Nobel Prize awarded to mRNA vaccine pioneers

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The story behind the discovery that made COVID-19 mNRA vaccines possible…

Hungarian biochemist Katalin Karikó and US immunologist Drew Weissman have been awarded the 2023 Nobel Prize in Medicine for discoveries that fundamentally changed our understanding of how mNRA interacts with our immune system, pacing the way for the rapid development of effective COVID-19 vaccines.

But while vaccines were developed at an unprecedented rate during the pandemic, the two scientists had toiled on the technology for decades.

Initial roadblocks

Since the discovery of mRNA in 1961, scientists have explored how it can be transported into human cells to induce protein expression. Efficient methods for producing mRNA without cell culture were introduced in the 1980s (called in vitro transcription) — but in vitro transcribed mRNA was considered unstable and challenging to deliver, requiring development of sophisticated carrier lipid systems to encapsulate the mRNA. Moreover, in vitro-produced mRNA led to severe inflammatory reactions. For these reasons, mNRA became a scientific backwater.

Fortunately, Katalin Karikó was not discouraged by these setbacks. She persisted with her goal of realising the therapeutic potential of mNRA while working as an assistant professor at the University of Pennsylvania in the early 90s— despite additional difficulties convincing research funders of the project’s significance.

She was soon joined by immunologist Drew Weissman. His expertise in dendritic cells, which can activate vaccine-induced immune responses, proved to be a perfect pairing to her work. Together, they studied how different types of RNA interact with the immune system.

The breakthrough

Karikó and Weissman noticed that while in vitro transcribed mRNA was recognised as a foreign substance, mRNA from mammalian cells was not—so no unwanted immune response was triggered.

This ‘spiked’ their curiosity. They knew that bases in RNA from mammalian cells are often chemically modified, while in vitro transcribed mRNA is not, so they decided to investigate whether the modified bases might be the cause of the unwanted immune response.

What the pair discovered was remarkable. The inflammatory response almost never occurred when base modifications were included in the mRNA.

This marked a fundamental shift in our understanding of how cells respond to different forms of mRNA.

The results were published in 2005 — 15 years before the COVID-19 pandemic.

Karikó and Weissman went on to demonstrate that base modifications in mRNA substantially increased protein production following an injection.

The COVID-19 mRNA vaccines

By 2010, pharmaceutical companies were developing the method, working to create vaccines against the Zika virus and MERS-CoV, a close relative to SARS-CoV-2.

These preliminary advances in mRNA technology meant that when the world entered the COVID-19 pandemic in 2019, two base-modified mRNA vaccines encoding the SARS-CoV-2 surface protein could be rapidly produced.

The vaccines by Moderna and Pfizer-BioNTech contain mRNA which directs cells to generate a ‘spike’ protein, which is a copy of a protein found on the outside of SARS-CoV-2 particles. By December 2020, both vaccines had gained approval for use, with effectiveness estimated at around 95%. To date, more than 13 billion mRNA COVID-19 vaccines have been administered worldwide, preventing millions of deaths and cases of severe disease.

The future

While Karikó and Weissman’s discoveries have been critical to rapid development of vaccines targeting COVID-19, the full potential has likely not yet been realised.

Experts are now examining how mRNA technology can be harnessed to create vaccines against other infectious diseases, such as influenza, malaria and HIV.

The Nobel committee said the technology may have even broader implications.

“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 may also be used to deliver therapeutic proteins and treat some cancer types,” they wrote.

Source: The Nobel Prize in Physiology or Medicine 2023 NobelPrize.org

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