mRNA vaccines - a new era in vaccinology

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.

Figure 1. Innate immune sensing of mRNA vaccines

Innate immune sensing of two types of mRNA vaccine by a dendritic cell (DC), with RNA sensors shown in yellow, antigen in red, DC maturation factors in green, and peptide–major histocompatibility complex (MHC) complexes in light blue and red; an example lipid nanoparticle carrier is shown at the top right. A non-exhaustive list of the major known RNA sensors that contribute to the recognition of double-stranded and unmodified single-stranded RNAs is shown. Unmodified, unpurified (part a) and nucleoside-modified, fast protein liquid chromatography (FPLC)-purified (part b) mRNAs were selected for illustration of two formats of mRNA vaccines where known forms of mRNA sensing are present and absent, respectively. The dashed arrow represents reduced antigen expression. Ag, antigen; PKR, interferon-induced, double-stranded RNA-activated protein kinase; MDA5, interferon-induced helicase C domain-containing protein 1 (also known as IFIH1); IFN, interferon; m1Ψ, 1-methylpseudouridine; OAS, 2′–5′-oligoadenylate synthetase; TLR, Toll-like receptor.

Figure 2. Major delivery methods for mRNA vaccines

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).

Figure 3. Considerations for effectiveness of a directly injected mRNA vaccine

For an injected mRNA vaccine, major considerations for effectiveness include the following: the level of antigen expression in professional antigen-presenting cells (APCs), which is influenced by the efficiency of the carrier, by the presence of pathogen-associated molecular patterns (PAMPs) in the form of double-stranded RNA (dsRNA) or unmodified nucleosides and by the level of optimization of the RNA sequence (codon usage, G:C content, 5′ and 3′ untranslated regions (UTRs) and so on); dendritic cell (DC) maturation and migration to secondary lymphoid tissue, which is increased by PAMPs; and the ability of the vaccine to activate robust T follicular helper (T_FH) cell and germinal centre (GC) B cell responses — an area that remains poorly understood. An intradermal injection is shown as an example. EC, extracellular.