At first, scientists explored how synthetic messenger RNA (mRNA) could be leveraged in gene therapy. This was attractive because it meant we didn’t actually have to change our DNA. There would be no risk of accidentally introducing mutations that could affect how healthy genes work or, worst case, cause cancer.
But, every time mRNA was introduced to cells for gene replacement, it caused a profound immune response. In other words, our immune system was doing its job: recognizing a foreign agent and trying to get rid of it.
This caused scientists to pivot as there is an obvious application for a situation where you want an immune response: vaccination. In 1993, an mRNA influenza test showed successful induction of anti-influenza T cells in mice. This was incredibly exciting.
But there was a major challenge: the mRNA vaccines activated the immune system too early. This resulted in a mediocre antibody response and diverted T cells from a pathway that supported antibody production.
Hou et al., Lipid nanoparticles for mRNA delivery. Nat Rev Mater (2021).
The solution
EnterKarikó, an RNA biochemist, and Weismann, an immunologist.
Karikó was confident she could fashion a vaccine from mRNA but encountered the same stubborn problem: the mice had trouble coping with the immune response after the mRNA vaccine. The quality of the immune response wasn’t as good as she’d hoped for either. Why did Karikó’s synthetic RNA do this when our cells constantly made mRNA with no such problem? Karikó’s RNA had to differ from the RNA our cells made, but how?
In 2005, Karikó and Weissman found the secret sauce: a group of RNA letter changes (i.e. modifications). A particular modification stood out: the change of U (uridine) to Ψ (pseudouridine, a common modification in our own RNA) prevented the immune system from recognizing the mRNA as foreign. They published these findings in Immunity, one of the top journals in the field of immunology.
(Nobel Committee)
As the 2010s progressed, mRNA vaccines trickled into early-phase clinical trials. However, another matter still limited confidence in the approach: mRNA is so fragile that it is very difficult to work with and requires very cold storage conditions.
The pandemic
Then the pandemic came. While we had a key puzzle piece above, there were also other things that needed to come together:
- Carrier: Needed to find an efficient way to deliver the mRNA to our cells before it degraded (we used fat bubbles, which also had a long history; see timeline above).
- Cell instructions: Needed to stabilize the SARS-CoV-2 spike antigen.
- Storage: Needed to supply special freezers to store the vaccine.
All of these were accomplished; the perfect storm that brought together scientific discovery, extensive investment, and global teamwork.
The implications
It is not an understatement to say that their discovery totally transformed our approach to vaccines. You would have a hard time naming a virus of public health importance for which an mRNA vaccine isn’t being attempted, but there are uses beyond that: