mRNA vaccines in the prevention and treatment of diseases

Abstract

Messenger ribonucleic acid (mRNA) vaccines made their successful public debut in the effort against the COVID-19 outbreak starting in late 2019, although the history of mRNA vaccines can be traced back decades. This review provides an overview to discuss the historical course and present situation of mRNA vaccine development in addition to some basic concepts that underly mRNA vaccines. We discuss the general preparation and manufacturing of mRNA vaccines and also discuss the scientific advances in the in vivo delivery system and evaluate popular approaches (i.e., lipid nanoparticle and protamine) in detail. Next, we highlight the clinical value of mRNA vaccines as potent candidates for therapeutic treatment and discuss clinical progress in the treatment of cancer and coronavirus disease 2019. Data suggest that mRNA vaccines, with several prominent advantages, have achieved encouraging results and increasing attention due to tremendous potential in disease management. Finally, we suggest some potential directions worthy of further investigation and optimization. In addition to basic research, studies that help to facilitate storage and transportation will be indispensable for practical applications.

Keywords: cancer; infectious diseases; lipid nanoparticles; mRNA delivery; mRNA vaccine.

FIGURE 1

Timeline of major findings and breakthroughs in the development of messenger ribonucleic acid (mRNA) vaccines. EMA, European Medicines Agency; COVID‐19, coronavirus disease 2019; FDA, U.S. Food and Drug Administration; LNP, lipid nanoparticle

FIGURE 2

Three types of messenger ribonucleic acid (mRNA) and their production and modification. (A) Features of conventional mRNA, self‐amplifying RNA, and circular RNA, as well as their typical synthesis processes in vitro. M in circle, methyl group. G in green, guanylate. UTR, untranslated region. IVT, in vitro transcription. pA, poly (A) sequence. NSP1‐4, sequence encoding four nonstructural proteins, namely nsP1‐4, which together form RNA‐dependent RNA polymerase. Sgp, subgenomic promoter. IRES, internal ribosome entry site. (B) Structure of cap analogue Cleancap AG, as well as uridine and its modifications. Note that for Cleancap AG, the two methyl groups are highlighted with purple circles.

FIGURE 3

Preparation and application of messenger ribonucleic acid (mRNA) vaccines. Once pathogens or tumors are identified, sequences for the target antigens are determined by the combined efforts of sequencing, bioinformatics, and computational approaches. Target DNAs are synthesized and transcribed into mRNAs in vitro, and then mRNA transcripts are purified to remove contaminants and reactants. Purified mRNA is mixed with lipids in a microfluidic mixer to form lipid nanoparticle mRNA vaccines. Dendritic cells are loaded with candidate mRNA to form DC‐mRNA vaccines. Various vaccines are produced by scaling up, then quickly tested and stored in sterilized bottles to treat various cancers and infectious diseases through different administration methods. DC, dendritic cells; LNP, lipid nanoparticle

FIGURE 4

Schematic diagram of the typical structure of messenger ribonucleic acid (mRNA)‐LNP and in vivo delivery. In an acidic environment, the cationic LNP can form a complex with nucleic acids via electrostatic interaction. In the neutral environment, the formula becomes neutrally charged and thereby interacts less with serum components. Once mRNA‐LNP reaches the cell membrane, cationic phospholipids fuse with and destabilize the cell membrane, promoting the delivery of mRNA molecules. After being internalized into the cell, the mRNA‐LNP is engulfed by the endosome. The endosomal environment acidifies the ionizable phospholipids, allowing fusion with the negatively charged primary lysosomal membrane. LNP integrity is disrupted by this interaction, and therefore mRNA is released. Membrane fusions and structural changes in LNPs are thought to be the main causes of endosomal membrane destabilization and mRNA escape.

FIGURE 5

Mechanisms of messenger ribonucleic acid (mRNA) vaccines for infectious diseases and cancers. mRNA molecules encoding tumor antigens are injected into body (either with or without delivery vehicles). The mRNA molecules are taken up and translated into protein antigens by antigen presenting cells (APCs). After proteasomal processing of proteins, antigen peptides associate with major histocompatibility complex (MHC) Class I molecule in the endoplasmic reticulum and are transferred to the APC surface, activating CD8+ T cells for a specific cellular immune response. Protein antigens, which are sorted for the endosome route, can activate CD4+ T cells via the MHC Class II presentation pathway. The secretory protein antigen or membrane antigen encoded by mRNA can stimulate B cells to produce neutralizing antibodies, and activate phagocytes such as macrophages to secrete inflammatory cytokines, facilitating the clearance of circulating infectious pathogens and tumor cells