By Mia Carleton, Winter 2021.
As we enter the second year of the COVID-19 pandemic, our most vulnerable are beginning to receive life-saving vaccines and cases are coming down thanks to increasing immunity. In just one year, we’ve lost over half a million American lives.
Pfizer-BioNTech and Moderna, the pharmaceutical companies behind the first two vaccines approved for use in the U.S., both rely on a similar yet unique synthetic mRNA mechanism. Previously, the shortest turnaround time for a vaccine was around 4 years, [1] but these novel mRNA vaccines reached the public in less than a year. While these are the first mRNA vaccines to be approved for use, research into the therapeutic applications of synthetic mRNA has been ongoing for years. BioNTech and Moderna were both researching mRNA therapies before switching to COVID-19 vaccine development when the pandemic hit.
A number of factors played a role in the vaccines’ quick development: increased funding, faster trials due to increased disease prevalence and rolling review of data, and a massive global demand. The actual development of a new vaccine did not take long. For reference, it took Moderna just six weeks to have doses produced and ready for animal trials. [2] One reason this went so quickly was the existing research into SARS-COV-1, the virus behind the 2003 epidemic, and its genetic similarity to the novel coronavirus. [3] The rest of the wait was spent in clinical trials and review processes to ensure that the vaccines met every standard of safety. Clinical trials are a lengthy process determined by how long it takes for a certain number of participants to become infected naturally. Once this benchmark is hit, the trial ends and incidence in the vaccine group is compared to incidence in the placebo group. This makes clinical trials a sort of ‘waiting game,’ particularly for less common diseases. In the case of COVID-19, which spread like wildfire, the trials moved quickly.
The novel synthetic mRNA vaccines rely on a unique mechanism—utilizing our bodies’ ability to read genetic blueprints and produce proteins. As Moderna co-founder Noubar Afeyan framed this challenge, “We were asking, could we turn a human into a bioreactor?”. [2] In essence, our bodies act as our own medicine-producing factories. mRNA vaccines contain the genetic framework to produce an important piece of the virus called a spike protein, to which your body mounts an immune response. They are unlike typical vaccines, most of which present weakened or dead versions of the virus or its parts to activate the immune system and create long-term immunity. Because of this, mRNA vaccines have no potential to cause infections. This is unlike some other vaccines, which in rare cases can be an issue for immunocompromised people. The synthetic mRNA breaks down after use in the body, and has no means of entering the nucleus to edit or even interact with your genome. [4]
Another factor that differentiates mRNA vaccines is their potency. They mimic natural infection better than other types of vaccines, facilitating a strong adaptive immune response. [5] They are “self-adjuvanted,” meaning they cause a strong immune response without the need of an added substance (adjuvant) to enhance it. With this comes a challenge—developing an mRNA vaccine that isn’t overly potent. An overactive immune response to a vaccine can actually be more harmful than helpful. The immune system is constantly scanning for foreign material, and synthetic mRNA is no exception. An overly potent dose can trigger an enzyme that rapidly degrades the mRNA before it can be used to create the viral spike protein, inhibiting the creation of long-term immunity. With the help of some genetic modifications, scientists were able to construct the mRNA such that it would not produce overactive effects. [3]
Pfizer and Moderna’s 94-95% efficacy [6] puts them on par with some of the best vaccines ever made. [7] Vaccines this efficacious have the potential to eradicate a virus, as has been nearly done with measles and polio, two long-forgotten viruses with nearly 100% effective vaccines. The mRNA vaccines are particularly impressive when compared to other COVID-19 vaccines, such as AstraZeneca and Johnson and Johnson, which have a respectable 66-72% efficacy. [6]
In addition to its high efficacy and safety profile, mRNA vaccine technology has the potential to simplify and speed up the process for future vaccine development. [8] The mRNA used in the vaccine is entirely synthetic, meaning its production isn’t complicated or slowed by reliance on live resources. [8] Most importantly, creating an mRNA vaccine for emerging COVID-19 variants or entirely new viruses will utilize the same production process in place. The only limiting factor is the actual sequence of the mRNA transcript.
Beyond vaccines, mRNA technology has the incredible capacity for numerous therapeutic applications. The same technology that can encode the viral spike protein in the COVID-19 vaccine can also encode any protein to treat other diseases. It can even be used to convert regular cells into stem cells, which have the potential to replace damaged tissues and even cure cancer. [9] While the COVID-19 vaccine does not edit our genome, a different application of the technology could repair deleterious mutations and cure genetic diseases like sickle-cell and cancer, as well as treat HIV. [2]
As far as a new pandemic, it is not a question of “if,” but rather “when.” As stated in a 2020 report from the WHO and the World Bank, “Expenditures for prevention and preparedness are measured in billions of dollars, the cost of a pandemic in trillions.” [10] Moderna CEO Stéphane Bancel calls for megafactories equipped for mass mRNA vaccine production in case of the next pandemic. He says, “If governments spend billions on nuclear weapons they hope to never use, we should equip ourselves so this never happens again.” [2] We are in dire need for a change in how we value public health research. If there’s one thing to learn from this pandemic, it is the knowledge that this will happen again, and that our future response is to be decided now.
[1] UCLA Health. 2020. “The fastest vaccine in history.” Last modified December 10, 2020. https://connect.uclahealth.org/2020/12/10/the-fastest-vaccine-in-history/
[2] MIT Technology Review. 2021. “The next act for messenger RNA could be bigger than covid vaccines.” Last modified February 5, 2021. https://www.technologyreview.com/2021/02/05/1017366/messenger-rna-vaccines-covid-hiv/
[3] Science Translational Medicine. 2021. “How to Administer RNA – And How to Do It Again.” Last modified March 3, 2021. https://blogs.sciencemag.org/pipeline/archives/2021/03/03/how-to-administer-rna-and-how-to-do-it-again
[4] Centers for Disease Control and Prevention. 2019. “Understanding mRNA COVID-19 Vaccines.” Last modified March 4, 2021. https://www.cdc.gov/coronavirus/2019-ncov/vaccines/different-vaccines/mrna.html
[5] Harvard Health Publishing. 2020. “Why are mRNA vaccines so exciting.” Last modified December 18, 2020. https://www.health.harvard.edu/blog/why-are-mrna-vaccines-so-exciting-2020121021599
[6] BioSpace. 2021. “UPDATED Comparing COVID-19 Vaccines: Timelines, Types and Prices.” Last modified February 8, 2021. https://www.biospace.com/article/comparing-covid-19-vaccines-pfizer-biontech-moderna-astrazeneca-oxford-j-and-j-russia-s-sputnik-v/
[7] Business Insider. 2020. “3 coronavirus vaccines so far seem to prevent COVID-19. Here’s how their efficacy compares to vaccines for flu, measles, and more.” Last modified November 30, 2020. https://www.businessinsider.com/how-pfizer-coronavirus-vaccine-compares-other-vaccines-2020-11
[8] BioNTech. 2021. “mRNA vaccines to address the COVID-19 pandemic.” https://biontech.de/covid-19-portal/mrna-vaccines
[9] Badieyan, Zohreh Sadat. et al. 2019. “Concise Review: Application of Chemically Modified mRNA in Cell Fate Conversion and Tissue Engineering.” Stem Cells Transl Med, 8(8): 833–843. https://doi.org/10.1002/sctm.18-0259
[10] U.S. News. 2020. “Countries Must Prepare for Future Pandemic, Board Warns.” Last modified September 14, 2020. https://www.usnews.com/news/best-countries/articles/2020-09-14/global-health-board-calls-on-countries-to-prepare-for-next-pandemic