In 2020, the emerging threat to humanity posed by the rapidly evolving COVID-19 pandemic called for accelerated development of vaccines at unprecedented speeds. While far less proven than traditional vaccines, recombinant vaccines were, at the time, the only option to quickly manufacture shots that could generate protection against the newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. Options included genetically engineered viral vectors and the yet unproven messenger RNA (mRNA) vaccines, which, in the end, became the favored choice. This transformative technology is based on delivery of in-vitro-transcribed mRNA that encodes the target pathogen antigen and is packaged in lipid nanoparticles (LNPs).1,2 The discoveries and pioneering work of Drs. Katalin Karikó and Drew Weissman, recipients of this year’s Nobel Prize in Medicine, enabled the development of mRNA vaccines.3 The ingenuity, determination, and close collaboration of these two scientists ultimately paved the way to a plug-and-play platform that enables rapid manufacturing of effective new vaccines while avoiding risks associated with inactivated pathogens.
Two decades ago, the utility of mRNA in medicine was seen as a long shot because mRNA was unstable, could only accomplish highly transient expression of proteins, and, in addition, was highly inflammatory. While working together at the University of Pennsylvania, Katalin Karikó and Drew Weissman combined their expertise in mRNA biology and immunology and chipped away at the problem. The first breakthrough observation was that the inflammatory properties of in-vitro-transcribed mRNA were due to sensing by innate immune receptors (Toll-like receptors), which could be eliminated by modifying some of the bases (e.g., methylating), making the molecules more similar to endogenous mammalian mRNA.4 Furthermore, such modifications substantially increased the expression of the encoded protein through diminished activation of RNA-dependent protein kinase (PKR), which potently induces inhibition of translation from unmodified in-vitro-transcribed mRNA.5,6 In addition, advances in lipid technology and formulation provided the final piece in the puzzle, namely the means to efficiently deliver the mRNA in vivo. Although Katalin Karikó and Drew Weissman published their key findings in 2005–2010, it was not until 2020 that the potential application of this approach to vaccination was fully realized. Going forward, mRNA vaccines against infectious disease and certain cancers, as well as other applications of mRNA therapeutics (e.g., rare diseases), will certainly constitute a major component of modern medicine. These advances became possible through the careful investigations and courageous persistence of laureates Karikó and Weissman, who started to pursue this approach at a time when its promise had yet to be widely recognized. Our journal editors are delighted that the Nobel committee recognized a paper published in Molecular Therapy in 2008 as one of the three key publications that documented the prize-winning research, representing the most significant of several impactful articles published by the laureates in our journals.4,5,6
Over the years, translational aspects of mRNA research have overwhelmingly been published in our journal family.6,7,8,9,10,11,12,13 As documented in several of these articles, innate immunity has remained a barrier in mRNA vaccine development.6,14 Innate immune signals are required to generate potent adaptive immunity (hence the use of adjuvants in vaccines) but may also be deleterious. Inflammatory reactions need to be limited and transient to have a safe vaccine. Downregulation of translation of the mRNA into protein as a result of innate signaling, e.g., within transfected dendritic cells, limits the amount of antigen that can be presented to B and T cells, thus preventing induction of specific immunity against the pathogen-derived target antigen. As aforementioned, these are exactly the problems that Karikó and Weissman recognized and solved. However, mRNA vaccines are not without limitations. Upon vaccination with mRNA, antigen expression is proportional to the number of successfully delivered transcripts, therefore requiring certain doses to be effective and possibly repeat dosing. These issues are being addressed through the development of self-amplifying RNAs, which are genetically engineered replicons derived from self-replicating single-stranded RNA viruses.8,9,15 Their manufacturing generates double-stranded RNA byproducts that, following administration to the patient, can limit protein production by inducing interferon I (IFN I) expression upon sensing by innate endosomal and cytoplasmic RNA sensors. Thus, the amount of double-stranded RNA in the vaccine needs to be minimized. Yet, IFN I also has an important role in generating the desired immune activation, so complete elimination of IFN I induction would profoundly weaken the vaccine.14 Finally, the lipids in LNPs have important immune stimulatory adjuvant effects but should not be overly inflammatory or cause systemic inflammation. Getting this balance just right between sufficient innate immune activation that drives the generation of protective immunity on the one hand and deleterious innate immunity that blunts expression of the protein antigen and/or exaggerates inflammation on the other hand is the goal of RNA vaccine developers.7,8
We are thankful to the RNA technology community for submitting many key advances to us and finding a home in our family of journals. Related topics include development of next-generation self-amplifying mRNA vaccines7,8,9,15 and of methods to stably store mRNA vaccines at ambient temperature to overcome current needs for freezing,12 as well as development of vaccines against diverse infectious diseases.10,11,13,15 Besides academic investigators, authors from the commercial sector frequently publish with us, e.g., scientists at BioNTech, Pfizer, Moderna, Arcturus Therapeutics, Acuitas Therapeutics, and Ziphius Vaccines. Our journal family will continue to provide a broad platform for the RNA research and technology development community to publish their outstanding work (including an upcoming special issue on RNA editing). In the recent past, Molecular Therapy published special issues on vaccine and therapeutics development for emerging infectious diseases and on the role of non-coding RNA in disease and its potential for therapeutic applications. We regularly publish articles on the role of post-transcriptional modifications of mRNA in disease, on functions of microRNAs contained in exosomes, on RNA components of gene-editing tools, and on small interfering RNA (siRNA) technology, just to name a few examples. These are essential components of the arsenal of molecular medicines. Similar to many gene therapies and cellular immunotherapies, the experience with mRNA vaccine development is yet another excellent example of paradigm-shifting innovation of medicine as a result of discoveries made in basic academic research long before one could have foreseen the clinical impact of these investigations. Such innovations provided by molecular medicines have the potential to save lives and substantially improve quality of life in patients affected by acquired or genetic diseases.
References
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