The story so far: On October 2, Nobel Prize week began with the 2023 Prize in Physiology or Medicine being awarded to Katalin Karikó and Drew Weissman. They were awarded the prize for their “discoveries concerning nucleoside base modifications that enabled the development of effective mRNA vaccines against COVID-19”.
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What are mRNA vaccines?
mRNA, which stands for messenger RNA, is a form of nucleic acid which carries genetic information. Like other vaccines, the mRNA vaccine also attempts to activate the immune system to produce antibodies that help counter an infection from a live virus. However, while most vaccines use weakened or dead bacteria or viruses to evoke a response from the immune system, mRNA vaccines only introduce a piece of the genetic material that corresponds to a viral protein. This is usually a protein found on the membrane of the virus called spike protein. Therefore, the mRNA vaccine does not expose individuals to the virus itself.
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According to an article by Thomas Schlake et al, in RNA Biology, RNA as a therapeutic was first promoted in 1989 after the development of a broadly applicable in vitro transfection technique. A couple of years later, mRNA was advocated as a vaccine platform. He says, “mRNA offers strong safety advantages. As the minimal genetic construct, it harbours only the elements directly required for expression of the encoded protein.” A common approach by vaccine makers during the pandemic was to introduce a portion of the spike protein, the key part of the coronavirus, as part of a vaccine. Some makers wrapped the gene that codes for the spike protein into an inactivated virus that affects chimpanzees, called the chimpanzee adenovirus. The aim is to have the body use its own machinery to make spike proteins from the given genetic code. The immune system, when it registers the spike protein, will create antibodies against it.
How are these vaccines different?
A piece of DNA must be converted into RNA for a cell to be able to manufacture the spike protein. While an mRNA vaccine might look like a more direct approach to getting the cell to produce the necessary proteins, mRNA is very fragile and will be shred apart at room temperature or by the body’s enzymes when injected. To preserve its integrity, the mRNA needs to be wrapped in a layer of oily lipids, or fat cells. One way to think of this is that an mRNA-lipid unit most closely mimics how a virus presents itself to the body, except that it cannot replicate like one. DNA is much more stable and can be more flexibly integrated into a vaccine-vector. In terms of performance, both are expected to be as effective.
A challenge with mRNA vaccines is that they need to be frozen from -90 degree Celsius to -50 degree Celsius. They can be stored for up to two weeks in commercial freezers and need to be thawed at 2 degrees Celsius to 8 degrees Celsius at which they can remain for a month. But a major advantage of mRNA and DNA vaccines is that because they only need the genetic code, it is possible to update vaccines to emerging variants and use them for a variety of diseases.
Viral vector vaccines, like Covishield, carry DNA wrapped in another virus, but mRNA are only a sheet of instructions to make spike proteins wrapped in a lipid (or a fat molecule) to keep it stable. In the case of COVID-19, mRNA vaccines developed by Moderna, Pfizer and Pune-based Gennova Biopharmaceuticals, these instructions alone are capable of producing the spike protein, which the immune system then uses to prepare a defence.
Why is it significant?
After the Nobel Prize was announced, Dr. Soumya Swaminathan, formerly chief scientist of the WHO, posted on X, formerly Twitter, that painstaking research over decades and a belief that mRNA technology would have human applications one day have earned the Nobel Prize for Dr. Karikó and Dr. Weissman. “We will see more mRNA products in the near future,” she said. In its release, the Nobel Assembly pointed out that enthusiasm for developing mRNA technology for clinical purposes was initially limited because of hurdles. “Ideas of using mRNA technologies for vaccine and therapeutic purposes took off, but roadblocks lay ahead. 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.”
What were the challenges Dr. Karikó faced?
Dr. Karikó’s struggles are of special note among this year’s winners. “Ten years ago...I was kicked out, from Penn [Pennsylvania University] and forced to retire,” she told Adam Smith during her interview with nobelprize.org after the winners were announced. Dr. Karikó spent a large part of her career on the periphery of academic circles, always in the pursuit of grants to fund her research. Dr. Karikó spent most of the 1990s writing grant applications to fund her mRNA research. She believed that mRNA was key to treating diseases that needed the right kind of protein to fix the problem.
Together with Dr. Weissman, she published a paper in 2005 that highlighted breakthrough research in the field. In 2015, they figured how to deliver mRNA into mice using a fatty coating called “lipid nanoparticles” that protected the mRNA from degradation. Both her innovations were key to the development of COVID-19 vaccines developed by Pfizer and its German partner BioNTech.
(With inputs from agencies)
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