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Nobel Prize in Physiology or Medicine; the prequel to mRNA vaccines

The Nobel prize in Physiology or Medicine 2023 was awarded to Katalyn Karikó and Drew Weissman for their discoveries concerning nucleoside base modifications; this later enabled the development of effective mRNA vaccines against COVID-19. Let’s look together at what this means.





Your genetic code consists of DNA, which carries the information your cells need to produce all of the proteins essential for their function. Before the code can be translated into protein, DNA is first copied to a molecule called messenger RNA (mRNA). Molecules of mRNA are made up of units called nucleotides, which comprise three parts: a sugar, a phosphate, and a nitrogenous base. There are four different nitrogenous bases: adenine (A), cytosine (C), guanine (G), and uracil (U); the order in which these occur within a molecule of mRNA tells the cell what type of protein to produce.  The mRNA can then undergo further modification that will regulate its stability and how much it is translated into proteins.


The purpose of vaccination is to induce an immune response from the body against a pathogen; this can be done by using inactivated or attenuated pathogens, or a part of the pathogen (protein, sugar, capsid, toxin…). Proteins can either be delivered directly or by providing the code for the body to produce it (in the form of DNA or RNA). mRNA is a very convenient platform to deliver code to cells, notably because it can be produced in vitro, in a fast, inexpensive and scalable process. Yet several problems had to be solved before mRNA could be used efficiently in a vaccine.


During the 1980s, the first methods to produce mRNA in vitro were developed. However, these mRNA were unmodified, resulting in instability, inflammation through activation of an innate immune response and poor translation. This impeded their use in research and in the clinic, and all attempts at vaccine development failed.


Katalin Karikó, a biochemist whose work was focused on mRNA, and her colleague Drew Weissman, an immunologist, began collaborating in the 1990s. Together, they were the authors of major studies on mRNA modifications, leading to the discoveries that overcame the limitations of in vitro-produced mRNA.


Karikó and Weissman focused on the differences between mRNA produced in vitro and that produced by mammalian cells. They were the first to show that mRNA modifications had an effect on the immune response induced by mRNA, and published their results in 2005 [1]. They then showed in 2008 that using a substitute of uridine, pseudouridine, allowed higher stability and translation efficacy of the mRNA and decreased side effects [2]. Further studies were then performed in academia and in industry to optimize the modifications of mRNA, their stability, immunogenicity and translation. One of the main two COVID-19 mRNA vaccine manufacturers, Moderna, is named after Modified RNA.


Another limitation of mRNA use in the clinic was that it needs to be delivered directly into cells in order to result in protein production. The first liposome based mRNA delivery system was developed in 1978 [3]. Mallone then improved these liposomes with the use of cationic lipids, producing key work for efficient mRNA delivery [4]. Years of research allowed the development of lipid nanoparticles that enabled a safe and efficient uptake of mRNA by cells. The cells then produce the protein encoded by the mRNA, the spike protein from SARS-CoV-2 in the case of the COVID-19 vaccine. As this protein is a ‘non-self’ signal, the body can then raise an immune response against it, and thus be ‘vaccinated’.


Dozens of clinical trials of mRNA vaccines against cancer and infectious disease such as rabies, Zika or influenza virus, were performed between 2010 and 2020. None were approved, some because of a lack of efficiency, others because of a lack of funding, need or urgency. However, these clinical trials showed the safety of mRNA vaccines, and allowed scientists to confirm such vaccines could work. COVID-19 mRNA vaccines were developed and approved in under 1 year, thanks to the work of thousands of scientists between 1980 and 2020. On a recent visit to the Institut Pasteur, the speed of this development was hailed by Anthony Fauci - director of the National Institutes of Allergy and Infectious Diseases from 1984-2022 and a leading member of the White House Coronavirus Task Force during the COVID-19 pandemic. Dr. Fauci described the mRNA vaccine as “an unprecedented scientific achievement, considering that vaccine development normally takes 7-10 years”. Emphasising how such innovation may benefit human health in years to come, he continued  “It is a good indicator of our research ability and of scientific preparedness for future pandemics”. The COVID-19 mRNA vaccines saved nearly twenty million lives according to models [5]


Not only did Karikó and Weissman’s work pave the way to efficiently use mRNA as a platform to produce proteins in cells, it also contributed to the fundamental understanding of the immune response to non-self mRNA.


References


1.Kariko, K., Buckstein, M., Ni, H. & Weissman, D. Suppression of RNA recognition by Toll-like receptors: the impact of nucleoside modification and the evolutionary origin of RNA. Immunity 23, 165-175 (2005). https://doi.org:10.1016/j.immuni.2005.06.008

2. Kariko, K. et al. Incorporation of pseudouridine into mRNA yields superior nonimmunogenic vector with increased translational capacity and biological stability. Mol. Ther. 16, 1833-1840 (2008). https://doi.org:10.1038/mt.2008.200


3.Dimitriadis, G. Translation of rabbit globin mRNA introduced by liposomes into mouse lymphocytes. Nature 274, 923–924 (1978). https://doi.org/10.1038/274923a0

[4] Malone RW, Felgner PL, Verma IM. Cationic liposome-mediated RNA transfection. Proc Natl Acad Sci U S A. 1989 Aug;86(16):6077-81. doi: 10.1073/pnas.86.16.6077. PMID: 2762315; PMCID: PMC297778.


4. Watson, O. J. et al. Global impact of the first year of COVID-19 vaccination: a mathematical modelling study. Lancet Infect. Dis. 22, 1293-1302 (2022). https://doi.org:10.1016/S1473-3099(22)00320-6


5. Watson, O. J. et al. Global impact of the first year of COVID-19 vaccination: a mathematical modelling study. Lancet Infect. Dis. 22, 1293-1302 (2022). https://doi.org:10.1016/S1473-3099(22)00320-6


This article was specialist edited by Olivier Schwartz and copy edited by Tom Cumming.

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