MOSCOW, October 2, Salma SultanovaThis year’s Nobel Prize winners in physiology or medicine were Katalin Kariko and Drew Weissman, whose discoveries made it possible to create effective mRNA vaccines against COVID-19 in a short time. This will help prevent many other dangerous diseases, including HIV and cancer.
What were vaccines like before the pandemic
The main task of a vaccine is to stimulate the body’s immune response to a particular pathogen. They are usually made from weakened or inactivated whole viruses. Live attenuated vaccines (eg, rubella or yellow fever) provide reliable, long-lasting immunity mediated by antibodies and T cells. Inactivated ones also produce effective immune responses, but these are temporary, so a booster shot is usually required. Max Theiler was awarded the Nobel Prize for the yellow fever vaccine in 1951.
The development of molecular biology and recombinant protein technologies has made it possible to create a new generation of vaccines, in particular vector vaccines that penetrate cells well. However, they require large-scale cell cultures, which makes the process more complex and expensive. A simpler synthetic technology was required.
A promising discovery
The genetic information in our cells, encoded in DNA, is transferred to messenger RNA (mRNA), which is involved in protein synthesis. In the 1980s, the first methods for producing mRNA without the use of cell culture were introduced. This was called in vitro transcription, that is, synthesis in a test tube. However, the widespread use of mRNA technologies for vaccines and therapeutics was still a long way off. The in vitro transcribed mRNA was unstable, difficult to transport, and also caused inflammatory reactions. It was these difficulties that biochemist Katalin Kariko tried to overcome.
The turning point
Kariko grew up in a small village in Hungary. From early childhood she showed interest in natural sciences and studied well. In 1978 she received her doctorate from the University of Szeged. At the Center for Biological Research, she studied the antiviral activity of short RNA segments and studied modified nucleosides — a type of synthetic mRNA in which certain nucleosides are changed or replaced with synthetic or naturally modified nucleosides. In 1985, these studies were no longer funded, and Kariko moved to the United States.
In the 1990s, immunologist Drew Weissman came to the University of Pennsylvania, where Katalin Kariko worked. He was interested in dendritic cells, which are responsible for activating immune responses. They soon began working together to study how different types of RNA interacted with the immune system.
Scientists noticed that dendritic cells perceived synthetic mRNA as a foreign substance. This leads to their activation and the release of inflammatory signaling molecules. But this did not happen with natural mRNAs from mammalian cells. So there must be key differences somewhere.
RNA contains four bases: adenine, uracil, guanine and cytosine. Kariko and Weissman knew that bases in RNA from mammalian cells are often chemically modified, while synthetic mRNA is not. To understand whether this was the problem, scientists created different versions of the molecules by making changes to their bases and then delivering them to dendritic cells. The results were amazing: the inflammatory reaction practically disappeared. This has revolutionized ideas about how cells recognize and respond to different forms of mRNA. The discovery of Kariko and Weissman, which they reported in 2005, made it possible to use mRNA in therapy.
Later, in 2008 and 2010, scientists demonstrated that delivery of mRNA with modified bases promotes better protein production. This has removed barriers to clinical application of mRNA.
“To outwit the immune system, it is enough to replace a few nucleotides in the mRNA molecule — this is what Kariko and Weissman showed. When the mRNA comes into contact with the cell, toll receptors are activated, preventing it from entering. Thanks to modifications of the bases, it was possible to deceive them, and the mRNA, entering the cytoplasm «, began to synthesize the protein that is programmed for it. If the cytoplasm contains a polymerase, the mRNA multiplies, increasing the amount of protein. As a result, the penetration of mRNA has increased thousands of times,» explains Mikhail Bolkov, senior researcher at the Institute of Immunology and Physiology of the Ural Branch of the Russian Academy of Sciences, Candidate of Medical Sciences.
In 2010, several companies began developing drugs based on mRNA, including vaccines against the Zika virus and Middle East respiratory syndrome coronavirus (closely related to SARS-CoV-2).
«Based on mRNA therapy in 2014- «The technology for creating vaccines against cancer and other serious diseases was ready. However, the first infection on which the technology was tested was COVID-19. The main value of the discovery is that they invented a universal method for the production of multifunctional mRNA vaccines,» concludes Mikhail Bolkov.
With the advent of the COVID-19 pandemic, two base-modified mRNA vaccines encoding the surface protein of SARS-CoV-2 were developed at record speed. They were estimated to be 95 percent protective. Both vaccines were approved for use in humans in December 2020.