mRNA Vaccines and the Future of Vaccination

Rodrigo Hontoria — McMaster University Honours Life Sciences 2023

Over the past 3 decades, scientists have been working with messenger RNA (mRNA) as a potential new method of producing simpler and more effective vaccines^{1 2}. mRNA is a promising topic to assess because of its ability to produce a vast number of proteins, all depending on the coding of each mRNA. In a cell, mRNA is transcribed from DNA and undergoes a series of modifications that provide protection from the cellular environment, before finally being released into the cytoplasm for translation. Incorporating mRNA into modern vaccinations would provide three very beneficial outcomes:

1. Safety – unlike other vaccines that require a weakened/damaged strain of the virus, mRNA vaccines provide a non-infectious route to immunity^{1 2}. Also, after translation has occurred, mRNA is quickly degraded by the cell avoiding any long-lasting effects¹.

2. Efficacy – mRNA vaccines provide a highly detailed method for producing an immune response by inducing the production of whichever desired viral protein. In other words, mRNA strands can be made to encode the exact viral protein, without any of the deleterious and self-replicating genes of the virus. The lifespan/stability of mRNA can also be adjusted through changes in its 5’ cap and poly-A tail, or carrier molecule to change the time span of its desired effects².

3. Cost of production – Synthetic viral mRNAs are significantly less costly to produce compared to the manufacturing of proteins and viral antigens¹.

Setbacks and Advancements

In 1990, a group of scientists performed the first successful mRNA injection using reporter genes to induce the production of the corresponding proteins in mice¹. In follow up experiments, physiological effects were observed in mice after the uptake of synthetic mRNA that stimulates the release of different hormones^{1 2}. Although these early successes were very exciting and provided a potentially prosperous technology, many advancements in research were still necessary to achieve safety and efficiency. mRNA vaccine setbacks have been outlined thoroughly in past research projects, some of the most notable being: 

1. Passage of mRNA from the bloodstream into the cell – through vaccination, mRNA will directly enter the bloodstream but how will cells be encouraged to uptake the mRNA?

2. Stability/protection of mRNA when inside the cell – how will the mRNA be protected to avoid mutagenesis or breakdown?

To overcome these problems, companies such as Pfizer, BioNTech, and Moderna invested a lot of time, money, and effort into making mRNA vaccines effective. To facilitate transport of mRNA into the cell, common transfection reagents such as cationic lipids, calcium phosphate, and cationic polymer liposomes are used^{3 4}. mRNA stability was achieved with the addition of untranslated regions (UTRs) added to the 5’ and 3’^{1 3}. 

COVID-19 and Future Applications

On January 9, 2020, the Global Health Organization along with Chinese Health Authorities identified the novel coronavirus as 2019-nCoV (COVID-19)⁶. 2 days later, the Chinese government globally released the genomic sequence of the virus⁶. Pfizer, BioNTech, and Moderna were quick to start working on the vaccine. Only 11 months after COVID-19 was identified, the United States and United Kingdom established the latest mRNA vaccines as safe and effective¹. 

Pfizer-BioNTech and Moderna mRNA vaccines code for a spike protein found on the membrane of the virus. Cellular uptake of the mRNA induces the production of a spike protein inside the host cell. The spike protein by itself is harmless and non-infectious but nonetheless, causes an immunological response that is remembered by the immune system. Pfizer-BioNTech and Moderna both require two doses of the vaccine, Pfizer-BioNTech requiring 21 days of separation, and Moderna requiring 28 days. Pfizer-BioNTech has a high effectiveness rate of 95% while Moderna is slightly lower at 94.1%.

Further applications for mRNA vaccines are contributing to the treatment of many more viral agents, among these are Ebola, Zika and Influenza. Cancer treatments, and genetic therapies are also looking at mRNA vaccines as a potential treatment to produce proteins that the body requires. 

References

1. Pardy N, Hogan MJ, Porter FW, Weissman D. mRNA vaccines — a new era in vaccinology. Nat [Internet]. 2018 Jan 12 [cited 2021 Feb 12];17:261–279. Available from: https://www.nature.com/articles/nrd.2017.243
2. Harvard Health Publishing: Why are mRNA vaccines so exciting? [Internet]. Komaroff A, editor. [cited 2021 Feb 12]. Available from: https://www.health.harvard.edu/blog/why-are-mrna-vaccines-so-exciting-2020121021599
3. Kim TK, Eberwine JH. Mammalian cell transfection: the present and the future. Nat Lib Med [Internet]. 2010 Jun 13 [cited 2021 Feb 14];397:3173–3178. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2911531/
4. Pfizer.com [Internet]. THE FACTS ABOUT PFIZER AND BIONTECH’S COVID-19 VACCINE. c2002 [cited 2021 Feb 13]. Available from: https://www.pfizer.com/news/hot-topics/the_facts_about_pfizer_and_biontech_s_covid_19_vaccine
5. Huang J, Yang C, Xu XF, Xu W, Liu S. Structural and functional properties of SARS-CoV-2 spike protein: potential antivirus drug development for COVID-19. Nat [Internet]. 2020 Aug 3 [cited 2021 Feb 13];41:1141–1149. Available from: https://www.nature.com/articles/s41401-020-0485-4
6. Whole genome of novel coronavirus, 2019-nCoV, sequenced. Sci Da [Internet]. 2020 Jan 31 [cited 2021 Feb 12]. Available from: https://www.sciencedaily.com/releases/2020/01/200131114748.htm
7. Zhang C, Maruggi G, Shan H, Li J. Advances in mRNA Vaccines for Infectious Diseases. Front In Immu [Internet]. 2019 Mar 27 [cited 2021 Feb 12]. Available from: https://www.frontiersin.org/articles/10.3389/fimmu.2019.00594/full