Scientists Katalin Karikó and Drew Weissman win Nobel for mRNA vaccine: How their cutting edge technology helped us tame COVID-19

How do mRNA vaccines work and what did Kariko and Weissman find out?

All vaccines work on the same principle – getting the body acquainted with a non-lethal form of the pathogen so that the immune system learns to defend itself against infection. The mRNA vaccines carry the genetic code for the proteins that make up the non-lethal but key parts of a virus. For example, the COVID-19 vaccines used the codes for the spike protein used by Sars-CoV-2 to enter the body. Once injected, the vaccine uses the body’s own protein manufacturing centre to produce these viral proteins. The immune system then responds by creating antibodies against the viral protein and learns to fight the actual infection.

In this undated image provided by Penn Medicine, Katalin Karikó and Drew Weissman pose for a photo at the University of Pennsylvania in Philadelphia. Karikó and Weissman won the Nobel Prize in medicine on Monday, Oct. 2, 2023, for discoveries that enabled the creation of mRNA vaccines against COVID-19 and that could be used to develop other shots in the future. (Peggy Peterson Photography/Penn Medicine via AP)

Kariko and Weissman realised that the immune system was able to recognise the lab-developed mRNA molecules as foreign substances, leading to inflammatory reaction. However, this did not happen when mRNA derived from animal cell assays were used. This led them to look for properties in the lab-developed mRNA molecules that were tripping off the immune system. They found that the mRNA derived from the animal cell assays frequently contained various modifications that were not seen in the lab-developed uniform mRNA molecules.

How did they solve the inflammation problem with mRNA vaccines?

To test whether the absence of these alterations were the reason the lab-developed molecules were considered to be foreign, while those from animal cells were not, Kariko and Weissman produced different variants of mRNA with chemical alterations. When they used these altered mRNA, the results were striking. The changes to the mRNA completely did away with the inflammatory response.

Subsequent studies by the two showed that the altered mRNA generated more viral proteins efficiently as compared to the unaltered ones. These discoveries eliminated critical obstacles to clinical applications of mRNA.

What were the types of vaccines available before the pandemic?

Two vaccine types with the complete virus have been in use for years. These include a live, attenuated vaccine, which has a weakened version of the pathogen, like the oral polio vaccine. The second type involves an inactivated vaccine that uses killed pathogens to elicit an immune response such as the rabies vaccine.

With the progress of molecular biology and techniques to edit genetic codes, vaccines using small, non-lethal parts of the pathogen have been developed. These are called sub-unit vaccines. Some vaccines also encode these non-lethal parts to another pathogen that carries and distributes it through the body – an example of this was the AstraZeneca vaccine available in India as Covishield that used parts of the COVID-19 virus attached to an adenovirus. These are called vector vaccines.

However, the challenge with all these types of vaccine is the need for animal cell assays, making it time-consuming and expensive to scale up. An additional problem with vector vaccines is that the immune system also develops responses to the carrier virus as well, making the booster shots not so effective.

Vaccines sending in the DNA were considered to be an alternative but they failed in producing good response in humans as compared to what was seen in lab animals. This is because DNA vaccines need to undergo two steps as compared to just one by mRNA – the DNA has to be transcribed as mRNA before proteins are produced. The mRNA vaccines circumvent all these challenges. An additional advantage with mRNA vaccines is that the delivered genetic code cannot influence the human genome, making it safer than DNA vaccines.

What were the challenges to mRNA technology before the pandemic?

The lab-based mRNA molecules were considered unstable and challenging to be delivered into the body in addition to the inflammatory responses. In addition to the research by Kariko and Weissman solving the issues of the inflammatory response and low production of protein, development of efficient fat molecules to carry the mRNA inside the body were key to the development of the vaccines.

What are the advantages of mRNA technology as compared to other vaccines?

Not only are nucleic acid-based vaccines easy to manufacture; they are also flexible since the sequence can be easily modified for different pathogens. In the future, the technology may also be used to deliver therapeutic proteins and treat some cancer types. Several companies have been working on developing mRNA vaccines since 2010,with MERS-CoV being one of them, which closely resembles the Sars-CoV-2 virus that causes Covid-19. Protective effects of around 95 per cent were reported, and both vaccines were approved as early as December 2020.