This site is intended for Global Healthcare Professionals.
mRNA vaccines represent an alternative to more conventional vaccines because of their potential to produce a robust and targeted antigenic immune response, combined with their tolerable administration profile and rapid, scalable manufacturing.
Technological innovations and research investment over the last decade have brought mRNA to the forefront of vaccine development.
Most current research for mRNA vaccines is for infectious diseases and cancer. Over 50 clinical trials are listed on clinicaltrials.gov for RNA vaccines in a number of cancers, including blood cancers, melanoma, glioblastoma (brain cancer) and prostate cancer.
mRNA is the natural intermediate molecule between the DNA template (found in the cell’s nucleus) and protein production (by ribosomes in the cell’s cytoplasm), making it an attractive candidate for use in a vaccine platform. Research into the development of therapeutic applications for mRNA dates back to 1990. The potential application of mRNA within a vaccine platform has traditionally been limited, because naked mRNA is quickly degraded by extracellular ribonucleases, and is not naturally internalized into cells efficiently. However, recent advances in lipid technology allow the mRNA to be encapsulated, protecting it against degradation, and enhancing uptake.
To circumvent the challenges of instability and inefficient in vivo uptake, the manufactured mRNA is engineered to resemble a stable, fully processed mature mRNA (i.e., 5’ cap, poly(A) tail, open reading frame (ORF) encoding the protein/antigen of interest, and 5’ and 3’ untranslated regions (UTRs)) found inside of cells and is attached to a lipid-based delivery system designed to facilitate the efficient uptake of the mRNA by cells and to produce noninfectious antigens inside the body. These molecular details enable the body to produce a robust and targeted antigenic immune response.,
mRNA vaccines have an inherent potential for rapid, scalable manufacturing—all key aspects needed to be able to respond quickly and strategically during a pandemic.
mRNA vaccines - an alternative to conventional vaccines
- Inherent immunogenicity through both B- and T-cell responses (CD4 and CD8 T cells)
- Potential for cross-protection to variants of the virus
- Ability to be designed and optimized to modulate immunogenicity
- Does not utilize a vector so avoids issues with anti-vector immunity, making multiple vaccinations/boosts possible
Flexible manufacturing process
- Synthetic variant of a natural intracellular molecule,
- Potential for modification of the genetic sequence, which can make mRNA more stable and highly translatable
- Flexibility to rapidly change the antigen if the pathogen mutates
- Potential for rapid, cost efficient, scalable manufacturing,
- Ability to be formulated with a lipid-based delivery system for efficient in vivo uptake by cells,
- Noninfectious platform that does not integrate into the human genome/DNA (mRNA stays in the cytoplasm, does not transport into the nucleus)
- In contrast to conventional vaccines such as influenza vaccines, the pathogenic virus is not required to manufacture mRNA vaccines. A viral vector to transport the mRNA into the target cells after administration of the vaccine is also not required. This excludes the possibility of an immune response against the viral vector.
- Ability to be degraded by normal cellular processes
- High purity and absence of animal products (egg- and cell-free)
- Favorable safety profile demonstrated to date
Despite these positive characteristics, some challenges for mRNA vaccines currently remain, including inherent low stability/high degradation rate of mRNA, requiring a cold chain storage of -70° to -80° C.
Mode of action of mRNA vaccines
The proposed mechanism of action of mRNA vaccines begins with intramuscular injection of the vaccine and assumes that some of the lipid-complexed mRNA will be taken up by nearby cells. The resulting protein expression of the mRNA is followed by antigen presentation and stimulation of immune responses to the antigen produced by the vaccine.
Intramuscular injection of the lipid-complexed mRNA vaccine activates the innate immune system., Dendritic cells (DCs) and other antigen-presenting cells (APCs) stimulate further immune responses, including secretion of cytokines and the recruitment of additional immune cells. In the draining lymph nodes, APCs also act to activate some antigen-specific B and T cells.,
The lipid-based delivery system encapsulates the naked mRNA, protecting it against ribonucleases at the injection site and facilitating and enhancing its uptake into cells. After being released from the delivery system into the cytoplasm, the mRNA is translated into the antigenic protein by the cell’s protein machinery.
Additional administrations of the vaccine will increase and fine-tune the memory immune responses, thus strengthening the overall efficacy of the vaccine.
- Lurie N, et al. N Engl J Med 2020;382:1969–1973.
- Le TT, et al. Nat Rev Drug Discov 2020;19:305–306.
- World Health Organization. Timeline of WHO’s response to COVID-19. https://www.who.int/news-room/detail/29-06-2020-covidtimeline. Updated September 9, 2020. November 27, 2020.
- International Federation of Pharmaceutical Manufacturers & Associations. The complex journey of a vaccine: the steps behind developing a new vaccine. https://www.ifpma.org/wp-content/uploads/2019/07/IFPMA-ComplexJourney-2019_FINAL.pdf. Accessed November 27, 2020.
- International Coalition of Medicines Regulatory Authorities. ICMRA aims for international alignment on policy approaches and regulatory flexibility during COVID-19 pandemic. www.icmra.info/drupal/en/news/21April2020. Accessed November 27, 2020.
- National Institutes of Health. NIH to launch public-private partnership to speed COVID-19 vaccine and treatment options. https://www.nih.gov/news-events/news-releases/nih-launch-public-private-partnership-speed-covid-19-vaccine-treatment-options. Published April 17, 2020. Accessed November 27, 2020.
- Centers for Disease Control and Prevention. Vaccine testing and the approval process. https://www.cdc.gov/vaccines/basics/test-approve.html. Reviewed May 1, 2014. Accessed September 30, 2020.
- Millen GC, et al. Arch Dis Child Educ Pract Ed. 2020;105(6):376–378.
- Pallmann P, et al. BMC Med. 2018;16:29.
- Yamey G, et al. Lancet 2020;395(10234):1405–1406.
- Funk CD, et al. Front Pharmacol 2020;11:937.
- Amanat F, et al. Immunity 2020;52:583–589.
- Zhang J, et al. Vaccines (Basel) 2020;8:153.
- National Institute of Allergy and Infectious Diseases. Vaccine types. https://www.niaid.nih.gov/research/vaccine-types. Content last reviewed July 1, 2019. Accessed November 27, 2020.
- Sharpe HR, et al. Immunology 2020;160:223–232.
- Nordén R, et al. Int J Mol Sci 2019;20:954.
- Science Media Centre. Science Media Centre Fact Sheet. DNA Vaccines. https://www.sciencemediacentre.org/uploads/2013/04/DNA-vaccines.pdf, Accessed November 27, 2020.
- Coban C. et al. Hum Vaccin 2008;4(6):453–456.
- Zhang C, et al. Front Immunol 2019;10:594.
- Jackson NAC, et al. NPJ Vaccines 2020;5:11.
- PHG Foundation. RNA vaccines: an introduction, https://www.phgfoundation.org/briefing/rna-vaccines, Accessed November 27, 2020.
- Corum J, et al. Coronavirus vaccine tracker. N Y Times. https://www.nytimes.com/interactive/2020/science/coronavirus-vaccine-tracker.html. Updated September 30, 2020. November 27, 2020.
- World Health Organization. Draft landscape of COVID-19 candidate vaccines. https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines. Published September 30, 2020. Accessed November 27, 2020.
- Pardi N, et al. Nat Rev Drug Discov 2018;17:261–279.
- BioNTech. BNT162 COVID-19 vaccine: program update [slide presentation]. https://investors.biontech.de/static-files/398d9bd8-e2cb-49ca-9d6d-7dfd01c66b8a. Presented April 23, 2020. Accessed November 27, 2020.
- Armbruster N, et al. Vaccines (Basel) 2019;7:132.
- Siegrist C. Chapter 2: Vaccine immunology. In: Plotkin SA, Orenstein WA, Offit PA, editors. Plotkin’s Vaccines. 7th edition. Philadelphia, PA: Elsevier; 2017. Available from WHO website: https://www.who.int/immunization/documents/Elsevier_Vaccine_immunology.pdf. Accessed November 26, 2020.
- Rauch S, et al. Front Immunol 2018;9:1963.
- Dengvaxia [prescribing information]. Swiftwater, PA, USA: Sanofi Pasteur Inc.; 2019.
- European Medicines Agency. Vaccines Working Party. www.ema.europa.eu/en/committees/working-parties-other-groups/chmp/vaccines-working-party. Accessed December 16 2020.
- European Medicines Agency. https://www.ema.europa.eu/en/human-regulatory/overview/public-health-threats/coronavirus-disease-covid-19/treatments-vaccines/covid-19-vaccines-development-evaluation-approval-monitoring. Accessed December 16 2020.
- U.S. Food & Drug Administration. Partnering with the European Union and Global Regulators on COVID-19. www.fda.gov/news-events/fda-voices/partnering-european-union-and-global-regulators-covid-19 Accessed December 16 2020.
- U.S. Food & Drug Administration. https://www.fda.gov/drugs/coronavirus-covid-19-drugs/coronavirus-treatment-acceleration-program-ctap#activ. Accessed December 16 2020.
- US Food and Drug Administration. Press Announcement. Available at: https://www.fda.gov/news-events/press-announcements/first-fda-approved-vaccine-prevention-ebola-virus-disease-marking-critical-milestone-public-health. Published December 19, 2019. Accessed December 16 2020.
- Guy B, et al. Vaccine. 2015;33:7100-7111.
- New York Times. Pfizer Gets $1.95 Billion to Produce Coronavirus Vaccine by Year’s End. https://www.nytimes.com/2020/07/22/us/politics/pfizer-coronavirus-vaccine.html. Accessed December 2020. Accessed December 16 2020.
- World Health Organization. JE Vaccine rates information sheet. Available at: https://www.who.int/vaccine_safety/initiative/tools/JE_vaccine_rates_information_sheet_Jan_2016.pdf Published January 2016. Accessed December 16 2020.