By: Charmaine Szalay-Anderson
Neuroscience Graduate Student
3… 2… 1… Happy New Years! The sound of champagne glasses clinking and cheers echoed as we entered the new decade. The sparkle of silver confetti on the floor dazzled, reflecting all of our hopes and dreams for what 2020 would bring. While many of us were sipping on bubbly, a virus that would wreak havoc on our once hopeful and shiny new year was rapidly infecting people all around the world. Flash forward to March 11, 2020 – the world was brought to a screeching halt as the World Health Organization declared COVID-19 a global pandemic. Public health emergencies were decried, and stay-at-home mandates were soon put into place.
While we were all hunkering down at home, scientists from all corners of the world worked tirelessly to develop treatments and a vaccine for the novel coronavirus. The eventual victor vaccines stemmed from a quiet technology that had been a promising treatment platform in cancer– mRNA vaccines. Even as a scientist, I had only vaguely heard of mRNA being used in vaccines. However, the technology has been in development for over 30 years and is truly revolutionary.
Messenger RNA, or mRNA, was first discovered independently by both Jim Watson and Sydney Brenner in 1961. Many of us are familiar with DNA being the genetic material that is the building block of life. After DNA is made, it creates instructions that then go on to make proteins in our body. These instructions are known as mRNA.
The therapeutic usage of mRNA has been the brainchild of Drs. Katalin Karikó and Drew Weissman for over 30 years. The two were focused on designing a synthetic mRNA to treat an onslaught of conditions ranging from viruses to cancer. Original attempts to introduce this mRNA were unsuccessful due to two major problems. First, the body’s natural defense mechanisms recognized the lab-made mRNA as a foreign invader. This was fixed by a subtle change where one letter in mRNA’s code was modified, allowing it to bypass the body’s bouncers. The second issue was finding an effective delivery method into the body’s cells. When mRNA floats freely in the body, it is quickly degraded. The walls of our cells are made of an oil-like substance that is selective in what it allows into each cell. Researchers struggled to pass mRNA through this wall. After many years of trial and error, they found that using a soap-like bubble package allowed mRNA to enter our cells. Similar to how oils mix well with other oils, this soap-like bubble containing mRNA was just the right carrier to pass through the oil-like walls of our cells.
So, exactly how do mRNA vaccines work? Most of us have become familiar with vaccines that contain inactivated virus, like our seasonal flu vaccine. However, mRNA vaccines do not introduce any form of a virus into your body, but rather the instructions to make a portion of a virus’ genetics. When an mRNA vaccine is injected into your arm, it enters your muscle cells and tells molecules known as ribosomes to get to work. Ribosomes act as small factories in our bodies that read mRNA like an instruction manual and create proteins from these instructions. Once the instructions have been read and executed, the mRNA is broken down. The proteins created are a part of the virus that is non-infectious but can teach the immune system what the virus looks like. This generates memory and the antibodies necessary should you ever come into contact with said virus.
Beyond Karikó and Weissman’s work, other scientists have been exploring the usage of injecting mRNA. The usage of mRNA in vaccines was first proposed in 1990. Shortly after, it was discovered that mRNA vaccines could engage both short-term and long-term immune responses. By 1995, mRNA was used as a means to train the immune system against certain cancer cells in mice. Fast-forward to the 21st century mRNA was being tested for flu vaccines and Zika virus. By 2017, personalized cancer vaccines were being tested pre-clinically with clinical testing on the horizon.
Though we may have many studies touting the success of mRNA vaccines, as with many other unfamiliar technologies, especially technology that contains genetic material, many people have raised concerns. One prevalent concern circulating is that the genetic material contained in mRNA vaccines can alter our genetics. However, our bodies very quickly break down any free floating mRNA. Further, mRNA is not capable of altering our DNA in any way. mRNA is not able to be made into DNA (which is what our genes are made of, and what we pass down), and can only be read as instructions to make proteins.
mRNA vaccines are truly an exciting step forward in science and have many advantages. First, being the rapidity at which we can develop them. Scientists only need the genetic sequence of the virus of interest. For vaccines that employ live-attenuated or whole-inactivated virus, production can take decades as scientists need to obtain, isolate, and grow a virus. While with mRNA vaccines, once we know what makes up a virus’ genetics, scientists can create the viral surface proteins in the lab. This process is both cheap and quick, allowing the vaccine to be made available for preclinical and subsequent clinical testing much quicker. Another benefit to mRNA vaccines is that they are synthetically developed in a lab and are standardized. This aids in both a quick production timeline and standardized safety and quality control.
As of March 2021, many countries have approved both the Pfizer/BioNTech and Moderna mRNA-based COVID-19 vaccines, with many frontline workers and at-risk populations already receiving their shots. With the mass production of mRNA vaccines ramping up, the door has been opened to use mRNA vaccines in an onslaught of other conditions. The most promising being immunotherapy for cancer treatment. While many of us welcomed 2021 socially distanced, in the not-too-distant future, mRNA vaccines have become a promising treatment that perhaps will even keep us safe against future pandemics and many other conditions in the future.
Literature References
Anderson, B. R., Muramatsu, H., Nallagatla, S. R., Bevilacqua, P. C., Sansing, L. H., Weissman, D., & Kariko, K. (2010). Incorporation of pseudouridine into mRNA enhances translation by diminishing PKR activation. Nucleic acids research, 38(17), 5884-5892.
Brenner, S., Jacob, F., & Meselson, M. (1961). An unstable intermediate carrying information from genes to ribosomes for protein synthesis. Nature, 190(4776), 576-581.
Graham, B. S., Mascola, J. R., & Fauci, A. S. (2018). Novel vaccine technologies: essential components of an adequate response to emerging viral diseases. JAMA, 319(14), 1431-1432.
Jackson, L. A., Anderson, E. J., Rouphael, N. G., Roberts, P. C., Makhene, M., Coler, R. N., ... & Pruijssers, A. J. (2020). An mRNA vaccine against SARS-CoV-2—preliminary report. New England Journal of Medicine, 383(20), 1920-1931.
Karikó, K., Muramatsu, H., Welsh, F. A., Ludwig, J., Kato, H., Akira, S., & Weissman, D. (2008). Incorporation of pseudouridine into mRNA yields superior nonimmunogenic vector with increased translational capacity and biological stability. Molecular therapy, 16(11), 1833-1840.
Linares-Fernández, S., Lacroix, C., Exposito, J. Y., & Verrier, B. (2020). Tailoring mRNA Vaccine to Balance Innate/Adaptive Immune Response. Trends in molecular medicine, 26(3), 311-323.
Malone, R. W., Felgner, P. L., & Verma, I. M. (1989). Cationic liposome-mediated RNA transfection. Proceedings of the National Academy of Sciences, 86(16), 6077-6081.
Pardi, N., Hogan, M. J., Porter, F. W., & Weissman, D. (2018). mRNA vaccines—a new era in vaccinology. Nature reviews Drug discovery, 17(4), 261.
Schlake, T., Thess, A., Fotin-Mleczek, M., & Kallen, K. J. (2012). Developing mRNA-vaccine technologies. RNA biology, 9(11), 1319-1330.
Smull, C. E., Mallette, M. F., & Ludwig, E. H. (1961). The use of basic proteins to increase the infectivity of enterovirus ribonucleic acid. Biochemical and Biophysical Research Communications, 5(4), 247-249.
Wolff, J. A., Malone, R. W., Williams, P., Chong, W., Acsadi, G., Jani, A., & Felgner, P. L. (1990). Direct gene transfer into mouse muscle in vivo. Science, 247(4949), 1465-1468.
Xu, S., Yang, K., Li, R., & Zhang, L. (2020). mRNA Vaccine Era—Mechanisms, Drug Platform and Clinical Prospection. International Journal of Molecular Sciences, 21(18), 6582.
Non-Literature References
Centres for Disease Control and Prevention (CDC) – Understanding mRNA COVID-19 Vaccines
Dr. Anthony Komaroff - Why are mRNA vaccines so exciting? Harvard Health Blog