Nano Today
Review
Three decades of messenger RNA vaccine development
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Section snippets
Introduction: the first steps in mRNA vaccine development
The concept of exploiting mRNA as a novel therapeutic drug class has taken off in 1989, when a start-up biotech company in San Diego, called Vical Incorporated, published their first successes. They demonstrated that mRNA packaged within a liposomal nanoparticle could successfully transfect mRNA into a variety of eukaryotic cells [1]. A few months later, Wolff et al. reported on their experiments where ‘naked’, unprotected mRNA was directly administrated in the muscle of mice. Although this
An immunological view on mRNA vaccines
Shortly after the discovery of the dendritic cell (DC) in 1973 by Ralph Steinman and Zanvil Cohn, this cell type was identified as the accessory cell that is required to initiate T cell responses [[5], [6], [7]]. DCs are specialized in the uptake, processing and presentation of protein antigens to lymphocytes, which links innate and adaptive immune responses. Antigen signalling by DCs can either originate from the cytoplasm, which involves the presentation of antigenic peptides in major
The in vivo approach
The first human trials evaluating mRNA delivery were focused on an ex vivo approach, where monocyte-derived DCs were transfected with antigen-encoding mRNA and re-infused into the patients as a cellular vaccine [69]. Excellent reviews on such mRNA-based DC vaccines can be found elsewhere [70,71]. Over the years, the focus has started to shift towards the direct administration of mRNA. In general, the alternative of in vivo approaches that directly target mRNA to APCs, holds a number of key
The “self-adjuvant” effects of mRNA: The Good, the Bad, and the Ugly
Contradictory results have been reported about the role of type I IFN responses on the immunogenicity of mRNA vaccines. A number of reports have revealed that the capacity of mRNA LNPs to evoke CTL responses strongly depended on the production of type I IFNs. Two papers showed that the i.v. administration of unmodified mRNA LNPs triggered a rapid and systemic induction of type I IFNs, which involved the selective targeting of DCs and macrophages and the activation of the TLR7 pathway [92,136].
Beyond the type I IFN response
Taking the dichotomous role of the anti-mRNA type I IFN response into account, we hypothesized that it could be of benefit to uncouple the translation and type I IFN activities of mRNA vaccines, and to replace the type I IFN response by another, more controllable immune activation. This strategy provides the freedom to optimize the mRNA construct to a high translation capacity, e.g., using nucleoside-modified mRNA, while chosing a “smarter” immune adjuvant: one that does not interfere with the
Combination of mRNA cancer vaccines with checkpoint therapies
For mRNA therapeutics in oncology or for cancer vaccines in general, it might not be enough to activate effector immune responses against cancer. In addition, it is of crucial importance to keep a close eye on several immunosuppressive mechanisms that might hamper the evoked immunity. Upon the activation of T cells, the expression of checkpoint molecules forms a strong negative feedback loop to maintain T cell responses within a desired physiologic range. Overall, the immune system should
Conclusions and perspectives
Starting from the earliest publications on the in vivo delivery of mRNA, this nucleic acid represents a versatile and promising platform for vaccination. In this review, we highlighted and explored the two key factors that can determine the mRNA vaccine’s chances of success.
Firstly, it is essential to ensure adequate intracellular delivery of mRNA molecules, preferably by targeting APCs in vivo. Over the years, a fairly large knowledge gap about the in vivo behaviour of mRNA has been filled,
Acknowledgements
H. Dewitte is a postdoctoral fellow of the Research Foundation-Flanders, Belgium (FWO-Vlaanderen; grant No. 12E3916N). This research is supported by the FWO grant No. G040319N and the Flemish agency for Innovation trough Science and Technology (IWT SBO NanoComit).
Rein Verbeke obtained his master’s degree in pharmaceutical sciences - drug development at Ghent University (Belgium) in 2013. After graduating, he joined the Ghent Research Group on Nanomedicines (Ghent University, Belgium) and started a PhD project under the supervision of Prof. Stefaan De Smedt. His PhD focused on mRNA-based vaccination for the treatment of cancer, with an emphasis on the design of mRNA lipid nanoparticles and the adjuvancy of mRNA vaccines. Currently Rein’s postdoctoral
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Rein Verbeke obtained his master’s degree in pharmaceutical sciences - drug development at Ghent University (Belgium) in 2013. After graduating, he joined the Ghent Research Group on Nanomedicines (Ghent University, Belgium) and started a PhD project under the supervision of Prof. Stefaan De Smedt. His PhD focused on mRNA-based vaccination for the treatment of cancer, with an emphasis on the design of mRNA lipid nanoparticles and the adjuvancy of mRNA vaccines. Currently Rein’s postdoctoral research continues on the translation and validation of a novel mRNA nanovaccine (GALSOMES). This mRNA platform combines the delivery of mRNA vaccines with glycolipid adjuvants, which has the potential to evoke effective antitumor immunity.
Ine Lentacker (°1981) obtained her master’s degree in pharmaceutical sciences at Ghent University in 2004. She was a (post-)doctoral fellow of the Fund for Scientific Research-Flanders (FWO-Vlaanderen). During this period she initiated the concept of drug loaded microbubbles for ultrasound guided drug delivery. Currently she is staff scientist at the Ghent research group on Nanomedicines focussing on the development of novel drug delivery strategies for cancer immunotherapy and ultrasound and microbubble assisted drug delivery.
Stefaan C. De Smedt studied pharmacy and graduated from Ghent University in 1995. He joined the pharmaceutical development group of Janssen Research Foundation (1995–97). Following post-doctoral research at the Departments of Pharmacy in Ghent and Utrecht he became Professor in Physical Pharmacy and Biopharmacy at Ghent University in 1999 where he founded the Ghent Research Group on Nanomedicines. He served as dean of his faculty from 2010–2014. Currently he is a Specially Appointed Professor of Nanjing Forestry University. Since 2015 he is Editor of the Journal of Controlled Release for the region Europe-Middle East & Africa. His research is situated at the interface between drug delivery, material sciences, physical chemistry and biophysics.
Heleen Dewitte (°1987) obtained her master’s degree in pharmaceutical sciences – drug development at Ghent University (Belgium) in 2010. After graduating, she focused on developing different biomaterial strategies for cancer immunotherapy in a joint PhD project between the Ghent Research Group on Nanomedicines (UGent) and the lab for Molecular and Cellular Therapy (VUB). She is currently a post-doctoral researcher at UGent and VUB, continuing to work on the interface between material science and cancer immunology. Heleen received a number of (inter)national prizes, including the 2017 Belgian Society for Pharmaceutical Sciences PhD thesis award and a science communication award.
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Last authors contributed equally to this work.