Advances of mRNA vaccines for COVID-19: A new prophylactic revolution begins

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. The results were highly impressive. Why were the mRNA vaccines produced from scratch in such a short time and so effective?
The formulation of mRNA vaccine is mainly composed of two parts: mRNA encoding the antigen and lipid nanoparticles encapsulating the mRNA. Natural mRNA has a single strand structure, consisting of 5 -cap, poly (A) tail, protein encoding open reading frame (ORF) and untranslated regions (UTRs) (Fig. S1) [ 9 ,10 ]. In order to improve the druggability of mRNA, a variety of chemical modifications to mRNA structures such as adding cap analogue, poly (A), modified nucleosides, etc. were explored. To date, several mRNA modalities are developed for infectious disease vaccination, including the uridine-containing mRNA (uRNA), nucleoside modified mRNA (modRNA), self-amplifying mRNA (saRNA) and trans-amplifying mRNA (taRNA). The saRNA resembles canonical mRNA encoding the protein of interest, but also encoding replicase that multiplies mRNA in the target cell. The taRNA is an advancement platform of saRNA, it enabled scientist to produce the replicase in advance for use with different vaccines, which makes the development of several therapeutic mRNAs at the same time and permitting production of multimeric antigen complexes in a single vaccine become possible.
Besides digging in optimizing the mRNA sequence, employment of proper delivery system is also crucial for mRNA vaccine development, because carrier materials not only can deliver mRNA to the intended site of action, but also protect mRNA from degradation. Among the available options, lipid nanoparticle (LNP) is the most advanced mRNA delivery systems and is employed by almost all COVID-19 mRNA vaccines, including mRNA-1273, BNT162b2, CVnCoV, ARCT-021 and ARCoV (Table S1). The LNP is mainly composed of ionizable lipid, helper lipid, PEG-lipid and cholesterol [9] . LNP is able to encapsulate RNAs in its cavity and form nanosized vesicles with well-organized lipid structures. It  Now we may understand why the mRNA vaccine "hit the line" in the first place. Firstly, design of mRNA sequence is extremely fast and efficient. As soon as Chinese scientists disclosed the complete RNA sequence of this newly-emerged coronavirus to the world, the design of antigen encoding mRNA immediately started. Secondly, unlike producing traditional virus vaccines, which requires more than one year for amplification of cell lines and clinical-grade subunit proteins, manufacturing mRNA can be achieved in a matter of weeks via an in vitro transcription process. If the virus mutates significantly and the vaccine becomes ineffective, a new mRNA vaccine can be quickly redesigned and manufactured according to the new virus sequence. Thirdly, in addition to the advantage of manufacturing speed, the immunogenicity of mRNA is highly controllable, which enables mRNA not only to be used in treatment of a variety of antigen-based diseases but also to be employed in protein replacement therapy [9] .
Nevertheless, as a newly emerged technology, several important concerns of mRNA vaccines remains to be addressed. The BNT162b2 mRNA vaccine has an extremely strict requirement of −70 °C storage temperature, which brings additional challenges for vaccine transportation and storage. According to the published results from clinical trials, around 20 thousand participants received BNT162b2 or mRNA-1273 injection, respectively [ 2 , 3 ]. Will side effects or unexpected safety issues arise when the number of people grows to millions and possibly billions? This is the first time mRNA vaccines have ever been marketed and applied worldwide. If the mRNA vaccines prove successful over time, it will not only have huge implications for prevention of COVID-19 (Table S1), but will also revolutionize the development of gene and protein therapeutics.

Conflicts of interest
The authors report no conflicts of interest.