The 2023 Nobel Prize in Medicine – Discoveries That Enabled mRNA Vaccines

The 2023 Nobel Prize in Physiology or Medicine was awarded to Katalin Karikó and Drew Weissman for work enabling effective mRNA vaccines against COVID-19—specifically, their discoveries concerning nucleoside base modifications.

The discoveries of these two Nobel laureates were crucial to developing effective mRNA vaccines against COVID-19 during the pandemic that began in early 2020. Their groundbreaking findings fundamentally changed our understanding of how mRNA interacts with our immune system, contributing to an unprecedented acceleration in vaccine development during one of the greatest threats to human health in modern times.

Vaccines Before the Pandemic

Vaccines stimulate an immune response to a particular pathogen, giving the body a head start in fighting disease after subsequent exposure. Vaccines based on killed or weakened viruses have long been available; examples include polio, measles, and yellow fever vaccines.

Advances in molecular biology enabled vaccines based on individual viral components rather than whole viruses. Prime examples are HPV and hepatitis-B vaccines. Portions of the viral genetic code, usually those encoding proteins on the virus's surface, were used to produce proteins that stimulate the formation of antibodies capable of blocking the virus.

Figure 1. Vaccine production methods before the COVID-19 pandemic.

mRNA Vaccines: A Promising Idea

In our cells, genetic information encoded in DNA is transferred to messenger RNA (mRNA), which serves as a template for protein production.

In the 1980s, introducing efficient methods for producing mRNA without cell culture—a technology known as in vitro transcription—was a decisive step in molecular biology applications. It accelerated research in several fields and demonstrated the potential of mRNA for vaccines and therapeutics. Serious obstacles nevertheless stood in the way.

In vitro-transcribed mRNA was considered unstable and difficult to deliver. Efficient delivery into cells required sophisticated lipid carrier systems to encapsulate the mRNA molecules. These systems were designed to deliver mRNA safely and effectively.

Laboratory-produced mRNA was also observed to cause inflammatory reactions. These responses created another obstacle to developing mRNA-based therapies or vaccines.

These barriers initially limited enthusiasm for clinical development of mRNA technology. Its instability and inflammatory effects dampened early interest and potential applications.

As these challenges were overcome and scientists learned more about optimizing mRNA and effectively delivering it to cells, research into mRNA-based therapeutics and vaccines gradually accelerated. This became particularly evident in the rapid development of mRNA vaccines during the COVID-19 pandemic.

These obstacles did not deter the Hungarian researcher committed to developing methods of using mRNA for therapy, biochemist Katalin Karikó. In the early 1990s, as an assistant professor at the University of Pennsylvania, she remained committed to her vision of therapeutic mRNA despite difficulty convincing research funders of the project's importance.

A new colleague at Karikó's university was immunologist Drew Weissman. He was interested in immune surveillance and the activation of vaccine-specific immune responses, important functions of dendritic cells. A productive collaboration began, focusing on how different types of RNA interact with the immune system.

The Groundbreaking Discovery

The Role of Dendritic Cells:

• Karikó and Weissman observed that dendritic cells recognized laboratory-produced (in vitro) mRNA as foreign. This triggered the release of inflammatory signaling molecules and activated the dendritic cells.
• Dendritic cells are part of the immune system, tasked with identifying foreign substances entering the body, such as microbes.

The Difference Between In Vitro mRNA and mRNA from Mammalian Cells:

• The researchers noticed that laboratory-produced mRNA was recognized as foreign, whereas natural mRNA from mammalian cells did not provoke the same response. This prompted them to investigate the fundamental differences between the types of mRNA.

The Chemical Composition of RNA:

• RNA has four bases (A, U, G, C) as its basic building blocks, and these bases pair with bases in DNA.
• Karikó and Weissman discovered that RNA from mammalian cells had chemical modifications in its bases, while laboratory-produced mRNA lacked them.

The Effect of Base Modifications on the Inflammatory Response:

• To test the effects of chemical base modifications, the researchers produced different mRNA variants and delivered them to dendritic cells.
• Variants containing base modifications almost completely abolished the inflammatory response, offering a new perspective on how cells recognize and respond to mRNA.

Conclusion and Applications:

• Karikó and Weissman realized that their discovery had great potential for using mRNA therapeutically.
• Published in 2005, these findings marked an important step toward advancing medical applications of mRNA. The work enabled rapid development of mRNA vaccines, particularly during the COVID-19 pandemic, and is therefore considered a major scientific contribution.

Figure 2 illustrates mRNA's four different bases, abbreviated A, U, G, and C. The Nobel laureates discovered that base-modified mRNA could be used to block inflammatory reactions (the release of signaling molecules) and increase protein production when mRNA is delivered to cells.

In further studies published in 2008 and 2010, Karikó and Weissman showed that delivering mRNA produced with base modifications significantly increased protein production compared with unmodified mRNA. The effect resulted from reduced activation of an enzyme regulating protein production. By discovering that base modifications both reduced inflammatory responses and increased protein production, Karikó and Weissman removed critical barriers on the path to clinical mRNA applications.

mRNA Vaccines Fulfilled Their Potential

Interest in mRNA technology began to grow, and by 2010 several companies were working to develop it. Vaccines against Zika virus and MERS-CoV were pursued; the latter is closely related to SARS-CoV-2. After the COVID-19 pandemic emerged, two base-modified mRNA vaccines encoding a SARS-CoV-2 surface protein were developed at record speed. Protective effects of around 95% were reported, and both vaccines were approved in December 2020.

The impressive flexibility and speed of mRNA vaccine development allow this platform to be used for vaccines against other infectious diseases. In future, it may also be used to deliver therapeutic proteins and treat certain cancers.

Several other vaccines against SARS-CoV-2, based on different methodologies, were also introduced rapidly. Together, worldwide, more than 13 billion COVID-19 vaccine doses were administered. Vaccines saved millions of lives and prevented severe disease in many people, allowing societies to reopen and return to normal conditions. By discovering the importance of base modifications in mRNA, this year's Nobel laureates made a critical contribution to this transformative development during one of the greatest health crises of our time.

Katalin Karikó was born in 1955 in Szolnok, Hungary. She received her PhD from the University of Szeged in 1982 and conducted postdoctoral research at the Hungarian Academy of Sciences in Szeged until 1985. She then carried out postdoctoral research at Temple University in Philadelphia and the University of Health Sciences in Bethesda. Appointed Assistant Professor at the University of Pennsylvania in 1989, she remained in that position until 2013. She subsequently joined BioNTech RNA Pharmaceuticals as Vice President and later Senior Vice President. Since 2021, she has served as Professor at the University of Szeged and Assistant Professor at the University of Pennsylvania's Perelman School of Medicine.

Drew Weissman was born in 1959 in Lexington, Massachusetts, United States. He received his MD and PhD from Boston University in 1987. He trained clinically at Harvard Medical School's Beth Israel Deaconess Medical Center and conducted postdoctoral research at the National Institutes of Health. In 1997, he established his research group at the University of Pennsylvania's Perelman School of Medicine. He is the Roberts Family Professor in Vaccine Research and Director of the Penn Institute for RNA Innovations.