Nobel medicine prize: How two scientists modified mRNA for vaccine breakthrough

In the battle against Covid-19, one of the gamechangers has been the mRNA vaccine, which was rolled out and administered in quick time. The road to the development of mRNA vaccines, however, was fraught with challenges. Messenger RNA (mRNA) produced in the lab could not be directly administered; part of its composition needed to be modified to make the vaccine safe and effective.

Two researchers who found the way to overcome those challenges, Katalin Kariko and Drew Weissman of University of Pennsylvania, were awarded the Nobel Prize for Medicine or Physiology on Monday.

The technology they developed is used in the Moderna and Pfizer-BioNtech vaccines for Covid-19. The citation mentions “their discoveries concerning nucleoside base modifications that enabled the development of effective mRNA vaccines against Covid-19”. In plain language, it means they made alterations to mRNA in order to make it suitable for vaccination.

mRNA vs other vaccines

Messenger RNA is a molecule that carries instructions to a cell for making proteins. When delivered by a vaccine, the mRNA carries instructions to make a viral protein. Once the protein is synthesised, the immune system mounts a response against it. The objective is for the body to recognise the protein of the virus if it infects the person in the future, and neutralise it. In Covid-19 vaccines, the protein being synthesised is Sars-CoV-2’s spike, which is responsible for latching on to and infecting a cell.

In fact, all vaccines work on the principle of priming the immune response by introducing the pathogen in advance. The key difference is that most vaccine platforms inject either the virus (killed or inactivated) or a part of it, while an mRNA vaccine delivers only the instructions, enabling the body to create the protein itself.

This has various advantages over other vaccine platforms: mRNA is non-infectious and cannot integrate with the host DNA; inactivated vaccines require time-consuming cell cultures while mRNA can be quickly designed and scaled up.

The hurdles

The therapeutic potential of mRNA was recognised more than three decades ago, once researchers developed ways to create it by a process called in vitro transcription. But mRNA so obtained was considered unstable, was difficult to deliver, and gave rise to inflammatory reactions.

Kariko, a Hungarian biochemist, set about researching this field at the University of Pennsylvania in the early 1990s. She was joined by her colleague Weissman, whose interest was dendritic cells that play a role in, among other functions, the immune response activated by vaccination.

They two researchers found that dendritic cells treat in vitro-transcribed mRNA as a foreign substance, which leads to the inflammatory reactions. In other words, the body began attacking the mRNA cells before they could get their target cells to create copies of the protein that was required for immunity training.

But if mRNA from mammalian cells was injected, there were no such reactions. Kariko and Weissman set out to find out why the cells make that distinction. They found the answer in nucleosides — a group of molecules that are part of genetic material. More specifically, it was in the nitrogenous base of nucleosides. In RNA from mammalian cells, nucleoside bases are often chemically modified, but in in vitro-transcribed mRNA, they are not. Was it the absence of these modifications that led to inflammatory reactions to mRNA?

The solution

As it turned out, these modifications were indeed key. Kariko and Weissman produced different variants of mRNA, and delivered each to dendritic cells. Indeed, the inflammatory response was almost abolished when these modifications were included. Kariko and Weissman published these seminal results in 2005.

In subsequent years, mRNA vaccines were developed against Zika virus and MERS-CoV, but the technology was fully exploited only in 2020, during the Covid-19 pandemic. The mRNA vaccines from Moderna and Pfizer-BioNTech vaccines, both with their nucleoside bases modified, were developed at record speed. Both use licensed University of Pennsylvania technology, the university said in a statement congratulating Kariko and Weissman.

Dipyaman Ganguli, principal biologist CSIR-IICB and winner of this year’s Shanti Swarup Bhatnagar Prize for medical science, said the Nobel selection shows how important it is to support basic foundational science research. “They first showed if the modifications are introduced into in vitro-transcribed mRNAs, these can then avoid inflammatory response and drive translation of protein in the host cells. Thus, they provided the theoretical basis for making mRNA vaccines possible,” he said.

In fact, mRNA technology can also be adapted to target evolving viruses, something we witnessed during Covid-19 when the virus went from one variant to another. “You can choose the mRNA that corresponds to the part of the virus that the body responds to. Importantly, as the virus evolves as in Covid-19, you can keep changing the relevant mRNA sequence. The ability to customise the vaccine as the virus evolves, and to be able to make a new vaccine very fast, that’s a crucial step that these people have made,” said theoretical physicist and computational biologist Gautam Menon, dean (research) at Ashoka University.

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