Kariko and Weissman eliminated critical obstacles on the way to clinical applications of mRNA, paving the way for speedy development of mRNA vaccines that saved millions during the pandemic
Illustration: The official website of the Nobel Prize - NobelPrize.org
The 2023 Nobel Prize for Medicine has been jointly awarded to United States scientists Katalin Kariko and Drew Weissman for their work concerning “nucleoside base modifications that enabled the development of effective messenger ribonucleic acid (mRNA) vaccines against COVID-19”, the Nobel Committee announced in a statement in Stockholm on October 2, 2023.
The discoveries and findings by Kariko and Weissman fundamentally changed the understanding of how mRNA interacts with the human immune system. This “contributed to the unprecedented rate of vaccine development during one of the greatest threats to human health in modern times”.
From the dawn of vaccination till recently, vaccines have been made from:
But, as the statement by the Committee noted, producing whole virus-, protein- and vector-based vaccines 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 attempted to develop vaccine technologies independent of cell culture, but this proved challenging.
Genetic information encoded in human DNA is transferred to messenger RNA (mRNA) in the body’s cells and is used as a template for protein production.
Scientists were able to produce mRNA without cell culture in the 1980s, in a process known as in vitro transcription. This also triggered research on how to use mRNA for vaccine and therapeutic purposes.
However, in vitro transcribed mRNA was considered unstable and challenging to deliver, requiring the development of sophisticated carrier lipid systems to encapsulate the mRNA. Moreover, in vitro-produced mRNA gave rise to inflammatory reactions.
That is where Kariko, a Hungarian-born biochemist stepped in. In the 1990s, she, along with her new colleague, immunologist Weissman started collaborating at the University of Pennsylvania in the US on how different RNA types interact with the immune system.
Weissman was interested in dendritic cells, which have important functions in immune surveillance and the activation of vaccine-induced immune responses.
“Karikó and Weissman noticed that dendritic cells recognize in vitro transcribed mRNA as a foreign substance, which leads to their activation and the release of inflammatory signaling molecules. They wondered why the in vitro transcribed mRNA 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 the different types of mRNA,” the statement observed.
RNA contains four bases, abbreviated A, U, G, and C, corresponding to A, T, G, and C in DNA, the letters of the genetic code.
Karikó and Weissman wanted to test a hypothesis as to whether the absence of altered bases in the in vitro transcribed RNA could explain the unwanted inflammatory reaction.
They produced different variants of mRNA, each with unique chemical alterations in their bases, which they delivered to dendritic cells.
They found that the inflammatory response was almost abolished when base modifications were included in the mRNA. This was in 2005, 15 years before the COVID-19 pandemic.
In further studies published in 2008 and 2010, Karikó and Weissman showed that the delivery of mRNA generated with base modifications markedly increased protein production compared to unmodified mRNA. It also reduced inflammatory responses.
By 2010, several companies were working on mRNA vaccines. After the outbreak of the COVID-19 pandemic, two base-modified mRNA vaccines encoding the SARS-CoV-2 surface protein were developed at record speed. Protective effects of around 95 per cent were reported, and both vaccines were approved as early as December 2020.
Such vaccines have resulted in saving saved millions of lives and prevented severe disease in many more, allowing societies to open and return to normal conditions.
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