I remember the relief I felt when I got my first Covid vaccine. At the time, people were dying by the thousands, and many of us were touched by the effects of the nasty virus. Vaccines are one of the most important scientific inventions, and they have increased, by decades, the life expectancy of people in countries that use them.
I remember what was like NOT having a vaccine when polio hit in the 1950s. Eventually, a Nobel Prize (1954) went to Enders, Weller, and Robbins for innovations that made the development of Sabin’s oral polio vaccine possible. When I was a child, I received both vaccines, Salk’s and Sabin’s, but they arrived too late for my younger brother, who was partly paralyzed by the virus (camphor bags didn’t work). Maybe that’s why I am always ready to get the next vaccine; I know what happens when there isn’t one.
So here we are, and there is another Nobel Prize for vaccine inventors/innovators. Katalin Karikó, a biochemist who started at Szeged University (Hungary), and Drew Weissman, an immunologist at UPenn, won this year’s Nobel Prize in Physiology or Medicine “for their discoveries concerning nucleoside base modifications that enabled the development of effective mRNA vaccines against COVID-19″. Their discoveries made possible the rapid development of effective vaccines during the COVID emergency.
“This year’s Nobel Prize recognizes their basic science discovery that fundamentally changed our understanding of how mRNA interacts with the immune system and had a major impact on society during the recent pandemic,” and “Karikó and Weissman made fundamental discoveries of the importance of base modifications in mRNA, which eliminated a major obstacle to mRNA-based clinical applications,” said Thomas Perlmann, secretary general of the 2023 Nobel Assembly.
Why are vaccines so valuable in the fight against viral infection? They give the immune system a head start, training it to recognize and attack the virus. The earliest antiviral vaccines, like those against polio and yellow fever, used dead or weakened viruses to induce immune protection. Advancements in molecular biology led to more targeted vaccination strategies that train the immune system using snippets of the viral genome encoding specific viral components, such as proteins on the virus surface. Depending on the type, the vaccine either directs the body to produce proteins that trigger the formation of antibodies or triggers an immune response in reaction to the presence of viral proteins delivered in a viral vector. These approaches are effective but slow to deliver vaccines, a problem when we need a fast response to an emergency. A new approach was required.
Karikó and Weissman studied how mRNA interacts with the immune system, particularly the molecular mechanisms that cause the inflammatory response to mRNA transcribed in vitro.
When these researchers gave mRNA encoding an HIV-1 protein to dendritic immune cells in culture, it triggered a large innate immune response. Karikó and Weissman’s research showed that specific nucleic acid patterns, like the unmethylated CpG motifs in the in vitro transcribed mRNA, activated Toll-like receptors (TLRs), triggering the downstream immune pathways.
In 2005, they came up with a great idea. Since RNA bases from mammalian cells undergo chemical modifications (this doesn’t happen to in vitro transcribed mRNA), Karikó and Weissman wondered whether this lack of modifications explained the immune reaction. To test their hypothesis, they introduced a variety of base modifications to in vitro transcribed mRNA, which they delivered to dendritic immune cells, and they found that these “mammal-like” base modifications canceled the inflammatory signaling. Later, they showed that introducing a different modification to in vitro transcribed mRNA increased protein yield. When they ran experiments on mice, they demonstrated the therapeutic potential of this approach.
One of the key characteristics of the mRNA-based approaches for developing vaccines is that they are modular. Researchers can respond quickly by plugging in the updated sequence when a new viral strain emerges (it always does!). The effects of Karikó and Weissman’s discoveries extend beyond the COVID-19 pandemic. Since their foundational work in the 2000s, interest in mRNA technology has grown rapidly. Using the same approach, scientists have developed several mRNA-based vaccines, including those targeted to SARS-CoV-2, Zika virus, and MERS-CoV. The future of mRNA technologies will likely include the development of cancer vaccines and vaccines against other infections.
To those who still can’t recognize the beneficial power of vaccines, let’s ask them to go back and read history books or watch movies about the misery of humans living in antiquity and the Middle Ages. Quarantine was the only resource when plagues decimated large parts of the world’s population. More recently, the 1918-1920 H1N1 flu epidemic may have killed as many as 100 million people.
I am happy to live in this century.
Weissman D, et al. (2000) HIV gag mRNA transfection of dendritic cells (DC) delivers encoded antigen to MHC class I and II molecules, causes DC maturation, and induces a potent human in vitro primary immune response. J Immunol. 165:4710-4717.
Karikó K, et al. (2005) Suppression of RNA recognition by Toll-like receptors: The impact of nucleoside modification and the evolutionary origin of RNA. Immunity. 2005;23:165–175.