What was the breakthrough behind the “sudden” feasibility of mRNA vaccines in 2020?
Answering my own question after reading the 2018 Nature review article “mRNA vaccines — a new era
in vaccinology”
The resources and motivation engendered by the COVID-19 pandemic are a major factor in the development of the first mRNA vaccines approved by national governments. However, before the COVID-19 pandemic, there were recent advances in mRNA vaccine pharmacology, which made everything possible.
Introduction
The Nature review points out that it was not a single breakthrough, but a lot of research that was conducted during the last couple of years.
Demonstrations of protective immune responses by mRNA vaccines against various infective pathogens were published in recent years. In the first one, published in 2012, direct injection of non-replicating mRNA vaccines was shown to be immunogenic against various influenza virus antigens in multiple animal models1. Since then, several studies on animals, and in some cases, healthy human volunteers, have managed to induce protective immunity against rabies2,3, HIV-14,5,6, Zika7,8,9, H10N8 and H7N9 influenza10, and other viruses.
The authors of the review, which was written before the COVID-19 pandemic, believed that “mRNA vaccines have the potential to solve many of the challenges in vaccine development”. Therefore, had the pandemic not happened, it is likely that we still would have seen effective mRNA vaccines being developed, albeit at a slower pace.
Recent technological advancement has largely overcome the main challenges in the development of mRNA vaccines.
The Challenges
1. Instability
Protein expression after the vaccine is administered might be insufficient if, for instance, the half-life of the vaccine is too low, or if in vivo mRNA translation is insufficient11,12.
2. Inefficient in vivo delivery
mRNA vaccine delivery is tricky. For instance, mRNA can aggregate with serum proteins and undergoes rapid extracellular degradation by RNases. Therefore, formulating mRNAs into carrier molecules is often necessary, and delivery formulations need to take into account factors such as the biodistribution of the vaccine after delivery, mRNA uptake, and protein translation rate13,14.
3. Safety
The complexity of modulating the immunogenicity of the mRNA used in vaccines can potentially lead to unwanted stimulatory effects on the immune response15,16,17.
The Recent Advances
1. Optimization of mRNA translation and stability
Sequence optimization techniques such as replacing rare codons with more frequently used synonymous codons18, as well as enrichment of G:C content16, have been examined for increasing in vivo protein expression.
2. Progress in mRNA vaccine delivery
There are numerous delivery methods for mRNA vaccines that have been examined in the literature. In recent years, the limitations of some of these, such as using physical methods (e.g., electroporation) to penetrate the cell membrane, were demonstrated19. On the other hand, progress was made toward the increased efficacy and reduced toxicity of other delivery methods such as cationic lipid and polymer-based delivery13,16,20,21.
3. Modulation of immunogenicity
Recent studies have demonstrated that the immunostimulatory profile of mRNA can be controlled more precisely using a variety of techniques. These include chromatographic purification to remove double-stranded RNA contaminants, the introduction of naturally-occurring modified nucleosides to prevent the activation of unwanted innate immune sensors, and complexing the mRNA with various carrier molecules (this includes novel approaches to adjuvants that take advantage of the intrinsic immunogenicity of mRNA)15,17,22,33.
Apart from the advances in techniques such as purification and the introduction of nucleosides, there was also an improvement in the understanding of when these techniques should be used, based on factors such as the mRNA platform used, RNA sequence optimization, and the extent of mRNA purification under consideration16,24.
References

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