mRNA Vaccine Era-Mechanisms, Drug Platform and Clinical Prospection

Abstract

Messenger ribonucleic acid (mRNA)-based drugs, notably mRNA vaccines, have been widely proven as a promising treatment strategy in immune therapeutics. The extraordinary advantages associated with mRNA vaccines, including their high efficacy, a relatively low severity of side effects, and low attainment costs, have enabled them to become prevalent in pre-clinical and clinical trials against various infectious diseases and cancers. Recent technological advancements have alleviated some issues that hinder mRNA vaccine development, such as low efficiency that exist in both gene translation and in vivo deliveries. mRNA immunogenicity can also be greatly adjusted as a result of upgraded technologies. In this review, we have summarized details regarding the optimization of mRNA vaccines, and the underlying biological mechanisms of this form of vaccines. Applications of mRNA vaccines in some infectious diseases and cancers are introduced. It also includes our prospections for mRNA vaccine applications in diseases caused by bacterial pathogens, such as tuberculosis. At the same time, some suggestions for future mRNA vaccine development about storage methods, safety concerns, and personalized vaccine synthesis can be found in the context.

Keywords: cancer therapeutics; delivery carriers; in vitro transcription; infectious diseases; mRNA; mRNA vaccine; self-adjuvanting property.

Figure 1

Timeline of some key discoveries and advances in the development of mRNA-based drug technology. Green boxes represent discoveries and advances in mRNA mechanisms; blue boxes represent discoveries and advances in mRNA-based drug applications. Abbreviations: mRNA, messenger RNA; 5′ cap, five-prime cap; LNP, lipid nanoparticles; COVID-19, coronavirus disease 2019; DCs, dendritic cells.

Figure 2

mRNA in vitro transcription and innate immunity activation. (A) mRNA in vitro transcription. Using DNA with the antigen-encoding sequence as template, mRNA in vitro transcription products contain single-stranded RNA (ssRNA), double-stranded RNA (dsRNA), etc. The ssRNA structure normally includes five-prime cap (5′ cap), five-prime untranslated region (5′ UTR), open reading frame (ORF) region, three-prime untranslated region (3′ UTR), and poly (A) tail structure. (B) RNA translation and antigen presentation. Through endocytosis, mRNAs enter the cytoplasm. Some mRNAs combine with ribosomes of the host cell and translate successfully. Antigen proteins can be degraded to antigenic peptides by proteasome in the cytoplasm and presented to cytotoxic T lymphocytes (CTLs) via major histocompatibility complex (MHC) I pathway. Or, they can be released out of the host cell and taken up by DCs. Then, they are degraded and presented to helper T cells and B cells via MHC-II pathway. B cells can also recognize released antigen proteins. (C) Self-adjuvant effect. Various of pattern recognition receptors (PRRs) can recognize mRNA in vitro transcription product. ssRNA can be recognized by endosomal innate immune receptors (e.g., Toll-like receptor 7 (TLR7), TLR8). dsRNA can be recognized by endosomal innate immune receptors (e.g., TLR3) and cytoplasmic innate immune receptors (e.g., protein kinase RNA-activated (PKR), retinoic acid-indu [21] cible gene I protein (RIG-I), melanoma differentiation-associated protein 5 (MDA5), and 2′-5′-oligoadenylate synthase (OAS). Based on those, mRNA products can stimulate the secretion of pro-inflammatory cytokines and type I interferon (IFN), which leads to antigen-presenting cells (APCs) activation and inflammatory reaction. However, they can also activate antiviral enzymes that cause stalled mRNA translation and mRNA degradation.