Medicine Nobel to Pioneers of mRNA COVID Vaccines

The Nobel Assembly at Karolinska Institutet has agreed to give Katalin Karikó and Drew Weissman the 2023 Nobel Prize in Physiology or Medicine jointly for their discoveries involving nucleoside base alterations, which enabled the development of successful mRNA COVID vaccines.

The two Nobel laureates’ discoveries were important in creating successful mRNA COVID vaccines during the pandemic that began in early 2020. The laureates contributed to an extraordinary rate of COVID vaccine development during one of the greatest risks to human health in modern times by their pioneering discoveries, which radically transformed our knowledge of how mRNA interacts with our immune system.

Vaccines in advance of a pandemic

Vaccination stimulates the development of an immunological response to a specific disease. This gives the body an advantage in the battle against sickness if it is exposed later. Vaccines based on killed or weakened viruses have long been available, as seen by polio, measles, and yellow fever vaccines. Max Theiler received the Nobel Prize in Physiology or Medicine in 1951 for creating the yellow fever vaccine.

Vaccines based on specific viral components, rather than complete viruses, have been created as a result of recent advances in molecular biology. Parts of the viral genetic code, typically encoding proteins located on the virus surface, are exploited to create proteins that promote the development of virus-blocking antibodies. Vaccines against hepatitis B and human HPV are two examples. Parts of the viral genetic code can also be transferred to a harmless carrier virus, known as a “vector.” This technique is employed in Ebola virus vaccinations. When vector vaccines are administered, the targeted viral protein is generated in our cells, triggering an immune response against the virus.

Cell culture on a large scale is required for the production of entire virus, protein, and vector-based vaccines. This resource-intensive technique limits the ability to produce vaccines quickly in response to outbreaks and pandemics. As a result, researchers have long endeavored to develop vaccine technologies that are not dependent on cell culture, but this has proven difficult.

mRNA vaccines: An exciting prospect

In our cells, DNA-encoded genetic information is translated to messenger RNA (mRNA), which serves as a template for protein creation. In the 1980s, efficient methods for synthesizing mRNA without cell culture, known as in vitro transcription, were introduced. This pivotal step hastened the development of molecular biology applications in a variety of sectors. Ideas for leveraging mRNA technologies for vaccination and therapeutic reasons also gained traction, but challenges remained. In vitro transcribed mRNA was thought to be unstable and difficult to distribute, necessitating the development of complex carrier lipid systems to encapsulate the mRNA. Furthermore, in vitro-produced mRNA elicited inflammatory responses. As a result, enthusiasm for developing mRNA technology for therapeutic applications was first restricted.

These challenges did not deter Katalin Karikó, a Hungarian biochemist who was dedicated to researching strategies to employ mRNA for therapy. Despite problems in convincing research funders of the importance of her study in the early 1990s, when she was an assistant professor at the University of Pennsylvania, she remained committed to establishing mRNA as a therapy. Drew Weissman, an immunologist, was a new colleague at Karikó’s institution. He was particularly interested in dendritic cells, which play critical roles in immunological surveillance and the activation of vaccine-induced immune responses. A fruitful partnership between the two quickly began, spurred on by fresh ideas, concentrating on how different RNA types interact with the immune system.

The ground-breaking

Dendritic cells detect in vitro produced mRNA as a foreign substance, which activates them and causes the production of inflammatory signaling molecules, according to Karikó and Weissman. They were perplexed as to why in vitro generated mRNA was detected as foreign whereas mRNA from mammalian cells was not. Karikó and Weissman realized that different kinds of mRNA must have distinct features.

RNA has four bases, abbreviated A, U, G, and C, which correspond to the letters of the genetic code, A, T, G, and C in DNA. Bases in RNA from mammalian cells are typically chemically changed, but not in vitro generated mRNA, according to Karikó and Weissman. They questioned if the lack of changed nucleotides in in vitro produced RNA could explain the unexpected inflammatory response. To examine this, they created various mRNA variants, each with unique chemical modifications in their bases, and transported them to dendritic cells. When base changes were added in the mRNA, the inflammatory reaction was nearly completely reduced. This was a paradigm shift in our knowledge of how cells perceive and respond to various types of mRNA. Karikó and Weissman recognized right away that their discovery had far-reaching implications for the use of mRNA in therapy. These ground-breaking findings were reported in 2005, fifteen years before the COVID-19 epidemic.

In subsequent research published in 2008 and 2010, Karikó and Weissman demonstrated that delivering mRNA with base changes significantly boosted protein synthesis compared to unmodified mRNA. The effect was caused by a decrease in the activity of an enzyme that controls protein synthesis. Karikó and Weissman had removed significant barriers to clinical applications of mRNA by discovering that base changes both lowered inflammatory responses and enhanced protein synthesis.

The promise of mRNA vaccines was realized

Interest in mRNA technology began to grow, and numerous companies were working on developing the process in 2010. Vaccines against Zika virus and MERS-CoV, which is closely linked to SARS-CoV-2, were pursued. Following the COVID-19 pandemic outbreak, two base-modified mRNA vaccines encoding the SARS-CoV-2 surface protein were created in record time. Both vaccinations were approved as early as December 2020, with reported protective effects of around 95%.

The new platform’s exceptional versatility and speed in developing mRNA vaccines pave the possibility for vaccinations against other infectious diseases. In the future, the technology could be utilized to deliver therapeutic proteins as well as treat certain cancers.

Several other SARS-CoV-2 vaccines based on other techniques were also quickly introduced, and more than 13 billion COVID-19 vaccine doses have been administered globally. Vaccines have saved millions of lives and stopped the spread of severe disease in many more, allowing society to reopen and return to normalcy. This year’s Nobel laureates made crucial contributions to this revolutionary development during one of our time’s most serious health crises by making key findings about the impact of base changes in mRNA.

About Scientists Behind COVID-19 Vaccine

Katalin Karikó was born in 1955 in Szolnok, Hungary. She received her PhD from Szeged’s University in 1982 and performed postdoctoral research at the Hungarian Academy of Sciences in Szeged until 1985. She then conducted postdoctoral research at Temple University, Philadelphia, and the University of Health Science, Bethesda. In 1989, she was appointed Assistant Professor at the University of Pennsylvania, where she remained until 2013. After that, she became vice president and later senior vice president at BioNTech RNA Pharmaceuticals. Since 2021, she has been a Professor at Szeged University and an Adjunct Professor at Perelman School of Medicine at the University of Pennsylvania.

Drew Weissman was born in 1959 in Lexington, Massachusetts, USA. He received his MD, PhD degrees from Boston University in 1987. He did his clinical training at Beth Israel Deaconess Medical Center at Harvard Medical School and postdoctoral research at the National Institutes of Health. In 1997, Weissman established his research group at the Perelman School of Medicine at the University of Pennsylvania. He is the Roberts Family Professor in Vaccine Research and Director of the Penn Institute for RNA Innovations.

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