Researchers Katalin Karikó and Drew Weissman have been awarded the 2023 Nobel Prize in Medicine or Physiology for their discoveries on nucleoside base modifications that allowed the development of effective mRNA vaccines against COVID-19, as announced this Monday by the Institute. Karolinska from Sweden.
The discoveries of the two Nobel laureates have been instrumental in developing effective mRNA vaccines against COVID-19 during the pandemic that began in early 2020. Through their groundbreaking discoveries, which have fundamentally changed the understanding of how mRNA interacts with the immune system, “the awardees contributed to the unprecedented rate of vaccine development during one of the greatest threats to human health in modern times.”
“Through their fundamental discoveries on the importance of base modifications in mRNA, this year’s Nobel Laureates made a fundamental contribution to transformative development during one of the greatest health crises of our time,” the committee said.
VACCINES BEFORE THE PANDEMIC
Vaccination stimulates the formation of an immune response to a particular pathogen. This gives the body an advantage in fighting disease in the event of subsequent exposure. Vaccines based on killed or weakened viruses have long been available, such as vaccines against polio, measles and yellow fever. In 1951, Max Theiler received the Nobel Prize in Physiology or Medicine for developing the yellow fever vaccine.
Thanks to advances in molecular biology in recent decades, vaccines have been developed based on individual viral components, rather than whole viruses. Parts of the viral genetic code, which typically encode proteins found on the surface of the virus, are used to produce proteins that stimulate the formation of virus-blocking antibodies. Some examples are vaccines against hepatitis B virus and human papillomavirus.
Alternatively, parts of the viral genetic code can be moved into a harmless carrier virus, a “vector.” This method is used in vaccines against the Ebola virus. When vector vaccines are injected, the selected viral protein is produced in our cells, which stimulates an immune response against the target virus.
The production of vaccines based on whole viruses, proteins and vectors requires large-scale cell culture. This resource-intensive process limits the possibilities for rapid vaccine production in response to outbreaks and pandemics. Therefore, researchers have long tried to develop cell culture-independent vaccine technologies, but this has proven to be challenging.
In cells, the genetic information encoded in DNA is transferred to messenger RNA (mRNA), which is used as a template for protein production. During the 1980s, efficient methods for producing mRNA without cell culture, called ‘in vitro’ transcription, were introduced. This decisive step accelerated the development of molecular biology applications in various fields. Ideas of using mRNA technologies for therapeutics and vaccines also took off, but there were still obstacles ahead.
‘In vitro’ transcribed mRNA was considered unstable and difficult to deliver, requiring the development of sophisticated carrier lipid systems to encapsulate the mRNA. Furthermore, in vitro produced mRNA gave rise to inflammatory reactions. Therefore, enthusiasm for developing mRNA technology for clinical purposes was initially limited.
“These obstacles did not discourage Hungarian biochemist Katalin Karikó, who dedicated herself to developing methods to use mRNA for therapeutic purposes,” they point out. In the early 1990s, when she was an assistant professor at the University of Pennsylvania, she remained true to her vision of realizing mRNA as a therapeutic despite encountering difficulties convincing research funders of the importance of her project. . A new colleague of Karikó at her university was immunologist Drew Weissman.
“He was interested in dendritic cells, which have important roles in immune surveillance and the activation of vaccine-induced immune responses. Spurred by new ideas, a fruitful collaboration soon began between the two, focusing on how different types of RNA interact with the immune system,” they explain.
Karikó and Weissman observed that dendritic cells recognize the transcribed mRNA ‘in vitro’ as a foreign substance, which leads to its activation and the release of inflammatory signaling molecules. They wondered why mRNA transcribed in vitro was recognized as foreign, while mRNA from mammalian cells did not give rise to the same reaction. Karikó and Weissman realized that some critical properties must distinguish different types of mRNA.
RNA contains four bases, abbreviated A, U, G and C, which correspond to A, T, G and C in DNA, the letters of the genetic code. Karikó and Weissman knew that the bases of RNA from mammalian cells are often chemically modified, while mRNA transcribed ‘in vitro’ is not. They wondered whether the absence of altered bases in the transcribed RNA in the in vitro study could explain the unwanted inflammatory reaction. To investigate this, they produced different mRNA variants, each with unique chemical alterations in their bases, which they delivered to dendritic cells.
The results were surprising: the inflammatory response was almost abolished when base modifications were included in the mRNA. This was a paradigm shift in our understanding of how cells recognize and respond to different forms of mRNA. Karikó and Weissman immediately understood that their discovery had profound importance for the use of mRNA as therapy. These pivotal results were published in 2005, fifteen years before the COVID-19 pandemic.
Karikó and Weissman removed critical obstacles on the path to clinical applications of mRNA.
MRNA VACCINES DISCOVERED THEIR POTENTIAL
Interest in mRNA technology began to increase, and by 2010, several companies were working on developing the method. Vaccines against the Zika virus and MERS-CoV were sought; the latter is closely related to SARS-CoV-2. After the outbreak of the COVID-19 pandemic, two mRNA vaccines with modified bases encoding the surface protein of SARS-CoV-2 were developed at a record pace. Protective effects of around 95% were reported and both vaccines were approved as early as December 2020.
“The impressive flexibility and speed with which mRNA vaccines can be developed pave the way for using the new platform also for vaccines against other infectious diseases. In the future, the technology could also be used to deliver therapeutic proteins and treat some types of cancer.” “, they say.
