An Update on mRNA-Based Viral Vaccines

Abstract

With the success of COVID-19 vaccines, newly created mRNA vaccines against other infectious diseases are beginning to emerge. Here, we review the structural elements required for designing mRNA vaccine constructs for effective in vitro synthetic transcription reactions. The unprecedently speedy development of mRNA vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was enabled with previous innovations in nucleoside modifications during in vitro transcription and lipid nanoparticle delivery materials of mRNA. Recent updates are briefly described in the status of mRNA vaccines against SARS-CoV-2, influenza virus, and other viral pathogens. Unique features of mRNA vaccine platforms and future perspectives are discussed.

Vaccines for COVID-19: A Systematic Review of Immunogenicity, Current Development, and Future Prospects

“…Both Moderna and BioNTech chemically modified their mRNA vaccines, replacing Uridine (U) with Pseudouridine (ψ), which reduced immunogenicity and increased stability of the mRNA ( 232 ). In contrast, CureVac, one of the three giants in mRNA vaccine research and development, employed unmodified uridine to enhance mRNA translation through sequence optimization and selection of untranslated regions (UTRs), perhaps to circumvent patent issues related to mRNA molecular modification, thus, resulting in high immunogenicity, low dose, and poor effect ( 233 , 234 ). In addition, lipid nanoparticles (LNPs) are the current most advanced and mainstream mRNA delivery system ( 235 ).…”

COVID-19 mRNA vaccines and pathological cell-cell fusion: an unintended consequence

“…The former is accomplished by hiding the nucleic acid backbone into LNPs, while the latter by attaching nucleobases, such as N1methylpseudouridine (m1Ψ) to the mRNA [18,19](Figure 1). The coding region of the mRNA is flanked by two untranslated regions (UTRs) followed by a polyadenylated (polyA) tail at 3' and a cap at 5' for further structural stabilization and protection (Figure 1) [17,19,20].…”

mRNA Therapeutic Modalities Design, Formulation and Manufacturing under Pharma 4.0 Principles

“…The Moderna mRNA product contains a 4004-nucleotide sequence encoding for the spike protein of the virus, whose features were not disclosed by the company but were retrieved through means of “reverse engineering” [ 45 , 46 ]. It features two serial proline substitutions at 986 and 987 aminoacid sites alongside the presence of the furin cleavage site, modifications that code for a stable prefusion S viral protein [ 47 , 48 ]. It is 5′ capped utilizing the cap 1 technology and its 5′ untranslated region is thought to be a patented V1-UTR [ 49 ].…”

“…It is 5′ capped utilizing the cap 1 technology and its 5′ untranslated region is thought to be a patented V1-UTR [ 49 ]. The main coding sequence is characterized by substitution of uridine with N1-methylpseudouridine and codon sequence optimization that substitutes all GAA codons with GAG [ 46 , 48 , 50 ]. As a 3′ untranslated region, Moderna employs the one located on the human β-globin gene and terminates the sequence using three stop codons, while the poly-A tail remains to be determined [ 46 ].…”

“…The latter could even prove advantageous, should mRNA translation be desired in cells that have suppressed cap-depended translation. It has to be noted though, that currently cap-less IRES containing mRNAs, while being translatable, are still considered vulnerable towards degradation by exonucleases due the lack of a cap structure [ 48 ].…”