The hearts and minds of people worldwide have been consumed by the life-altering consequences of the Coronavirus disease 2019 (COVID-19) pandemic. Vaccine development is a cornerstone of the world’s return to normalcy, and 2 mRNA-based vaccines have recently received Emergency Use Authorization from the Food and Drug Administration (FDA). Medical professionals have been offered these vaccines first due to their increased risk of infection with the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes COVID-19. Although work done at our University was instrumental in the development of mRNA vaccines,1 we have encountered, among some medical staff, a reluctance to receive the vaccine.
While logistical hurdles such as scheduling and availability may decrease vaccine utilization, a sizeable number of health care staff have expressed reservations about vaccination. One concern is that mRNA vaccine technology is new and long-term adverse effects in humans are unknown. Vaccines are traditionally composed of inactivated virus, live-attenuated virus, or antigenic proteins. Normally, mRNA is transcribed from DNA and is then translated to protein. mRNA has not been historically widely used as a vaccine due to the lability of RNA, which is typically rapidly degraded by ribonucleases. The Moderna and Pfizer/BioNTech COVID-19 vaccines that received Emergency Use Authorizations mitigate this and other problems via the use of modified mRNA and lipid nanoparticles (LNPs).
The use of modified mRNA may be a source of concern for some. Nucleosides are the building blocks of DNA and RNA. Previous work has demonstrated that substitution of the nucleoside uridine for pseudouridine or N1-methylpseudouridine enhances the stability of mRNA and decreases immunogenicity, so these nucleosides are used in both COVID-19 mRNA vaccines.2, 3, 4 Both of these modifications are naturally occurring in eukaryotic cells, thereby mitigating concerns of toxicity.
To mediate its therapeutic effect, the mRNA in the vaccine must traverse the cell membrane and be translated to protein; however, cellular uptake of mRNA is limited because it is anionic. LNPs encapsulate RNA and facilitate cellular entry. The use of LNPs and liposomes is not limited to mRNA vaccines. These compounds have already been used in FDA-approved chemotherapies, vaccines, antifungals, and analgesics.5
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-Frederick L. Hitti, MD, PhD, Drew Weissman, MD, PhD
