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The Evolution of mRNA Vaccines

  • Writer: TLPMC - Taylor's Lakeside Pre-Medical Club
    TLPMC - Taylor's Lakeside Pre-Medical Club
  • May 10
  • 3 min read

Article by: Sharon Wong Shi May


Introduction

        Vaccines are essential for preventing the spread of infectious diseases. One of the groundbreaking advancements in this field is the development of mRNA-based vaccines. It became widely recognized during the COVID-19 pandemic in 2020. Unlike conventional vaccines, mRNA vaccines do not incorporate into the genome, thereby preventing mutagenesis. Their production is rapid, scalable, cost-effective, and they can encode multiple antigens within a single formulation, making them ideal for addressing diseases with multiple variants. In the past, mRNA vaccines were not widely pursued or studied due to their poor stability, efficacy, and excessive immunostimulation. However, this can be overcome by understanding its pharmacology, incorporating suitable delivery vehicles, and controlling the immunogenicity of mRNA.


Structure of mRNA

         mRNA consists of a 5' cap structure and a 3’ poly(A) tail, which protects it from degradation by exonucleases. The 5’ and 3’ UTRs regulate the mRNA translation, half-life, and subcellular localization. Additionally, they help minimize degradation by excluding miRNA-binding sites, thereby preventing miRNA from degrading the mRNA. The open reading frame (ORF) contains the coding sequence necessary for protein synthesis during translation.


Fig. 1 - Structure of mRNA
Fig. 1 - Structure of mRNA

Principle

            Once administered, the synthesized mRNA molecules travel through the bloodstream via delivery vehicles to their target sites. There, the mRNA serves as a template for the production of antigens. The presence of these foreign antigens triggers an immune response in the body, building up the body's immunity over time.


Designing mRNA-based vaccine

Fig. 2 - Process of Designing mRNA-based Vaccine
Fig. 2 - Process of Designing mRNA-based Vaccine

Figure 2 shows the process involved in synthesizing mRNA vaccine. (1) The genome of the desired pathogen is first studied to identify the region encoding for the target antigen. A sequence for this target antigen is designed and incorporated into a plasmid DNA construct. (2) By using bacteriophage polymerases, its mRNA is transcribed from the plasmid DNA. (3) This mRNA is then purified by high performance liquid chromatography (HPLC) to remove any contaminants. (4) Next, mRNA is mixed with lipids in a microfluidic mixer, forming lipid nanoparticles, encapsulating mRNA instantaneously. (5) The mixture is then filtered to remove any unencapsulated mRNA. (6) The resulting mRNA vaccine solution is stored in sterilized vials and are ready to be administered.


Delivery vehicles

               The most advanced delivery vehicles are lipid-based nanoparticles (LNPs) due to their ease of formulation, modularity, biocompatibility, and large mRNA payload capacity. While cationic lipids are effective for encapsulation, they can exhibit toxicity. Consequently, ionizable lipids are often preferred over cationic lipids because they are capable of switching their charge from neutral to cationic (during encapsulation), from cationic to neutral (when traveling in the bloodstream), and finally back to cationic again (promoting the release of mRNA into the cytoplasm).


Fig. 3 - Structure of LNP
Fig. 3 - Structure of LNP

Another type of delivery vehicle is polyplexes and polymeric nanoparticles. These are composed of cationic polymers that condense mRNA, forming complexes known as polyplexes. Besides that, peptides-based mRNA vaccines are also used as delivery vehicles. These vaccines employ positively charged peptides to bind to and protect mRNA. For example, repetitive arginine-alanine-leucine-alanine (RALA) peptides change their structure in acidic environments, facilitating the entry of mRNA into dendritic cells. Squalene-based mRNA vaccines consist of squalene oil with a lipid shell that captures mRNA on its surface. This formulation is used as an adjuvant in vaccines to enhance immune responses.


Fig. 4 - Structure of Polyplex
Fig. 4 - Structure of Polyplex

Safety

            mRNA-based vaccines demonstrate promising safety profiles, with only mild to moderate adverse effects reported. According to Chaudhary, Weissman, and Whitehead (2021), there were approximately 4.7 per million anti-COVID-19 vaccinations with the Pfizer–BioNTech vaccine and 2.5 per million vaccinations with the Moderna vaccine present with anaphylactic reaction. Therefore it is not advisable to give mRNA vaccines to individuals with a history of allergic response to any of the components of the vaccines by Pfizer–BioNTech or Moderna.


Conclusion 

The development of mRNA-based vaccines represents a significant advancement in the medical field for combating infectious diseases. Despite their success during the pandemic, the mechanisms of action and the delivery of mRNA into target cells still require further research for improvement.



Citations:


Chaudhary, N., Weissman, D. and Whitehead, K.A. (2021). mRNA Vaccines for Infectious diseases: principles, Delivery and Clinical Translation. Nature Reviews Drug Discovery, [online] 20(11), pp.817–838. doi:https://doi.org/10.1038/s41573-021-00283-5.


 
 
 

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