Breaking through the barrier of the immune response to mRNA vaccines

mRNA pioneers Karikó and Weissman were awarded the 2022 Breakthrough Prize in Life Sciences and the 2021 Lasker Award for the development of mRNA technology that has enabled the rapid development of COVID-19 vaccines.

Author: Molly Martin
Editor: Sara Maria Majernikova
Artist: Amaranta Chavez

Within a year of the World Health Organisation (WHO) declaring COVID-19 a pandemic, three SARS-CoV-2 vaccines had been approved for use in the UK, two of which (Pfizer/BioNTech and Moderna) are mRNA-based. This vaccine technology was pioneered by Katalin Karikó and Drew Weissman at the University of Pennsylvania. They demonstrated how mRNA could be altered for safe and efficacious therapeutic use. Now, both researchers are among the winners of one of science’s most lucrative awards, a $3 million Breakthrough Prize, in addition to the $250,000 Lasker Award, dubbed ‘America’s Nobel’.

mRNA is a single-stranded molecule that acts as a blueprint for making proteins. It carries the genetic code stored in DNA from the nucleus to ribosomes, which are the cell’s protein-making machinery. The Pfizer/BioNTech and Moderna vaccines use a synthetic version of the SARS-CoV-2 mRNA that codes for the harmless ‘spike protein’ found on the surface of the virus. Once the vaccine is injected into the body, cells use the mRNA to make the ‘spike protein’ and subsequently display it on their surface. The immune system recognises the protein as foreign and mounts an immune response, synonymous with that which occurs during natural infection with SARS-CoV-2. This results in immunity against the virus, thus preventing symptomatic COVID-19 infection 95% and 94.1% of the time for the Pfizer/BioNTech and Moderna vaccines, respectively. The effectiveness of these vaccines are especially impressive considering they are the first mRNA vaccines to be approved for the treatment of any disease!

However, the mRNA vaccines’ development has been far from easy. They are the product of various breakthroughs from hundreds of researchers over more than 30 years, intertwined with rejections, dead ends, and patent disputes. One leading setback was the fact that injecting mRNA triggers an unwanted immune response because the body senses the molecule as an intruder. In 2005, Karikó and Weissman demonstrated that chemical modification of the mRNA building blocks, nucleosides, prevents the body’s defences from being alerted. In this alternative form, the nucleoside uridine is substituted for its analogue pseudouridine. They also found that changing nucleosides can increase the production of protein from the mRNA.

This key finding, which has paved the way for the rapid development of viable and highly effective mRNA vaccine technology, initially went rather unnoticed. The University of Pennsylvania sold the patent rights for $300,000 to the technological company Cellscript in 2010. Moderna and BioNTech subsequently sublicensed the patent from Cellscript, which has underpinned their highly successful COVID-19 vaccines. A combined 117 million doses have been bought by the UK with global sales expected to surpass $50 billion in 2021 alone, making these some of the most important and profitable vaccines in history.

Beyond COVID-19, Karikó and Weissman’s work will undoubtedly act as the foundation for the future mRNA-based therapies. A huge advantage of these vaccines is that they are much quicker to manufacture than traditional vaccines, as they do not rely on large scale protein purification or the safe inactivation of live viruses, which can be time-consuming. Before 2020, no vaccine had been developed and approved within four years. The COVID-19 mRNA vaccines had been developed within 11 months of the SARS-CoV-2 virus being sequenced by Chinese scientists – an incredible feat of science.

Whilst Weissman is now focusing on the development of vaccines for future coronavirus pandemics, Karikó is planning to use the prize money to set up a company for neurodegenerative disease treatment. One thing for certain is that their discovery has shaped the course of the pandemic and has laid the foundation for the development of future mRNA-based treatments for a range of different diseases, such as Influenza and Zika Virus.

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