Question

Katalin Karikó and Drew Weissman were awarded the Nobel Prize in Physiology or Medicine for the year 2023 for their observation that pseudo-uridine ($\psi$) incorporated mRNA (but not mRNA with normal bases A, U, G, and C) is better for RNA vaccine production. These observations paved the way for developing the RNA vaccine against SARS-CoV-2 (the vaccine produces the spike protein of the virus in a cell). The reason that pseudo-uridine incorporated mRNA worked as a better vaccine candidate is:

• A. The innate immune system does not recognise the pseudo-uridine incorporated mRNA allowing translation of the spike protein.
• B. Unmodified mRNA encoding spike protein cannot be translated by the ribosome.
• C. Antigen-presenting cells can translate only pseudo-uridine incorporated mRNA.
• D. Spike protein from unmodified mRNA cannot induce immune response.

Answer 1

Answer: (A)

The innate immune system does not recognise the pseudo-uridine incorporated mRNA allowing translation of the spike protein.

Answer 2

The Nobel Prize in Physiology or Medicine 2023 was awarded to Katalin Karikó and Drew Weissman for their discoveries concerning nucleoside base modifications that enabled the development of effective mRNA vaccines against COVID-19. Their key finding was that incorporating modified nucleosides, such as pseudo-uridine ($\psi$), into mRNA significantly reduces its immunogenicity.

Here's a breakdown of why this is crucial for vaccine production:

1. Innate Immune Recognition: Our cells have evolved mechanisms to detect foreign RNA (like viral RNA) as a sign of infection. This detection is primarily mediated by pattern recognition receptors (PRRs) of the innate immune system, such as Toll-like receptors (TLRs) like TLR3, TLR7, and TLR8. When unmodified mRNA is introduced into a cell, these receptors recognize it as foreign.

2. Immune Response and mRNA Degradation: This recognition triggers an innate immune response, leading to inflammation and, importantly, the degradation of the foreign mRNA and inhibition of its translation. This means that unmodified mRNA would be rapidly destroyed and would not produce enough of the desired protein (e.g., the SARS-CoV-2 spike protein) to elicit a strong and sustained adaptive immune response.

3. Role of Pseudo-uridine: Karikó and Weissman discovered that incorporating pseudo-uridine (a naturally occurring modified nucleoside found in tRNA and rRNA) into mRNA makes it "look" more like endogenous, self-RNA to the immune system. This modification effectively "cloaks" the mRNA from immune recognition.

4. Enhanced Translation: By evading the innate immune system's surveillance, the pseudo-uridine incorporated mRNA remains stable for a longer period and is translated much more efficiently into the target protein. This leads to a higher and more sustained production of the spike protein antigen, which is essential for inducing a robust and protective antibody and T-cell response.

Pseudo-uridine incorporated mRNA is better for RNA vaccine production because the modification reduces its recognition by the innate immune system. This allows the mRNA to evade immune degradation and inhibition of translation, leading to more efficient and sustained production of the desired antigen (e.g., spike protein), which is crucial for eliciting a robust immune response.