The discovery of Kariko and Weissman, which could have changed the trajectory of the COVID-19 pandemic, and the fates of many other illnesses. Image credit: Mat Napo via Unsplash
A few years ago, one of the questions on University Challenge was, “What does the ‘m’ stand for in mRNA?”. Until recently, most people would have struggled to come up with an answer to that unless they were either exceptionally good guessers or had paid very close attention in GCSE biology. Since the COVID-19 pandemic, however, the term “mRNA” has very much found its place in society’s vocabulary, mainly because of the high-profile development of a new class of vaccine: the mRNA vaccine. There were many players in the development of the mRNA vaccine, and the work of two of these players was recently acknowledged by the Nobel Prize Committee. It was announced on Monday 2nd October that Katalin Kariko and Drew Weissman were the winners of the 2023 Nobel Prize in Physiology and Medicine. Their work in the 1990s and 2000s on developing mRNA that could be injected safely into cells was crucial to the development of the COVID-19 vaccines during the recent pandemic. Developing mRNA that could be injected safely into cells was crucial to the development of the COVID-19 vaccines during the recent pandemic.
“What does the ‘m’ stand for in mRNA?”.
Vaccines train your immune system to recognise the danger presented by a particular pathogen, in a way where the actual risk of you becoming unwell is very low. It’s a bit like the first aid sessions you have in school where you try to avoid touching the mouth of the CPR dummy with your lips, and then ten years later you’re hailed a hero for saving a lady having a cardiac arrest on a train. Some vaccines use live viruses that have been weakened, such as the original smallpox vaccine, MMR and rotavirus. Other vaccines use subunits, which are small pieces of virus, and these include both the Meningitis ACWY and hepatitis B vaccines.
Generally, the more closely the vaccine resembles a natural infection, the better the immune response. Live vaccines are described as being more “immunogenic”, meaning they help your body develop better immunity than subunit vaccines do. So, it may seem strange that we bother producing subunit vaccines when we know that live vaccines deliver better immunity.
The problem with live vaccines is that the weakened virus can regain strength and virulence in people who are immunocompromised. Indeed, this has been a recent problem with polio, for which there is a live vaccine. Polio has been almost entirely eradicated, but in recent years, the remaining cases that do crop up are often caused by vaccination. So we have a problem; we want a vaccine which is safe for everyone, like the subunit vaccine, and also one which induces a long-lasting and effective immune response, like a live vaccine. In some ways, mRNA vaccines do both.
We have a problem; we want a vaccine which is safe for everyone, like the subunit vaccine, and also one which induces a long-lasting and effective immune response, like a live vaccine. In some ways, mRNA vaccines do both.
Scientists started to look at how mRNA could be delivered into cells in the 1970s. mRNA is the in-between molecule of DNA and protein, and if you give a cell some mRNA which codes for a certain protein, the cell can make that protein. Some scientists began to wonder; if you get a human cell to make pathogen proteins, can those pathogen proteins then trigger an immune response?
There was a big problem with this idea—scientists found that when they injected mRNA straight into cells, the cells would become angry and inflamed. The reason why this was happening was unknown, or at least it was before the work of Kariko and Weissman.
Kariko and Weissman conducted their studies on dendritic cells, which are a type of white blood cell in your body that are crucial for the early stages of an immune response and have an exceptional ability to identify foreign substances. Through their research, Kariko and Weissman realised that dendritic cells were treating injected mRNA as if it were a foreign substance and triggered an inflammatory response, a bit like the rejection of an organ following a transplant. But this felt counter-intuitive: the cytoplasm of our cells is brimming with mRNA that we need to constantly make new proteins, so it seems odd that injecting it was causing an inflammatory response.
The explanation to this dilemma is that mammalian cells can chemically modify their mRNA bases, meaning that the mRNA that was synthesised in the lab and then injected into cells, and was not chemically modified in the same way, probably looked a bit suspicious floating around in the cytoplasm. So, to overcome this, Kariko and Weissman modified the mRNA they were using and then injected it into dendritic cells to find out whether this removed the inflammatory response. These modifications included changes like the addition of groups to bases in the RNA: the addition of a methyl group to adenine, or the addition of a sulphur group to uracil. For some of the modifications, they found that the dendritic cells released significantly fewer cytokines and activation markers, meaning the inflammatory response was much lower. The pair published their results in 2005, followed by another paper in 2008 where they showed that replacing one RNA base, uridine, with pseudouridine, greatly increased how much of the injected mRNA was translated into proteins. These discoveries overcame some of the major challenges to mRNA vaccines and 15 years later, the Pfizer COVID-19 vaccine became the first mRNA vaccine to achieve full FDA approval.
These discoveries overcame some of the major challenges to mRNA vaccines and 15 years later, the Pfizer COVID-19 vaccine became the first mRNA vaccine to achieve full FDA approval.
The mRNA vaccine has advantages over traditional vaccines. mRNA usually only codes for one protein from the pathogen, so there is no risk of reactivation of the pathogen like there is with live vaccines. Furthermore, one major limitation of subunit vaccines is that many fail to recruit a particular kind of white blood cell, the CD8+ T-cell. These cells join the immune response only when pathogen products are found inside body cells, which does not normally happen with subunit vaccines. With mRNA vaccines, the pathogen products are made inside your cells, so that means these CD8+ T cells will be activated.
mRNA vaccines cannot address all vaccination challenges, like HIV, or malaria. Nonetheless, they remain an impressive development of a life-saving technology. Edward Jenner is known for developing the first successful vaccine, but the history of inoculation stretches back a long time before him and will continue to stretch far into the future. Kariko and Weissman are examples of the many scientists whose work is helping us to develop better vaccines and save more lives than ever before, and we congratulate them on their incredible achievements.
