THE STORY BEHIND THE COVID-19 VACCINE: KATALIN KARIKÓ AND DREW WEISSMAN'S NOBLE PRICE 2023

 

Since Dr. Edward Jenner's development of the vaccine in 1796, it has consistently thwarted countless diseases and been instrumental in preserving countless lives annually. The freedom from polio that we enjoy today can be directly attributed to the effectiveness of vaccines. A conventional vaccine like subjecting live attenuated and inactivated pathogens as a vaccine has protected against a variety of diseases. Despite this improvement, there remain still some bumps with vaccine development against certain infectious pathogens, especially those that can evade adaptive immune response. In addition, for emerging viruses, the main problem is not the effectiveness of conventional vaccines but the need for more rapid development and large-scale deployment.

Nucleic acid therapeutics, as an alternative to traditional vaccine strategies, have gained significant attention. In 1990, the first successful use of in vitro transcribed (IVT) mRNA in animals was reported, where mice were injected with reporter gene mRNAs resulting in detectable protein production. Subsequently, in 1992, another study demonstrated that introducing vasopressin-encoding mRNA into the hypothalamus of rats could induce a physiological response. However, despite these initial promising findings, the development of mRNA therapeutics faced limited investment at that time due to concerns regarding mRNA stability, its strong innate immunogenicity, and challenges with efficient in vivo delivery. Consequently, the field chose to explore alternative therapeutic approaches based on DNA and proteins.

This all changed when Katalin Karikó and Drew Weissman found the first mRNA vaccine that doesn't cause the body to trigger an immune reaction and break the mRNA. The foundation for these developments can be traced back to 2005 when Katalin Karikó and Drew Weissman published a paper titled "Suppression of RNA recognition by Toll-like receptors: the influence of nucleoside modification and the ancestral source of RNA." In this paper, they elucidated how altering specific nucleosides in mRNA can hinder the initiation of an immune response.

They stated that DNA and RNA stimulate the mammalian innate immune system by activating certain receptors known as Toll-like receptors (TLRs). Additionally, it was specifically identified that DNA with methylated CpG motifs doesn't stimulate the immune system. Then the question of whether certain modifications in naturally occurring RNA have similar effects, and this question was explored. It was revealed that RNA activates three TLRs: TLR3, TLR7, and TLR8. But Katalin Karikó and Drew Weissman suggested that RNA incorporated with specific modified nucleosides like m5C, m6A, m5U, s2U, or pseudouridine make the ability of the RNA to dampen or inhibit the activation of receptors. This suggests that these modifications in RNA reduce its immune-stimulatory effects. 

Furthermore exposing the modified and unmodified RNA to dendritic cells (DCs) produced significantly fewer cytokines (signalling molecules of the immune system) and produced fewer activation markers compared to unmodified RNA. The study also notes that bacterial and mitochondrial RNA can strongly activate DCs and cells with TLRs, while RNA from mammals (which typically contains a lot of modified nucleosides) does not have the same immune-stimulatory effect. This leads to the conclusion that nucleoside modifications in RNA appear to suppress its ability to activate dendritic cells and the innate immune system. As a result, the innate immune system might use the absence of nucleoside modifications as a way to selectively respond to bacterial or necrotic tissue, indicating a potential mechanism for distinguishing between different types of RNA in the immune response.

This understanding led to the development of the COVID-19 vaccines by Katalin Karikó and Drew Weissman. The COVID-19 vaccines created by Moderna and the Pfizer-BioNTech partnership use mRNA to provide instructions to cells, prompting them to produce copies of a specific protein present on the surface of SARS-CoV-2 virus particles, which is known as the spike protein.  This process encourages the body to generate antibodies that specifically recognize and target this protein, while also initiating various other immune responses. An essential element of COVID-19 mRNA vaccines included lipid nanoparticles (LNPs), which encase the modified RNA and facilitate its entry into cells. Many scientists played a role in advancing the technology of LNPs for vaccine development.

This led to a breaking thought and was considered a “Vaccine revolution”, and to address it biochemist Katalin Karikó and immunologist Drew Weissman were awarded the Nobel Prize in Physiology or Medicine this year for discoveries that enabled the development of mRNA vaccines against COVID-19. According to the Nobel Committee, these vaccines have been given billions of times, resulting in the preservation of millions of lives and the prevention of millions of severe COVID-19 cases. And through this inspiration mRNA vaccines are in development for a number of other diseases, including influenza, HIV, malaria and Zika.

Interesting Fact

Karikó is the 13th female scientist to be awarded the Nobel Prize in medicine or physiology, hails from Hungary and relocated to the United States during the 1980s. She expressed her hope that this recognition will serve as an inspiration for women, immigrants, and young individuals, encouraging them to persist and exhibit resilience in their pursuits.

Reference 

Pardi N, Hogan MJ, Porter FW, Weissman D. mRNA vaccines — a new era in Vaccinology. Nature Reviews Drug Discovery. 2018;17(4):261–79. doi:10.1038/nrd.2017.243 

Karikó K, Buckstein M, Ni H, Weissman D. Suppression of RNA recognition by toll-like receptors: The impact of nucleoside modification and the evolutionary origin of RNA. Immunity. 2005;23(2):165–75. doi:10.1016/j.immuni.2005.06.008

Callaway E, Naddaf M. Pioneers of mRNA Covid vaccines win medicine Nobel [Internet]. Nature Publishing Group; 2023 [cited 2023 Oct 21]. Available from: https://www.nature.com/articles/d41586-023-03046-x