mRNA Vaccines; Protein Replacement Therapy

Nucleic acid therapeutics have emerged as promis­ing alternatives to conventional vaccine approaches. The first report of the successful use of in vitro transcribed (IVT) mRNA in animals was published in 1990, when reporter gene mRNAs were injected into mice and pro­tein production was detected.

  • However, their application has until recently been restricted by the inefficient in vivo delivery, high innate immunogenicity, mRNA instability and efficacy.

Over the past decade, major technological innova­tion and research investment have enabled mRNA to become a promising therapeutic tool in the fields of vaccine development and protein replacement ther­apy.

The mRNA vaccine field is developing extremely rap­idly; a large body of preclinical data has accumulated over the past several years, and multiple human clinical trials have been initiated.

Beneficial features:

  • Safety: as mRNA is a non-infectious, non-integrating platform, there is no potential risk of infection or insertional mutagenesis.
  • mRNA is degraded by normal cellular processes, and its in vivo half-life can be regulated through the use of vari­ous modifications and delivery methods.
  • The inherent immunogenicity of the mRNA can be down-modulated to further increase the safety profile.
  • Efficacy: various modifications make mRNA more stable and highly translatable.
  • Efficient in vivo delivery can be achieved by formulating mRNA into carrier molecules, allowing rapid uptake and expression in the cytoplasm.
  • mRNA is the minimal genetic vector; therefore, anti-vector immunity is avoided, and mRNA vaccines can be administered repeatedly.
  • Production: mRNA vaccines have the potential for rapid, inexpensive and scalable manufacturing, mainly owing to the high yields of in vitro transcription reactions.

Two major types of RNA are currently studied as vaccines: non-replicating mRNA and virally derived, self-amplifying RNA. Conventional mRNA-based vaccines encode the anti­gen of interest and contain 5ʹ and 3ʹ untranslated regions (UTRs), whereas self-amplifying RNAs encode not only the antigen but also the viral replication machinery that enables intracellular RNA amplification and abundant protein expression.


A number of technologies are currently used to improve the pharmacological aspects of mRNA. e.g.

  • Synthetic cap analogues and capping enzymes, Regulatory elements in the 5ʹ‑untranslated region (UTR) and the 3ʹ‑UTR,
  • Poly(A) tail
  • Modified nucleosides
  • Separation and/or purification techniques: RNase III treatment, and fast protein liquid chromatography (FPLC)
  • Sequence and/or codon optimization
  • Modulation of target cells

Whereas the majority of early work in mRNA vaccines focused on cancer applications, a number of recent reports have demonstrated the potency and versatility of mRNA to protect against a wide variety of infectious pathogens, including influenza virus, Ebola virus, Zika virus, Streptococcus spp. and T. gondii.

The future of mRNA vaccines is therefore extremely bright, and the clinical data and resources provided by these companies and other institutions are likely to substantially build on and invigorate basic research into mRNA-based therapeutics.


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