The 2023 Nobel Prize in Physiology or Medicine has been awarded to Katalin Karikó of Szeged University and Drew Weissman of the University of Pennsylvania for their discoveries concerning nucleoside base modifications that enabled the development of effective mRNA vaccines against COVID-19.
Historically, vaccines have used portions of molecules such as proteins or glycans from the surface of viruses or bacteria to train the immune system. Researchers hoped for decades to be able to use DNA and RNA, which encode proteins and can be adapted more easily than proteins, to make vaccines.
However, it was difficult to use mRNA produced in the lab to generate effective long-lasting immune responses, even after challenges in delivering the mRNA were resolved. This is because of the two-part nature of the human immune system; the generalist part of the immune system detects and degrades foreign mRNA, launching an inflammatory response.
Karikó and Weissman who met at the University of Pennsylvania in 1997, collaborated to try to use RNA to produce vaccines that could be adapted more quickly. They combined Karikó’s expertise in RNA biochemistry with Weissman’s in immunology. In a landmark paper published in 2005 in Immunity, the pair proved that it was the lack of base modifications in synthetic RNA that made it immunogenic. They showed that converting the RNA base uridine to pseudouridine in mRNA produced in vitro could reduce the inflammatory response (DOI: 10.1016/j.immuni.2005.06.008).
It was, according to Stanford RNA biologist Jin Billy Li, “the first important attempt to try multiple RNA modifications and see how that would activate the immune system.” Later, Weissman and Karikó also showed that this modification produced a more stable RNA construct and better more protein yields (Mol. Ther. 2008, DOI: 10.1038/mt.2008.200).
“Their early discovery that RNA could be modified to avoid detection of the innate immune system now underpins the successful future of RNA vaccine and therapeutics,” writes Robin Shattock, a professor of infection and immunity at Imperial College London, in an email to C&EN.
The prize is “really well deserved,” says Thomas Carell of the Ludwig Maximilian University of Munich, noting the key role of mRNA vaccines during the COVID-19 pandemic. “They really saved the day,” he says. Two companies that used modified mRNA, Moderna and BioNTech, produced vaccines that could protect against COVID-19 infection. In contrast, Carell says, the firm CureVac used unmodified mRNA and never made it to market.
Following the success of mRNA-based COVID-19 vaccines, the pharmaceutical industry has rapidly adopted RNA technology to generate vaccines against other pathogens, such as influenza, and against cancer. Weissman and Kariko have shared a series of high-profile prizes, including the Lasker Award and the Breakthrough Prize in Life Sciences.
However, prior to the COVID-19 pandemic, mRNA vaccines were a promising but relatively untested technology. Romesh Subramanian, president and CEO of the RNA biotech startup Ascidian Therapeutics, says that at one point, “nobody believed mRNA could really be a medicine.”
“We couldn’t get funding; we couldn’t get publications; we couldn’t get people to recognize RNA as something interesting,” Weissman said at a press conference sponsored by the University of Pennsylvania on the day the prize was announced. Karikó had such difficulty funding her research that she had to leave the University of Pennsylvania; she found work at German company BioNTech. Many scientists who spoke to C&EN highlighted Kariko’s resilience and dedication to a vision of RNA therapeutics. Li notes that the adversity Karikó and Weissman faced is not unique.. “A lot of people do great science, but they may or may not be fundable based on today’s criteria.”
According to Kathryn Whitehead, a nanoparticle scientist at Carnegie Mellon University who works on RNA delivery, “it's just a wonderful story of people sticking to their guns, and continuing to work in areas that they believed were important. And look at what we have now."
Stefan Hell, a Nobel laureate in chemistry, posted to X (formerly Twitter), “Huge congratulations Katalin! So deserved for the live-saving work that hardly anyone expected a decade ago. Creativity + perseverance is a recipe for real breakthroughs and #NobelPrize.”
This story was updated twice on Oct. 2 to provide quotes from Jin Billy Li, Robin Shattock, Thomas Carell, Stefan Hell, Romesh Subramanian, Drew Weissman and Katie Whitehead, as well as more detail about the laureates’ prize-winning work.