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mRNA technology

mRNA technology

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.[4]

Technological innovations and research investment over the last decade have brought mRNA to the forefront of vaccine development.[24]

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.[3]

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.[2] 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.[4] However, recent advances in lipid technology allow the mRNA to be encapsulated, protecting it against degradation, and enhancing uptake.[5]

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.[4] These molecular details enable the body to produce a robust and targeted antigenic immune response.[4],[5]

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.[1]

mRNA vaccines - an alternative to conventional vaccines

mRNA vaccines represent an alternative to conventional vaccines because of their beneficial characteristics, which are subject to translation with clinical data, including:
Immunogenicity
  • Inherent immunogenicity through both B- and T-cell responses (CD4 and CD8 T cells)[4]
  • Potential for cross-protection to variants of the virus[4]
  • Ability to be designed and optimized to modulate immunogenicity[4]
  • Does not utilize a vector so avoids issues with anti-vector immunity, making multiple vaccinations/boosts possible[2]
Flexible manufacturing process
  • Synthetic variant of a natural intracellular molecule[4],[5]
  • Potential for modification of the genetic sequence, which can make mRNA more stable and highly translatable[4]
  • Flexibility to rapidly change the antigen if the pathogen mutates[4]
  • Potential for rapid, cost efficient, scalable manufacturing[4],[5]
  • Ability to be formulated with a lipid-based delivery system for efficient in vivo uptake by cells[4],[5]
Safety
  • Noninfectious platform that does not integrate into the human genome/DNA (mRNA stays in the cytoplasm, does not transport into the nucleus)[4]
  • 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[4]
  • High purity and absence of animal products (egg- and cell-free)[5]
  • Favorable safety profile demonstrated to date[4]

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.[4]

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.[6]

Intramuscular injection of the lipid-complexed mRNA vaccine activates the innate immune system.[6],[7] 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.[6],[7]

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.[6] After being released from the delivery system into the cytoplasm, the mRNA is translated into the antigenic protein by the cell’s protein machinery.[6]

Additional administrations of the vaccine will increase and fine-tune the memory immune responses, thus strengthening the overall efficacy of the vaccine.[6]

References

  1. Lurie N, et al. N Engl J Med 2020;382:1969–1973.
  2. Yamey G, et al. Lancet 2020;395(10234):1405–1406.
  3. PHG Foundation. RNA vaccines: an introduction, https://www.phgfoundation.org/briefing/rna-vaccines, Accessed November 27, 2020.
  4. Pardi N, et al. Nat Rev Drug Discov 2018;17:261–279.
  5. 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.
  6. Armbruster N, et al. Vaccines (Basel) 2019;7:132.
  7. 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.

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