On October 2, 2023, the Nobel Prize in Physiology or Medicine was awarded to two of the founders of mRNA technology—Katalin Karikó and Drew Weissman.
The prize was awarded for their discovery of nucleoside base modifications that led to the development of an effective mRNA vaccine against COVID-19. The duo's discovery was critical to the development of an effective mRNA vaccine against COVID-19 during the pandemic that began in early 2020. Their groundbreaking discovery has fundamentally changed our understanding of how mRNAs interact with the immune system, and they have contributed to an unprecedented pace of vaccine development during a period of one of the greatest threats to human health in modern times.
Vaccines before COVID-19
Vaccination stimulates an immune response to a specific pathogen, which allows our bodies to start fighting the disease earlier if we are later exposed to that pathogen. Vaccines based on inactivated or attenuated viruses have been around for a long time, such as those against polio, measles, and yellow fever. In 1951, Max Theiler was awarded the Nobel Prize in Physiology or Medicine for the development of the yellow fever vaccine.As a result of advances in the field of molecular biology in recent decades, vaccines have been developed that are based on a single component of the virus rather than the entire virus. Parts of the viral genetic code, which usually encodes proteins on the surface of the virus, are used to make proteins that stimulate the formation of virus-blocking antibodies. Examples include vaccines against the hepatitis B virus (HBV) and the human papillomavirus (HPV). Alternatively, parts of the viral genetic code can be transferred to harmless viral "vectors," such as the Ebola vaccine developed in this way.
When these vector vaccines are injected, selected viral proteins are produced in our cells, stimulating an immune response against the target virus. Producing vaccines based on whole viruses, proteins, and vectors requires large-scale cell culture. This resource-intensive process limits the possibility of rapid vaccine production in response to outbreaks and pandemics. As a result, researchers have long tried to develop vaccine technologies that do not need to rely on cell culture, but this has proven to be very challenging.
mRNA vaccines: a promising idea
In our cells, the genetic information encoded in DNA is first transcribed into mRNA, which is then translated into proteins that carry out life's activities. The 1980s saw the introduction of an efficient method for producing mRNA without cell culture—in vitro transcription. This decisive step accelerated the development of applications of molecular biology in several fields.The idea of using mRNA technology for vaccine and therapeutic purposes also began to take off, but obstacles still lie ahead. The mRNAs obtained from in vitro transcription were unstable, and their delivery was challenging, requiring the development of complex carrier-lipid systems to encapsulate the mRNAs. In addition, mRNAs produced in vitro elicited an inflammatory response. As a result, there was initially little interest in developing mRNA technologies for clinical use.
But these obstacles did not stop a Hungarian-born biochemist, Katalin Karikó, from working to develop therapeutic approaches using mRNA.
In the early 1990s, when she was an assistant professor at the University of Pennsylvania, she was holding on to the vision of realizing mRNA as a therapeutic tool but had not been able to get a research grant. Then she met Drew Weissman, an immunologist at the University of Pennsylvania, who was then interested in dendritic cells, which play a crucial role in immune monitoring and vaccine-induced activation of immune responses.
Fueled by new ideas, the two soon began a fruitful collaboration focused on how different types of RNA interact with the immune system.