The mRNA technology in COVID-19 vaccines got its start in Penn Medicine labs, and its impact could reach far beyond the pandemic.
On December 18, 2020, Drew Weissman, MD, PhD, and Katalin Karikó, PhD, arrived at the Perelman Center’s 15th floor pop-up COVID-19 vaccine clinic to receive their first dose of the Pfizer/BioNTech vaccine. They were only two people out of thousands vaccinated at Penn Medicine in the final weeks of 2020, but they were two people who made it all possible.
More than 15 years earlier, the pair of researchers paved the way to the development of the vaccine with a groundbreaking discovery in messenger RNA (mRNA) technology. “I’m not a person who gets excited very easily, as anyone who knows me can attest to, but even I was excited about the fact that a vaccine I helped create was being injected into my arm that day,” said Weissman, the Roberts Family Professor of Vaccine Research at the University of Pennsylvania’s Perelman School of Medicine.
Karikó, who carries her emotions a little closer to the surface, felt her eyes well up with tears as she walked into a conference room to receive her first jab. “It’s hard to put that feeling of overwhelming joy into words,” said the BioNTech executive and adjunct professor of Neurosurgery at the Perelman School of Medicine.
These days, Karikó and Weissman are approaching celebrity status in the biomedical research community, having recently won the Princess of Asturias Award, the Albany Medical Center Prize in Medicine and Biomedical Research, the $3 million Breakthrough Prize, and, most recently, the 2021 Lasker Award — the top biomedical research prize in the United States. But while media appearances and awards ceremonies consume an increasing portion of their time, they spent the majority of their careers in their laboratories, laboring steadily in a pursuit of a vision.
Where It All Began
In 1997, Karikó and Weissman met at Penn. She’d immigrated to the United States from her native Hungary to expand her professional opportunities, and he had just landed here from the National Institutes of Health, where he’d been on a fellowship under the supervision of Dr. Anthony Fauci. They struck up a conversation about their work as they waited to use a photocopier to print journal articles.
Soon, the researchers were discussing ways they could work together. Karikó, who had always wanted to unleash the power of mRNA to make it into treatments for disease, agreed to create mRNA for Weissman, who was interested in it as a new approach to vaccines. In exchange, Weissman introduced Karikó to the field of immunology.
By 2000, Karikó and Weissman hit a major roadblock. The mRNA they created was causing a response in cultured human cells that could be damaging if it happened in the body. Five years later, they were able to circumvent the inflammatory response by slightly tweaking one of the building blocks of mRNA. In 2015, they built on their research by developing a delivery technique that uses lipid nanoparticles to package the mRNA in a way that helps it reach its intended destination.
Together, these findings made mRNA a viable vaccine platform. “Our research reignited interest in mRNA vaccines, and the field really took off at that point,” said Weissman. For years, they focused on testing mRNA vaccines for diseases like genital herpes, influenza, and HIV.
But when the COVID-19 pandemic struck, they knew that their 15-year-old discoveries could help — and fast. “One of the advantages of an mRNA vaccine was how quickly it could be created,” said Weissman.
In an mRNA vaccine like the COVID-19 vaccines, modified mRNA instructs cells to create proteins that resemble the proteins of a virus. The body then responds to the perceived threat by producing antibodies, leading to long-term protection against the real virus.
The rest, as they say, is history. To date, a combined 360 million doses of the Pfizer/BioNTech and Moderna vaccines have been administered in the U.S. alone, with an additional 125 countries using the Pfizer/BioNTech vaccine and 70 countries using the Moderna version.
Next Frontiers
Ultimately, what Weissman and Karikó discovered years ago was a platform, not a treatment for a single disease. The genius of the mRNA technology they discovered lies in its limitless potential. In a setup often referred to as “plug and play,” researchers only have to plug in the sequence of the protein they want to create or replace in order to target a specific disease.
Weissman and his lab have begun to develop a slew of new vaccines, including a pancoronavirus vaccine and a universal flu vaccine. At BioNTech, where Karikó serves as senior vice president, she is overseeing parallel but distinct research mRNA that encodes for therapeutic proteins for a range of diseases.
Like branches of a tree, research projects based on Weissman and Karikó’s foundational research are sprouting quickly at Penn. In early 2022, Weissman will partner with Harvey Friedman, MD, also of Infectious Diseases, to begin human clinical trials of an mRNA vaccine for herpes, the most common sexually transmitted disease.
Nearby at the newly created Center of Excellence for Influenza Research and Response (CEIRR), Scott Hensley, PhD, a professor of Microbiology, is creating mRNA vaccines for a wide range of shapeshifting influenza virus strains.
At least eight pharmaceutical companies, many in collaboration with institutions like Penn, are studying mRNA cancer vaccines in ongoing clinical trials.
For Norbert Pardi, PhD, an assistant professor of Microbiology, who was mentored early in his career by Karikó and joined Penn in a postdoctoral position 10 years ago, mRNA has formed a central career focus already. His work with Karikó and Weissman between 2011 and 2013 on mRNA technology has set the stage for his own exploration of mRNA vaccines for influenza, malaria, and more.
“We were all very enthusiastic and believed that we could use mRNA for vaccination and therapy one day,” recalls Pardi. “It is super-motivating and inspiring knowing that what I have been working on for 10 years is something that can be useful for people — just think of the impact of the COVID-19 mRNA vaccines!”
Attitude of Gratitude
Indeed, a grateful campus — and world — is thanking those who helped to pave the way for an end to the pandemic. This year, Karikó and Weissman have received notes of congratulations and encouragement from strangers around the world and from countless Penn colleagues and students, both past and present.
“Thank you for your years of research and tireless effort,” reads one such note. “And thank you from the bottom of my heart for the coronavirus vaccine. My family and I are alive because of you.”
“It’s humbling to receive such an outpouring of support because we were just a few of many people who contributed to this achievement,” Karikó said.
For visual proof of these overwhelmingly positive emotions, just look at the “I Got the Shot” posters featuring Penn staff and providers who were among the first to get their COVID-19 shots, using mRNA technology developed right here.
For instance, Occupational Medicine Nurse Danielle Lutz, RN, marveled, “This is a historical moment — we’re ending a pandemic. The importance of this is enormous.”
But many saw the opportunity on a more personal level, like Alex Bonilla, administrator of practice operations. He got the shot “to be able to hug my friends and family again. The COVID-19 vaccine is a symbol of hope.”
And that hope has horizons far past the end of the COVID pandemic.
“We’re only just beginning to discover all the ways we can use mRNA,” says Weissman. “At Penn and beyond, there is so much more to come.”
To learn more about ongoing mRNA research at Penn Medicine, visit https://www.pennmedicine.org/mrna.