Researchers Katalin Karikó and Drew Weissman have been awarded the Nobel Prize in Medicine for their pioneering work on messenger RNA (mRNA). Their discoveries on nucleoside base modifications enabled the development of mRNA vaccines against COVID-19 during the pandemic that began in 2020.
In our cells, the genetic information encoded in DNA is transferred to mRNA, which is used as a template for protein production. While traditional vaccines often contain a weakened or killed version of a pathogen, pathogenic proteins made in laboratories or viruses genetically modified to produce those proteins in the body, mRNA alone can instruct cells to produce particular proteins that trigger immune responses.
The idea of the mRNA vaccine was raised in the 1980s, after the development of techniques in the field of genetics in the laboratory. In vitro transcribed mRNA was considered unstable, difficult to administer and gave rise to inflammatory reactions, requiring the development of carrier lipid systems to encapsulate it and thus facilitate its effectiveness.
Katalin Karikó, born in Hungary in 1955, and Drew Weissman, born in Massachusetts in 1959, began collaborating at the University of Pennsylvania in the late 1990s, combining Karikó’s expertise in RNA biochemistry with Weissman’s expertise in immunology. Karikó focused on developing methods to use mRNA for therapeutic purposes, while Weissman became interested in dendritic cells, which have important roles in the surveillance and activation of vaccine-induced immune responses.
Karikó and Weissman observed that dendritic cells recognize in vitro transcribed mRNA as a foreign substance, which leads to their activation and the release of inflammatory signaling molecules, while mRNA from mammalian cells did not give rise to the same reaction.
They soon realized that the inflammatory reaction was related to a fundamental difference between mRNAs produced inside mammalian cells and those produced by scientists in the laboratory: while the natural ones had various chemical modifications, the ones made in the laboratory did not and this was the reason why they triggered an inflammatory response. The introduction of base modifications in the in vitro transcribed mRNA prevented this undesirable response, opening the way to its possible therapeutic use.
The researchers reproduced some of these modifications in mRNA in the laboratory and then presented the resulting molecules to immune cells called dendritic cells. The results were surprising: the inflammatory response was almost suppressed when base modifications were included in the mRNA. In 2005 they published in the journal Immunity that replacing an mRNA base with modified bases of natural origin could greatly reduce the inflammatory response.
In 2010, interest in mRNA technology grew and several companies began working on its development. Vaccines against the Zika virus and the MERS-CoV coronavirus were produced at that time. Following the outbreak of the COVID-19 pandemic in 2020, two nucleoside base-modified mRNA vaccines encoding the surface protein of SARS-CoV-2 were developed in record time. Both vaccines were approved in December 2020.
The effectiveness of these new vaccines, the ease of adapting them to the variability of infectious agents and their short manufacturing process predicts a significant future in the field of immunization with mRNA techniques.
The side effects associated with these treatments do not seem to be important, although given the short time of their clinical use, it will be necessary to monitor them over time in order to detect hitherto unknown long-term complications. To date, the benefit-risk ratio of the new immunization treatments using mRNA techniques is clearly favorable.