to develop it into a full-fledged product,” said Erin Overstreet, OTC’s director of licensing.
UT owns the patent for the technology, which has been licensed to Jurata Thin Film, a company based in Chapel Hill, North Carolina, for which Croyle serves as chief scientific officer. Jurata’s two cofounders also founded AskBio, a company in Durham, North Carolina, that develops gene therapies for rare diseases and was recently sold to Bayer. The two firms see a clear synergy between their respective missions.
“Gene therapy has a lot of the same logistical struggles that vaccines do,” said Megan Livingston, the director of business development at Jurata. “Gene therapies and vaccines both require freezing-temperature storage, are highly expensive to ship, and require lots of infrastructure to mass-produce.” Thin-film technology could solve all of those problems.
In that recent Science Advances article, Croyle and her team noted that distributing and administering a vaccine globally is an extremely expensive task. One study suggests that over a ten-year period, more than half of the cost of introducing a vaccine may be spent on distribution and administration. Some, for instance, need to be freeze-dried to stay stable; if doses sit unprotected on a FedEx truck too long in the middle of a Houston summer, their potency can be compromised.
“Fixing those parts of the vaccine chain could help increase vaccine coverage, especially in poorer parts of the world,” said Dr. Seema Yasmin, the director of Stanford Health Communication Initiative. Yasmin, a former professor of public health at UT-Dallas who has taught epidemiology, said that sometimes disease outbreaks occur among those who have been immunized with a vaccine that wasn’t stored or handled properly. “Other times, vaccines don’t reach communities in need because it’s logistically challenging to maintain a cold chain, or there’s a lack of health-care workers to administer the vaccines.”
All of these factors will come into play as the various COVID-19 vaccines roll out across the world. Jurata’s Livingston notes that even if distributors maintain the cold chain while transporting vaccines, hospitals and pharmacies may not have enough freezer space for them. “The more rural you get, the less storage you’re going to have available,” Livingston said. “These logistics are going to limit the number of people who can actually get the vaccine when it becomes available.”
Jurata is in talks with several pharmaceutical developers, including COVID-19 vaccine producers who are interested in the company’s technology, with hopes of going to clinical trials sometime over the next two years. While this means that it almost certainly won’t be used in the first round of COVID-19 vaccines, Croyle is aiming for the technology to be available in the rounds of vaccines that would be administered over the next couple of years. Experts estimate that about a quarter of the world’s population may not get a COVID-19 vaccine until 2022.
“The companies we’ve spoken with are very interested in fast-tracking the process,” Croyle said. “We are currently working around the clock to scale up the film-forming process so that we can easily stabilize around 5,000 doses of vaccine in the film on a given day,” with the goal of being able to produce 275,000 doses a day—100 million a year.
Though the thin film could potentially come to market in a number of formats, Livingston emphasized that the pharmaceutical industry tends to prefer injection, since it’s a tried-and-true technique. Health workers in poorer countries, by contrast, prefer methods that offer fewer barriers to immunization, such as by mouth. “Vaccine manufacturers have asked us if it can be injected,” Croyle said. “That’s not really how we designed it, but we have adapted the platform to make it injectable.”
Rachel Roper, an associate professor of microbiology and immunology at East Carolina University who is an expert on vaccines, believes that such resistance to the film’s novel format isn’t surprising. “Sometimes it’s just difficult to get a new technology adopted,” she said, “even if it’s superior.”
Julissa Treviño is a Fort Worth–based medical writer whose work has appeared in the Dallas Morning News and Popular Science.
This article originally appeared in the March 2021 issue of Texas Monthly with the headline “Needles No More.” Subscribe today.
