mRNA vaccines for COVID-19: what, why and how

Abstract

The Coronavirus disease-19 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus -2 (SARS-CoV-2), has impacted human lives in the most profound ways with millions of infections and deaths. Scientists and pharmaceutical companies have been in race to produce vaccines against SARS-CoV-2. Vaccine generation usually demands years of developing and testing for efficacy and safety. However, it only took less than one year to generate two mRNA vaccines from their development to deployment. The rapid production time, cost-effectiveness, versatility in vaccine design, and clinically proven ability to induce cellular and humoral immune response have crowned mRNA vaccines with spotlights as most promising vaccine candidates in the fight against the pandemic. In this review, we discuss the general principles of mRNA vaccine design and working mechanisms of the vaccines, and provide an up-to-date summary of pre-clinical and clinical trials on seven anti-COVID-19 mRNA candidate vaccines, with the focus on the two mRNA vaccines already licensed for vaccination. In addition, we highlight the key strategies in designing mRNA vaccines to maximize the expression of immunogens and avoid intrinsic innate immune response. We also provide some perspective for future vaccine development against COVID-19 and other pathogens.

Keywords: COVID-19; SARS-CoV-2; efficacy and safety; mRNA vaccine.

Figure 1

The schematic for designing an mRNA vaccine. mRNA molecules are synthesized in vitro with cap1 structure (m7GpppNm), the substitution of uridine with pseudouridine, and the use of the preferred codon in humans, optimized UTR and polyA tail sequence. These modifications results in the increase of RNA stability and translation efficiency as well as the reduction of immunogenicity.

Figure 2

Delivery and working mechanism of a mRNA vaccine. mRNA vaccine, containing the coding region of S protein flanked by the optimized 5'- and 3'-UTRs and polyA tail, is synthesized via IVT, followed by 5'-capping with a 5'-cap analogy and encapsulation with LNP for IM injection (step 1). The vaccine is delivered into muscle cells or antigen-presenting cells such as dendritic cells or macrophages via endocytosis (step 2). mRNA molecules are unloaded from LNPs and translated to S protein in the ribosome (step 3). Newly synthesized S protein is secreted to extracellular space, internalized via endocytosis into antigen-presenting cells and incorporated as a part of MHC class II antigen presentation complex (steps 5b, 6b, and 7) to present the antigen to immune cells including T and B cells . Partially degraded S peptides by proteosomes are incorporated into MHC class I complexes, which are then transported to plasma membranes and also presented as antigens to immune cells (steps 4a, 4b, 5a, and 7).

Figure 3

Mechanism of innate immune response to external mRNA. IVT-synthesized mRNA vaccines are recognized by PRRs including the endosomal TLR3, -7, and -8, and cytoplasmic innate immune receptors, RIG-I and MDA5. dsRNA, produced by inaccurate T7 polymerase activity, is recognized by TLR8 and RIG-I to induce the expression of proinflammatory cytokines and promote RNA degradation and translation inhibition mediated by 2′-5′-oligoadenylate synthase/RNase L and PKR-dependent phosphorylation of eIF2α.