To honor the recent Nobel laureates in Medicine and Physiology,
Katalin Karikó and Drew Weissman, who were bestowed with the prestigious award on October 2, 2023, for their groundbreaking work on nucleoside base modifications enabling the creation of highly effective mRNA vaccines against COVID-19, let's delve into the remarkable advancements and the factors that made the realization of COVID-19 vaccines possible in a world grappling with a pandemic.
Their pivotal research yielded three significant papers:
1. “Suppression of RNA Recognition by Toll-like Receptors: The Impact of Nucleoside Modification and the Evolutionary Origin of RNA.”
2. “Incorporation of Pseudouridine Into mRNA Yields Superior Nonimmunogenic Vector With Increased Translational Capacity and Biological Stability.”
3. “Incorporation of pseudouridine into mRNA enhances translation by diminishing PKR activation.”
All of which led to the slow advancements towards the popularization of use of mRNA vaccines. Their work allowed for the creation of stable and efficient mRNA molecules, which in turn facilitated the successful development of COVID-19 vaccines.
Let us now understand what each of these papers said and how it helped us further our vaccine development, not only for COVID-19 but also for diseases like Influenza, HIV and even cancer.
In our cells, genetic information encoded in DNA is transferred to messenger RNA (mRNA), which is used as a template for protein production. During the 1980s, efficient methods for producing mRNA without cell culture were introduced, called in vitro transcription. 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. Bases in RNA from mammalian cells are frequently chemically modified, while in vitro transcribed mRNA is not.
They wondered if the absence of altered bases in the in vitro transcribed RNA could explain the unwanted inflammatory reaction. To investigate this, they produced different variants of mRNA, each with unique chemical alterations in their bases, which they delivered to dendritic cells. The results were striking: The inflammatory response was almost abolished when base modifications were included in the mRNA. DNA and RNA stimulate the mammalian innate immune system through activation of Toll-like receptors (TLRs). Immune system utilizes TLRs to recognize conserved pathogen-associated molecular patterns and orchestrate the initiation of immune responses. Unmethylated cytosine–guanine dinucleotide (CpG) motifs are potent stimulators of the host immune response. DNA containing methylated CpG motifs, however, is not stimulatory.
This was a paradigm change in our understanding of how cells recognize and respond to different forms of mRNA. Karikó and Weissman immediately understood that their discovery had profound significance for using mRNA as therapy. These seminal results were published in 2005, fifteen years before the COVID-19 pandemic. This made the basis of our first paper and arguably the most important one.
In further studies published in 2008 and 2010, Karikó and Weissman showed that the delivery of mRNA generated with base modifications markedly increased protein production compared to unmodified mRNA. This was because in vitro transcripts containing uridine activate RNA-dependent protein kinase (PKR), which then phosphorylates translation initiation factor 2-alpha (eIF-2α), and inhibits translation. In contrast, in vitro transcribed mRNAs containing pseudouridine activate PKR to a lesser degree, and translation of pseudouridine-containing mRNAs is not repressed. Through their discoveries that base modifications both reduced inflammatory responses and increased protein production, Karikó and Weissman had eliminated critical obstacles on the way to clinical applications of mRNA.
How did these discoveries help us in creation and formulation of the COVID-19 vaccines?
Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
The major contribution of our Nobel laureates was making mRNA vaccines possible so that we could tailor those specifically towards the SARS-CoV-2 virus. Production of mRNA vaccines does not require culturing cells or viruses as in traditional vaccine production technology, relying instead on in vitro synthesis technology. Therefore, the production cycle is shorter and easy to scale up, hence offering the possibility of quick industrialization of vaccine production. From IVT of mRNA to preparation of mRNA-LNP complexes, the entire production cycle for an mRNA vaccine might last approximately 10 days.
Overall, the progression of mRNA vaccines represents a monumental leap forward in the field of medicine, ushering in unprecedented levels of life-saving potential.
Reference
by-JOOHI GADODIA
Comments