By Ayisha Malik, EMEA
Messenger RNA (mRNA) vaccines are the first COVID-19 vaccines
You’ve most likely seen news of emerging COVID-19 vaccines dominating media coverage over the last few months. Hailed as the means to end the social restrictions imposed by the pandemic, they hold the key to our optimism for the new year. The first of the vaccines to hit the market was the Pfizer-BioNTech BNT162b2 – a lipid nanoparticle–formulated, nucleoside-modified RNA vaccine that encodes a prefusion stabilised, membrane-anchored SARS-CoV-2 full-length spike protein; quickly followed by a similar mRNA vaccine from Moderna.
What is a messenger RNA (mRNA) vaccine?
Most known vaccines make use of virus particles that are grown in mammalian cells or chicken eggs. These are then attenuated or deactivated before being incorporated into the vaccine formulations. However, mRNA vaccines take a different approach. The new technology leverages antigen coding sequences from the viral pathogen to produce the required immune response in the host.
Nucleic acid therapeutics, messenger RNA (mRNA) vaccines, represent a promising alternative to the conventional vaccine approaches. They offer high potency, rapid and low-cost development potential, and easy large-scale deployment possibilities, not just for viral diseases such as COVID-19, but also for non-infectious illnesses such as cancer.
Messenger RNA pharmacology
Messenger RNA is the intermediate product that bridges the protein-coding DNA to its final protein product. The mRNA strand used in a vaccine is engineered to ensure the final protein product resembles a fully processed mature mRNA molecule that is naturally found in eukaryotic cells. They are transcribed from linear DNA templates and contain an open reading frame that encodes the protein of interest, 3’ and 5’ untranslated regions, a 5′ cap, and a poly(A) tail.
Naked mRNA is quickly degraded by extracellular RNases and as a result cannot be administered efficiently as a therapeutic. Therefore, a great variety of in vitro and in vivo reagents have been developed to protect them from degradation and to facilitate their cellular uptake. Furthermore due to this fragile nature, mRNA vaccines require cold or ultra-low temperature storage and transportation to preserve their integrity and prevent them from being damaged by heat or increased kinetic activity.
Once these mRNA molecules reach the cytosol, the cellular translation machinery gets to work, producing the proteins encoded by the genetic fragment. It then undergoes post-translational modifications that result in properly folded, fully functional proteins. This feature of mRNA pharmacology is particularly advantageous for vaccine functionality. On top of that, once the mRNA has served its purpose, it is degraded by normal physiological processes, reducing the risk of unwanted metabolite toxicity.
Advantages of mRNA therapeutics
The first report of successful in vitro transcribed (IVT) mRNA was published in 1990, where mice injected with reporter gene mRNA were able to produce the corresponding protein. In 1992, another study, demonstrated physiological response in rats from injected mRNA particles. Despite these promising early results, mRNA therapeutics were shelved for many years in favour of DNA and protein-based approaches.
However, the use of mRNA vaccines has several benefits over conventional ones. Firstly, mRNA is a non-infectious, non-integrating platform, which poses no potential risk of infection or insertional mutagenesis. It is degraded by normal cellular processes, and its in vivo half-life can be regulated through appropriate alterations. Secondly, various modifications can make mRNA more stable and highly translatable, increasing final efficacy. Efficient in vivo delivery can be also be achieved by formulating mRNA into carrier molecules, allowing rapid uptake and expression. Finally, thanks to high yielding in vitro transcription reactions, mRNA vaccines have the potential for rapid, inexpensive and scalable production.
The mRNA coronavirus vaccines
BioNTech partnered with Pfizer to develop the coronavirus vaccine BNT162b2, while Moderna partnered with the National Institutes of Health (NIH) to develop their coronavirus vaccine known as mRNA-1273. Both of which target the novel coronavirus.
We know the SARS-CoV-2 virus is studded with spike proteins that helps them enter and infect human cells; so, naturally this is a good target for vaccines and treatments. BNT162b2 and mRNA-1273 both feature mRNA fragments that code for the spike proteins flanked by sequences required for mRNA stability and functionality. Like any other naked mRNA molecule, the fragments used in the vaccine are highly susceptible to RNase degradation. Therefore, it has been enveloped in a lipid nanoparticle coating that ensures the mRNA molecules can travel from the site of administration to their target cells without being destroyed.
Once they reach their target cells, the vaccine particles fuse with the cell membrane and release the mRNA into the cytosol, where the cell’s molecular machinery can read its sequence and build spike proteins before destroying the mRNA molecule itself. Once translated and folded, some spike proteins can migrate to the host cell’s surface as a whole, while others get broken down into fragments, which also present on the surface of the vaccinated cells. These protruding proteins can then be recognised by the immune system.
When a vaccinated cell dies, the spike proteins and its fragments are taken up from the debris by antigen-presenting cells of the immune system. These cells present the spike protein fragments on their surfaces for helper T-cells to detect the antigens and raise the alarm to initiate involvement from other immune system cells. Some B-cells, recruited to the site, are able to lock on to the spike proteins; and when activated by helper T-cells, start to proliferate and pump out antibodies that can target these coronavirus spike proteins with total specificity. The antigen-presenting cells also activate killer T-cells that seek and destroy any coronavirus-infected cells that display the spike protein fragments on their surfaces.
If a coronavirus enters a vaccinated host, antibodies will latch on to the spikes and mark the virus for destruction. This process also prevents the viruses from attaching to potential host cells but if they manage to gain access, the killer T-cells spring into action.
Over time, the number of antibodies and killer T-cells tend to drop but the immune system has another tool up its sleeve; memory B- and T-cells. The memory cells help retain the information about the virus and initiate immune cell proliferation if there is another encounter with the pathogen. Survival duration of these memory cells tend to be varied; an early study of the Moderna vaccine found that it can provide protection for at least 3 months.
The Moderna vaccine requires two injections, given 28 days apart, to prime the immune system sufficiently to fight off the coronavirus. On the other hand, the Pfizer-BioNTech vaccine has been found to work best when administered in two doses, 21 days apart. However, researchers do not yet know how long its protection might last.
References / Sources:
Pardi, N., Hogan, M. J., Porter, F. W., & Weissman, D. (2018). mRNA vaccines – a new era in vaccinology. Nature reviews. Drug discovery, 17(4), 261–279. Accessed, January, 14, 2021. https://doi.org/10.1038/nrd.2017.243
Polack, F., Thomas, S., Kitchin, N., Absalon, J., Gurtman, A., & Lockhart, S. et al. (2020). Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine. New England Journal of Medicine, 383(27), 2603-2615. doi: 10.1056/nejmoa2034577. Accessed January, 14, 2021. https://www.nejm.org/doi/full/10.1056/NEJMoa2034577
Corum, J., & Zimmer, C. (2020). How the Pfizer-BioNTech Vaccine Works. The New York Times. Accessed January 14, 2021. http://nytimes.com/interactive/2020/health/pfizer-biontech-covid-19-vaccine.html
Corum, J., & Zimmer, C. (2021). How Moderna’s Vaccine Works. The New York Times. Accessed, January 14, 2021. https://www.nytimes.com/interactive/2020/health/moderna-covid-19-vaccine.html