Breakthroughs in mRNA vaccines and innovations in drug development

On October 2, 2023, Drs. Katalin Kariko and Drew Weissman from the University of Pennsylvania were awarded the Nobel Prize in Physiology or Medicine "for their discoveries concerning nucleoside base modifications that enabled the development of effective mRNA vaccines against COVID-19". mRNA was first discovered in 1961 and characterized as a class of RNA molecules that can transfer genetic information from DNA to ribosomes for protein synthesis. In eukaryotes, mRNAs are transcribed by RNA polymerase II and go through multiple rounds of co- or post-transcriptional modifications, including m7pppG cap at 5'-ends, poly(A) tails at 3'-ends, various reversible chemical modifications in coding regions and 3' untranslated regions. These modifications can significantly increase mRNA stability, half-life, nuclear export, and translational efficiencies. During 1961.1984, along with the discoveries of tRNAs, codons, anticodons, cell-free mRNA translation systems, and in vitro RNA synthesis, researchers began to show broad interest in delivering exogenous mRNAs into the cells or body for disease prevention and treatment. Since the 1990s, many attempts have been made to achieve such a purpose. However, these attempts are unsuccessful due to the severe inflammatory responses induced by exogenous RNA, which can activate cellular RNA sensors, including Toll-like receptor 3/7/8, PKR, and RIG-I/MDA5. Such limitation severely restricted the clinical applications of RNA-based drug development. Drs. Katalin Kariko and Drew Weissman discovered that introducing RNA modifications, such as pseudouridine, to exogenous RNAs can significantly reduce cellular inflammatory responses and increase RNA stability and translation efficiency. Their groundbreaking works promote the rapid transformation of highly effective mRNA vaccines targeting COVID-19 from basic research to clinical applications. In December 2020, the FDA approved two mRNA vaccines against COVID-19, BNT162b2 from Pfizer-BioNTech and mRNA-1273 from Moderna, to prevent COVID-19. These vaccines have been proven safe and effective in preventing SARS-CoV-2 infection, saving millions of lives. The success of COVID-19 mRNA vaccines also set an extraordinary standard for other RNA-based drug development. Up to early 2023, more than 60 RNA-based vaccines or drugs have initiated clinical trials. These vaccines or drugs aim to prevent and treat different types of diseases, including COVID-19, cancer immunotherapy, personalized therapy, and infectious diseases such as influenza virus, Zika virus, and hepatitis B virus. Alternatively, several therapies for protein deficiency diseases are under development. In this paper, we reviewed the journey of mRNA vaccines from the initial discovery of mRNA molecules, the in vitro synthesis of mRNA, the various modifications on mRNA, and the specific modification, pseudouridine, which can efficiently prevent the immunogenicity of exogenously introduced RNAs when delivered into the cells. These discoveries together promoted the success of mRNA vaccines against COVID-19. We also discussed the possibilities of setting noncoding RNAs as therapeutic targets and promising drug candidates based on our understanding of their crucial roles in regulating life and health. In contrast to protein- and small-molecule-based drugs, mRNA- and RNA-based therapies are more programmable and druggable. Scientists can easily and quickly design drugs based on RNA primary sequences and higher-order structures, significantly reducing the time and cost of traditional drug research and development. RNA-based therapies will definitely revolutionize drug development and show more substantial power in preventing infectious diseases and cancers.