The 2023 Nobel Prize in Physiology or Medicine

has been awarded to

• Katalin Karikó, University of Pennsylvania, Philadelphia, USA, and University of Szeged, Hungary, and
• Drew Weissman, University of Pennsylvania, Philadelphia, USA.

for “their discoveries concerning nucleoside base modifications that enabled the development of effective mRNA vaccines against COVID-19” [1].

 

Research

The development of effective mRNA vaccines was a crucial medical breakthrough during the COVID-19 pandemic. Katalin Karikó and Drew Weissman have made discoveries that were critical for the unprecedented speed of vaccine development that was achieved in this global health crisis.

 

Vaccines

Vaccines stimulate an immune response to a particular pathogen and can, thus, prevent disease when the real pathogen is encountered later. Vaccines can be based on killed or weakened viruses, but more modern vaccines have often used individual viral components, such as proteins found on the virus surface. Alternatively, parts of the viral genetic code can be introduced in a harmless carrier virus, or vector, to induce the production of viral protein in human cells.

Producing vaccines based on whole viruses, proteins, or vectors requires large-scale cell cultures, is resource-intensive, and limits the speed of vaccine production in response to outbreaks of novel viruses or variants.

 

mRNA

Messenger RNA (mRNA) carries genetic information from the DNA in the cell nucleus to the ribosomes in the cytoplasm, where the information is used to construct proteins. Unlike DNA therapeutics, mRNA does not have to enter a cell’s nucleus to exert its effect and does not integrate into the genome of its target cell. Thus, mRNA could be useful to induce the production of viral proteins in human cells for vaccination purposes.

However, in contrast to DNA, mRNA is very unstable. In addition, the immune system generally considers external mRNA as an unwanted intruder, which can prevent the translation of externally derived mRNA.

 

Blunting the Immune Response

The biochemist Katalin Karikó and the immunologist Drew Weissman studied how different RNA types interact with the immune system, working with dendritic cells, which have important functions in immune surveillance and the activation of vaccine-induced immune responses. The two researchers noticed that dendritic cells recognize external mRNA as a foreign substance, which leads to their activation and the release of inflammatory signaling. They knew bases in RNA from mammalian cells are frequently chemically modified, while bases in in-vitro-transcribed mRNA are not.

The team produced different variants of mRNA with chemical alterations in their bases, which they delivered to dendritic cells. The inflammatory response was blunted when base modifications were included in the mRNA.

This discovery had profound significance for therapeutic uses of mRNA. These results were published in 2005 [2]. In 2008 and 2010 [3,4], Karikó and Weissman showed that the delivery of mRNA with base modifications also markedly increased protein production when compared to unmodified mRNA.

 

Fast Vaccine Development

After the outbreak of the COVID-19 pandemic, base-modified mRNA vaccines encoding SARS-CoV-2 surface proteins were developed at record speed. The flexibility and speed with which mRNA vaccines can be developed will likely be useful for vaccines against other infectious diseases. The method might also be used to deliver therapeutic proteins and treat some cancer types in the future.

 

Laureates

Katalin Karikó, born on January 17, 1955, in Szolnok, Hungary, studied biology at the University of Szeged, Hungary, where she received her Ph.D. in 1982. After a postdoctoral stay at the Biological Research Centre (BRC) of the Hungarian Academy of Sciences, Szeged, she moved to the United States in 1985. She was a postdoctoral fellow at Temple University, Philadelphia, PA, USA, from 1985 to 1988, and at the Uniformed Services University of the Health Sciences, Bethesda, MD, USA, from 1988 to 1989. In 1989, she assumed the role of Assistant Professor at the University of Pennsylvania, maintaining this position until 2013. Following that, she transitioned to the roles of Vice President and subsequently Senior Vice President at BioNTech AG in Mainz, Germany. Starting in 2021, she has held the position of Professor at Szeged University, in addition to her role as an Adjunct Professor at the Perelman School of Medicine at the University of Pennsylvania.

Katalin Karikó has received numerous awards, including the Japan Prize in 2022, the Breakthrough Prize in Life Sciences 2022, the Paul Ehrlich and Ludwig Darmstädter Prize 2022, the Széchenyi Prize 2021, the Wilhelm Exner Medal in 2021, the Semmelweis Prize 2021, the Princess of Asturias Award 2021, and the Rosenstiel Award in 2020, and is a Member of the Academia Europaea.

 

Drew Weissman, born in 1959 in Lexington, Massachusetts, USA, studied biochemistry and enzymology at Brandeis University, Waltham, MA, USA, and immunology and microbiology at Boston University, MA, USA, where he received his Ph.D. in 1987. Then, he served as a resident at Beth Israel Deaconess Medical Center, Boston, USA, followed by a fellowship at the National Institutes of Health (NIH), Bethesda, MD, USA. In 1997, Drew Weissman moved to the University of Pennsylvania, where he currently serves as Roberts Family Professor in Vaccine Research.

Among many other honors, Weissman has received the Japan Prize in 2022, the Princess of Asturias Award 2021, the Rosenstiel Award in 2020, and an honorary degree from the Drexel University College of Medicine, Philadelphia, PA, USA.

 

References

[1] nobelprize.org

[2] Katalin Karikó, Michael Buckstein, Houping Ni, Drew Weissman, Suppression of RNA Recognition by Toll-like Receptors: The impact of nucleoside modification and the evolutionary origin of RNA, Immunity 2005, 23, 165–175. https://doi.org/10.1016/j.immuni.2005.06.008

[3] Katalin Karikó, Hiromi Muramatsu, Frank A. Welsh, János Ludwig, Hiroki Kato, Shizuo Akira, Drew Weissman, Incorporation of pseudouridine into mRNA yields superior nonimmunogenic vector with increased translational capacity and biological stability, Mol. Ther. 2008, 16, 1833–1840. https://doi.org/10.1038/mt.2008.200

[4] Bart R. Anderson, Hiromi Muramatsu, Subba R. Nallagatla, Philip C. Bevilacqua, Lauren H. Sansing, Drew Weissman, Katalin Karikó, Incorporation of pseudouridine into mRNA enhances translation by diminishing PKR activation, Nucleic Acids Res. 2010, 38, 5884–5892. https://doi.org/10.1093/nar/gkq347

 

Selected Publications

Selected Publications by Katalin Karikó

• Lipid nanoparticles enhance the efficacy of mRNA and protein subunit vaccines by inducing robust T follicular helper cell and humoral responses,
  Mohamad-Gabriel Alameh, István Tombácz, Emily Bettini, Katlyn Lederer, Chutamath Sittplangkoon, Joel R. Wilmore, Brian T. Gaudette, Ousamah Y. Soliman, Matthew Pine, Philip Hicks, Tomaz B. Manzoni, James J. Knox, John L. Johnson, Dorottya Laczkó, Hiromi Muramatsu, Benjamin Davis, Wenzhao Meng, Aaron M. Rosenfeld, Shirin Strohmeier, Paulo J. C. Lin, Barbara L. Mui, Ying K. Tam, Katalin Karikó, Alain Jacquet, Florian Krammer, Paul Bates, Michael P. Cancro, Drew Weissman, Eline T. Luning Prak, David Allman, Michela Locci, Norbert Pardi,
  Immunity 2021, 54, 2877–2892.e7.
  https://doi.org/10.1016/j.immuni.2021.11.001
• mRNA-based therapeutics — developing a new class of drugs,
  Ugur Sahin, Katalin Karikó, Özlem Türeci,
  Nat. Rev. Drug Discov. 2014, 13, 759–780.
  https://doi.org/10.1038/nrd4278
• Sequence- and target-independent angiogenesis suppression by siRNA via TLR3,
  Mark E. Kleinman, Kiyoshi Yamada, Atsunobu Takeda, Vasu Chandrasekaran, Miho Nozaki, Judit Z. Baffi, Romulo J. C. Albuquerque, Satoshi Yamasaki, Masahiro Itaya, Yuzhen Pan, Binoy Appukuttan, Daniel Gibbs, Zhenglin Yang, Katalin Karikó, Balamurali K. Ambati, Traci A. Wilgus, Luisa A. DiPietro, Eiji Sakurai, Kang Zhang, Justine R. Smith, Ethan W. Taylor, Jayakrishna Ambati,
  Nature 2008, 452, 591–597.
  https://doi.org/10.1038/nature06765

 

Selected Publications by Drew Weissman

• mRNA vaccines — a new era in vaccinology,
  Norbert Pardi, Michael J. Hogan, Frederick W. Porter, Drew Weissman,
  Nat. Rev. Drug Discov. 2018, 17, 261–279.
  https://doi.org/10.1038/nrd.2017.243
• Zika virus protection by a single low-dose nucleoside-modified mRNA vaccination,
  Norbert Pardi, Michael J. Hogan, Rebecca S. Pelc, Hiromi Muramatsu, Hanne Andersen, Christina R. DeMaso, Kimberly A. Dowd, Laura L. Sutherland, Richard M. Scearce, Robert Parks, Wendeline Wagner, Alex Granados, Jack Greenhouse, Michelle Walker, Elinor Willis, Jae-Sung Yu, Charles E. McGee, Gregory D. Sempowski, Barbara L. Mui, Ying K. Tam, Yan-Jang Huang, Dana Vanlandingham, Veronica M. Holmes, Harikrishnan Balachandran, Sujata Sahu, Michelle Lifton, Stephen Higgs, Scott E. Hensley, Thomas D. Madden, Michael J. Hope, Katalin Karikó, Sampa Santra, Barney S. Graham, Mark G. Lewis, Theodore C. Pierson, Barton F. Haynes, Drew Weissman,
  Nature 2017, 543, 248–251.
  https://doi.org/10.1038/nature21428
• Generating the optimal mRNA for therapy: HPLC purification eliminates immune activation and improves translation of nucleoside-modified, protein-encoding mRNA,
  Katalin Karikó, Hiromi Muramatsu, János Ludwig, Drew Weissman,
  Nucleic Acids Res. 2011, 39, e142.
  https://doi.org/10.1093/nar/gkr695

 

Also of Interest

• • Nobel Prize in Physiology or Medicine 2022,
    ChemistryViews 2022.
    The prize was awarded to Svante Pääbo for his discoveries concerning the genomes of extinct hominins and human evolution
  • Chemistry Nobel Prize Quiz,
    ChemistryViews 2019.
    How much do you know about the Nobel Prize Laureates?
  • Collection: Nobel Prize in Chemistry
    Collection of interviews with Nobel Laureates and Nobel Prize quizzes
  • Clever Picture: Comparing COVID-19 Vaccines
    Four Covid-19 vaccines have been approved in the EU to date
    ChemistryViews 2021.
    https://doi.org/10.1002/chemv.202100033
  • Clever Picture: Searching for a Vaccine
    Picture describes what happens during vaccination and gives a snapshot of which Covid-19 vaccine candidates are in which clinical phases
    https://doi.org/10.1002/chemv.202000075