mRNA was discovered in 1961. mRNA vaccine science and technology has been in development for 60 years…

Key Points:

  • Recent improvements in mRNA vaccines act to increase protein translation, modulate innate and adaptive immunogenicity and improve delivery.

  • mRNA vaccines have elicited potent immunity against infectious disease targets in animal models of influenza virus, Zika virus, rabies virus and others, especially in recent years, using lipid-encapsulated or naked forms of sequence-optimized mRNA.

  • Diverse approaches to mRNA cancer vaccines, including dendritic cell vaccines and various types of directly injectable mRNA, have been employed in numerous cancer clinical trials, with some promising results showing antigen-specific T cell responses and prolonged disease-free survival in some cases.

  • Therapeutic considerations and challenges include scaling up good manufacturing practice (GMP) production, establishing regulations, further documenting safety and increasing efficacy.

  • Important future directions of research will be to compare and elucidate the immune pathways activated by various mRNA vaccine platforms, to improve current approaches based on these mechanisms and to initiate new clinical trials against additional disease targets.

Abstract

mRNA vaccines represent a promising alternative to conventional vaccine approaches because of their high potency, capacity for rapid development and potential for low-cost manufacture and safe administration. However, their application has until recently been restricted by the instability and inefficient in vivo delivery of mRNA. Recent technological advances have now largely overcome these issues, and multiple mRNA vaccine platforms against infectious diseases and several types of cancer have demonstrated encouraging results in both animal models and humans. This Review provides a detailed overview of mRNA vaccines and considers future directions and challenges in advancing this promising vaccine platform to widespread therapeutic use.

DOI https://doi.org/10.1038/nrd.2017.243

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Progress in mRNA vaccine delivery

Efficient in vivo mRNA delivery is critical to achieving therapeutic relevance. Exogenous mRNA must penetrate the barrier of the lipid membrane in order to reach the cytoplasm to be translated to functional protein. mRNA uptake mechanisms seem to be cell type dependent, and the physicochemical properties of the mRNA complexes can profoundly influence cellular delivery and organ distribution. There are two basic approaches for the delivery of mRNA vaccines that have been described to date. First, loading of mRNA into DCs ex vivo, followed by re-infusion of the transfected cells58; and second, direct parenteral injection of mRNA with or without a carrier. Ex vivo DC loading allows precise control of the cellular target, transfection efficiency and other cellular conditions, but as a form of cell therapy, it is an expensive and labour-intensive approach to vaccination. Direct injection of mRNA is comparatively rapid and cost-effective, but it does not yet allow precise and efficient cell-type-specific delivery, although there has been recent progress in this regard59. Both of these approaches have been explored in a variety of forms (Fig. 2; Table 1).

Commonly used delivery methods and carrier molecules for mRNA vaccines along with typical diameters for particulate complexes are shown: naked mRNA (part a); naked mRNA with in vivo electroporation (part b); protamine (cationic peptide)-complexed mRNA (part c); mRNA associated with a positively charged oil-in-water cationic nanoemulsion (part d); mRNA associated with a chemically modified dendrimer and complexed with polyethylene glycol (PEG)-lipid (part e); protamine-complexed mRNA in a PEG-lipid nanoparticle (part f); mRNA associated with a cationic polymer such as polyethylenimine (PEI) (part g); mRNA associated with a cationic polymer such as PEI and a lipid component (part h); mRNA associated with a polysaccharide (for example, chitosan) particle or gel (part i); mRNA in a cationic lipid nanoparticle (for example, 1,2-dioleoyloxy-3-trimethylammoniumpropane (DOTAP) or dioleoylphosphatidylethanolamine (DOPE) lipids) (part j); mRNA complexed with cationic lipids and cholesterol (part k); and mRNA complexed with cationic lipids, cholesterol and PEG-lipid (part l).

Reprinted for educational purposes and social benefit, not for profit. 

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