Dr John Tregoning, Professor in Vaccine Immunology, recounts his experience of working with Dr Katalin Karikó, Nobel Prize winner and the tenacious force behind the mRNA vaccines that helped change the course of the COVID-19 pandemic. Their recently published study investigates how RNA modifications impact the body’s immune response to infection, with the hopes of aiding the development of more effective mRNA vaccines.
Science is collaborative, we work with lots of different people to understand the world around us. Working with other people is one of the joys of the job. In our recently published study, Reducing cell intrinsic immunity to mRNA vaccine alters adaptive immune responses in mice, we had the privilege of working with Dr Katalin Karikó, joint winner of the 2023 Nobel prize in Physiology or Medicine.
I first met Kati in what film makers might describe as her dark night of the soul; the period in the wilderness just before the triumph. She came to Imperial to give a seminar in around 2016, 3 years after she had left U Penn where she famously did not get tenure. She had moved to BioNTech the German RNA company; we were working with them on another project that was published in 2018. It should be noted that this is before they were cool, the RNA vaccine equivalent of seeing The Beatles in Hamburg; the audience was only the hardcore vaccinologists who came to the talk.
The importance of persistence
We set up a follow-up study and did some of the preliminary experiments but the project stalled slightly. It was only during the first COVID lockdown when my lab closed that I remembered we had half a story with one of the coolest scientists in the world. And Kati is exceptional, her biography has now often been retold, but it is worth highlighting her leaving communist Hungary as a child with a teddy bear stuffed with money to put her life in the context of history. Somehow, on top of all this, she has supported her daughter to become an Olympic champion in rowing. Kati took the time to chat with me during the COVID pandemic, when the vaccine that her research was integral to was being launched to restart my project. One of her most important qualities is persistence; she carried on working on her idea about nucleotide silencing even when it was unfashionable and not receiving the attention from grant bodies or academic journals. Luckily, some companies were interested and licensed the work to develop the vaccine that helped reduce disease and death during the COVID pandemic.
The key finding that Kati made with Professor Drew Weissman whilst working at U Penn was that subtly changing the chemistry of the building blocks of RNA could alter the way in which the body sees the vaccine. RNA is made up of four units called nucleotides, these are often represented as the letters A, U, C and G. For vaccines, the RNA is made in a test tube so that it can be engineered. Critically, if the U (for Uridine) is replaced with a similar component called pseudouridine then the immune system cannot see it quite so well. This is important because in order to work effectively, RNA vaccines need to be converted by the body into proteins (a process called translation).
Kindness pays off
In our recent work, we compared the response to RNA vaccines made with unmodified RNA to the response to the pseudouridine containing, ‘silenced’ version. We observed that there were striking differences between the different RNA vaccine types. As predicted by Kati’s initial ground-breaking research, the unmodified RNA did trigger the cellular alarm system much more strongly than the silent RNA. This led to changes in the way the immunised cells talked to each other, and ultimately the unmodified RNA was less able to protect against infection than the silent RNA.
The resulting paper describing the work was accepted on Sunday 1st October 2023, one day before the Nobel prize was announced. In spite of everything else that was going on, Kati took the time to email me to say congratulations on getting the paper published. I feel truly blessed to have worked with her, and to see how there are other routes to the top of science; that kindness and perseverance does pay off.
Hadi Sallah works in my lab and on the project