As the mRNAs encoding different antigens are chemically and physically highly similar, formulation design and manufacturing processes of new mRNA vaccines follow the same steps ( Petsch et al., 2012). After identification of the protective protein antigen(s) and sequencing the corresponding gene(s), the mRNA can be made within weeks ( Jackson et al., 2020). A general advantage of mRNA vaccines is that their development is relatively fast, as mRNA-LNPs are a true platform technology. MRNA vaccines have several benefits over other types of vaccines. The in vivo antigen production post-administration that can be achieved with mRNA vaccines, together with the self-adjuvant properties of mRNA-LNP vaccines, ultimately leads to the efficient generation of neutralizing antibody responses and cellular immunity, decreasing the risk of developing COVID-19 for the vaccine recipients. Interestingly, Pfizer/BioNTech and Moderna specifically use nucleoside-modified mRNA that decrease (rather than increase) the inherent mRNA immunogenicity, underlining the need to properly balance the innate immune activity of mRNA vaccines (see below). Recruited APCs are capable of LNP uptake and protein expression and can subsequently migrate to the local draining lymph nodes where T cell priming occurs ( EMA, 2020a).’ Because of this inherent innate immune activity, it is not necessary to formulate the mRNA vaccines with additional adjuvants. The EMA assessment report formulates the mechanism of action of mRNA vaccines at the injection site as follows: ‘Administration of LNP-formulated RNA vaccines IM results in transient local inflammation that drives recruitment of neutrophils and antigen presenting cells (APCs) to the site of delivery. In addition, part of the temporally produced Spike proteins enter antigen presentation pathways, providing antigen recognition by T cells via MHC presentation of T-cell epitopes ( Verbeke et al., 2021). After post-translation processing by the host cells, the S protein is presented as a membrane-bound antigen in its prefusion conformation at the cellular surface, providing the antigen target for B cells. Upon intramuscular (IM) administration, the LNP system enables the uptake by host cells and the delivery of mRNA inside the cytosol, where the translation of the mRNA sequence into the S protein occurs in the ribosomes. These mRNA COVID-19 vaccines encode the viral Spike (S) glycoprotein of SARS-CoV-2 that includes two proline substitutions (K986P and V987P mutations), in order to stabilize the prefusion conformation of the glycoprotein ( Wrapp et al., 2020). The efficacy of these mRNA vaccines developed by BioNTech/Pfizer and Moderna is about 95% ( Baden et al., 2021 Polack et al., 2020) and they were the first mRNA vaccines to receive ‘emergency use authorization’ (by FDA) and ‘conditional approval’ by EMA. Of the many COVID-19 vaccines under development, the two vaccines that have shown the most promising results in preventing COVID-19 infection represent a new class of vaccine products: they are composed of messenger ribonucleic acid (mRNA) strands encapsulated in lipid nanoparticles (LNPs). Moreover, drying techniques, such as lyophilization, are promising options still to be explored. Secondly, a better understanding of the milieu the mRNA is exposed to in the core of LNPs may help to rationalize adjustments to the LNP structure to preserve mRNA integrity. To improve the stability of mRNA-LNP vaccines, optimization of the mRNA nucleotide composition should be prioritized. It is currently unclear how water in the LNP core interacts with the mRNA and to what extent the degradation prone sites of mRNA are protected through a coat of ionizable cationic lipids. mRNA hydrolysis is the determining factor for mRNA-LNP instability. The neutral helper lipids are mainly positioned in the outer, encapsulating, wall. Analysis of mRNA-LNP structures reveals that mRNA, the ionizable cationic lipid and water are present in the LNP core. In this review we discuss proposed structures of mRNA-LNPs, factors that impact mRNA-LNP stability and strategies to optimize mRNA-LNP product stability. Understanding the root cause of the instability of these vaccines may help to rationally improve mRNA-LNP product stability and thereby ease the temperature conditions for storage. A drawback of the current mRNA-lipid nanoparticle (LNP) COVID-19 vaccines is that they have to be stored at (ultra)low temperatures.
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