Profile of Katalin Karikó and Drew Weissman: 2023 Nobel laureates in Physiology or Medicine

The 2023 Nobel Prize in Physiology or Medicine has been awarded to Katalin Karikó and Drew Weissman "for their discoveries concerning nucleoside base modifications that enabled the development of effective mRNA vaccines against COVID-19". The use of their discovery for the development of COVID-19 mRNA vaccines has saved millions of lives (1, 2) and technologies based on their discovery will likely lead to the advancement of many additional promising vaccines and therapeutics. This marks only the second time a Nobel Prize was awarded for vaccines, after Max Theiler received the award in 1951 for the yellow fever vaccine.

Katalin Karikó. Image credit: István Sahin-Tóth (University of Szeged, Szeged, Hungary).

The Food and Drug Administration approval of the mRNA/lipid nanoparticle (LNP) vaccine for COVID-19 was extraordinarily speedy. SARS-CoV-2 causing the disease appeared at the beginning of 2020 and the first emergency use authorization (EUA) was granted on 11 December 2020. This rapid development was largely made possible by the generous and continuous support of basic research by the US government over many years. The Trump administration started a public–private partnership for the development of SARS-CoV-2 vaccines on 15 May 2020, with an initial $ 10 billion funding for warp-speed (ref. 1) (3). The name was inspired by the terminology for faster-than-light travel in Star Trek. While it took less than 12 months to get the first EUA, hard work over decades by many investigators led to this major breakthrough for medicine and the world. What were the fundamental scientific contributions made by Katalin Karikó and Drew Weissman, which made this major breakthrough possible?

Drew Weissman. Image credit: Penn Medicine.

Biochemistry: Katalin Karikó was born in 1955 in Hungary, which was at that time a satellite state of the Soviet Union. Despite growing up under relatively poor circumstances, Karikó excelled in science early on, received her PhD in biochemistry in 1982 from the University of Szeged, and then continued as postdoctoral fellow at the Institute of Biochemistry, Biological Research Center of Hungary. During that time she already worked on lipids and liposome-mediated DNA transfer (4), a prescient choice for what would be important for her scientific direction in the future. In 1985, Karikó left Hungary and joined the laboratory of Robert J. Suhadolnik at Temple University in Philadelphia where she stayed until 1988, working on DNA transfer into mammalian cells and RNA biology (5–10). After a brief stint at the Uniformed Services University of the Health Sciences in Bethesda, she moved to the University of Pennsylvania to work on mRNA with Elliot Barnathan. During this time, she discovered her passion for mRNA-based therapy. While struggling to get funding, she persistently, diligently, and methodically worked on a better understanding of mRNA regulation, translation, and various approaches toward mRNA therapeutics. Unable to gain funding, she was demoted in 1995 but decided to still continue her research at University of Pennsylvania. In 1997, she met Drew Weissman at a photocopier in the laboratory and started a discussion over a research paper.

Immunology: Drew Weissman was born in 1957 in Massachusetts and received his B.S. and M.S. degrees from Brandeis University in 1981. He performed his PhD work in immunology and microbiology at Boston University with Gerald Fasman and received his MD and PhD degrees in 1987. After a residency at Beth Israel Deaconess Medical Center, he trained from 1990 to 1997 with Anthony Fauci (then already director of the National Institute of Allergy and Infectious Diseases) at the NIH, focusing his research on HIV and immune responses to HIV. In 1997, he accepted a position as Assistant Professor at the University of Pennsylvania where he met Katalin Karikó.

Context: The development of mRNA vaccines is rooted in foundational work that elucidated the structure and function of mRNA and in work that made it possible to produce mRNA in vitro. Early results with in vitro transcribed RNA, published in 1989, showed that mRNA can be used to transfect cells and that the transfected cells actually produce proteins encoded by the transfected mRNA (11). In 1990, the first gene transfer with mRNA in vivo was demonstrated by a team led by Philip Felgner (12). Although RNA is less stable than, e.g., plasmid DNA, the ability to transfect cells with mRNA and make them produce specific proteins sparked excitement, especially for the development of therapeutics (13). In the mid-1990s, the concept was also picked up by researchers working on cancer vaccines and therapeutics (14, 15). In the 2000s, the development of mostly cancer-targeting mRNA vaccines continued and first clinical trials were initiated (e.g., refs. 16 and 17). A large development effort for infectious disease-targeting vaccines started in the 2010s (18–21), initially driven by CureVac and by Novartis, in both cases with "unmodified" mRNA.

At this point, we have to pause and take a closer look at how mRNA vaccines work and what types there are. "Classical" mRNA vaccines include a cap structure, an open reading frame and a poly-A tail. These mRNAs are delivered to cells, ribosomes recognize the mRNAs, and their open reading frames are translated. If the open reading frame encodes for an antigen, an immune response against that antigen is mounted, both by T cells and B cells leading to cellular and antibody-based immunity. However, there is a second type of mRNA vaccine, called self-amplifying mRNA (SAM). In this case, the mRNA also has a cap and a poly-A tail but in addition encodes for a replicon, e.g., from an alphavirus. In this case, the replicon is translated and then further amplifies the mRNA. Potentially, using this concept, less initial RNA needs to reach the cell since it is amplified. Infectious disease vaccines championed in the early 2010s by CureVac were classical mRNA vaccines, while vaccines championed by Novartis were SAM-based vaccines.

Collaboration: But back to Katalin Karikó and Drew Weissman. The two of them meeting at University of Pennsylvania led to a long term and highly successful collaboration. Their respective backgrounds in biochemistry and immunology complemented each other and so did their personalities, leading to very fruitful and innovative research. They discovered that, in general, mRNA can induce innate immune responses and can activate innate immune cells, even when only present in the extracellular space (22). They reported that this activation is triggered by sensing of the RNA by toll-like receptor 3 (23). Of course, activation of innate immune responses and subsequent shut-off of translation of "foreign" RNA is a hurdle for efficient gene delivery via mRNA, a major goal toward which Karikó and Weissman were working. The same problem occurs with DNA delivered to cells, where CpG motifs are recognized by toll-like receptor 9 and trigger an innate immune response. However, if the CpG motifs in DNA are methylated, innate immune responses are not induced. Karikó and Weissman thought that similar modifications must exist to make mRNA less immunogenic. In a 2005 Immunity paper (the paper was initially rejected by both Science and Nature), they showed that several modifications, including using pseudo-uridine (ψ) instead of uridine, suppressed innate immune responses (24). Their thoughts on the impact of this on development of mRNA-based therapeutics are expressed in their review (25). They drilled down more into mechanisms of (foreign) gene expression and the development of therapeutics. In a hallmark paper in 2008, they showed that they achieved higher expression levels in vitro and in vivo with pseudo-uridine modified RNA as compared to unmodified RNA (26). In addition, they also found that reduced induction of innate immune responses was not necessarily directly linked to higher expression levels (26). In several additional follow-up studies, they showed how the pseudo-uridine modification made an impact on therapeutic mRNA candidates (27) as well as mRNA vaccines (28). In addition, the team worked on better purification techniques for mRNA to remove contaminants that can also induce unwanted innate immune responses (29–31) and on efficient delivery methods including LNPs (32). They also made great progress in the mRNA vaccine space (33, 34) and developed methods to express monoclonal antibodies in vivo using the mRNA platform (35). Further, they developed a 2.0 version of the modified mRNA which uses 1-methylpseudo-uridine (m1ψ) instead of uridine (34) and this modification is applied in current COVID-19 mRNA vaccines. Their technology was picked up by Moderna as well as BioNTech and was also used under a collaborative agreement between Pfizer and BioNTech to develop influenza virus mRNA vaccines. With the onset of the pandemic, they of course made also significant scientific contributions directly to the development of COVID-19 vaccines (with Weissman still being at the University of Pennsylvania and Karikó having moved on to BioNTech in Germany, in 2013 after 28 years in the United States). However, their key contributions to the mRNA vaccine technology was the realization that a lower innate immune response to mRNA would be beneficial for target protein expression and that the solution to this problem would be the substitution of uridines with pseudo-uridines. Of note, both Karikó and Weissman are, as of today and despite their major scientific contributions, not members of the National Academy of Sciences.

Beyond COVID-19: Of course, COVID-19 vaccines saved millions of lives (1) but the potential of mRNA technology does not end there. mRNA vaccines can be adapted quickly and are a perfect tool to respond to outbreaks and pandemics. In addition, their flexibility allows for testing of many different antigens and antigen designs in parallel which simplifies vaccine development. Furthermore, the short time that is needed to update vaccine constructs will improve the process to make seasonal influenza virus vaccines. Typically, strains for influenza virus vaccines are selected in February for the Northern hemisphere for the ensuing winter season (six to ten months away). However, this selection has to be based on a "best guess" and new strains may take over between the time of strain selection and when the vaccine is rolled out by industry. This can have a negative impact on vaccine effectiveness. With mRNA vaccines, the strain selection could be done just 2 months before distribution of the vaccine takes place, allowing for a more accurate selection, which results in a better match between circulating viruses and the vaccine strains. A number of modified mRNA vaccine candidates against different pathogens is currently in the development including respiratory syncytial virus (RSV), additional respiratory viruses, cytomegalovirus (CMV), and other pathogens. These vaccines could make a strong impact in the future. In addition to vaccines against infectious diseases, cancer vaccines (36) and treatments based on modified mRNA are in clinical development. The mRNA/LNP system allows for a lot of flexibility and vaccines and treatments could be combined in the same formulation. Of course, mRNA technology also has significant potential for the development of other—gene therapy-like—therapeutic approaches in which the absence or the deficiency of a protein is supplemented via mRNA. An emerging field is also the in vivo expression of monoclonal antibodies which could be revolutionary in terms of access to mAb treatments. Protein-based mAb treatments are cost-prohibitive in many low- and middle-income countries but treatment via mRNA delivery of mAbs is likely much more accessible and economic. We should not forget that non-modified mRNA technologies also have potential and the mRNA technology in general is not a silver bullet that can by itself solve complex immunological or general biological challenges. It is worth mentioning that Karikó and Weissman have trained many highly promising young investigators like Norbert Pardi, who will undoubtedly make significant contributions and move mRNA vaccines and therapeutics forward in many different directions.

The 2023 Prize for Physiology or Medicine was given for discovering a biological phenomenon, which allowed the development of safe and protective mRNA vaccines administered to many millions of human beings. While the safety record of the mRNA vaccines has been extraordinary and the benefits of COVID-19 vaccinations continue to outweigh any potential risks (37), the principle of giving foreign RNA as a licensed drug to humans is new. Recent evidence shows that short and long non-protein-coding RNAs function at many levels of gene expression (38, 39). These important host cell functions may be affected by the administration of foreign RNAs. In the future it will be imperative to continue basic research on these novel non-coding RNA/protein interactions which could also open up novel avenues for RNA therapeutics. In any case, the administration of foreign RNAs will have to be carefully monitored for unwanted adverse events as we move forward with this exciting new medical technology.

In summary, Katalin Karikó’s and Drew Weissman’s discoveries made it possible to develop COVID-19 mRNA vaccines, which saved millions of lives. Furthermore, the modified mRNA technology holds significant potential for the development of future vaccines, for future pandemic preparedness and for the development of therapeutics, especially in the cancer space. In addition, Katalin Karikó’s story inspires and teaches us that hard work, diligence, and persistence in science—despite facing hardship—ultimately pays off and can lead to discoveries that enhance science and improve the lives of millions.