0
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Literature Mining and Mechanistic Graphical Modelling to Improve mRNA Vaccine Platforms

      brief-report

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          RNA vaccines represent a milestone in the history of vaccinology. They provide several advantages over more traditional approaches to vaccine development, showing strong immunogenicity and an overall favorable safety profile. While preclinical testing has provided some key insights on how RNA vaccines interact with the innate immune system, their mechanism of action appears to be fragmented amid the literature, making it difficult to formulate new hypotheses to be tested in clinical settings and ultimately improve this technology platform. Here, we propose a systems biology approach, based on the combination of literature mining and mechanistic graphical modeling, to consolidate existing knowledge around mRNA vaccines mode of action and enhance the translatability of preclinical hypotheses into clinical evidence. A Natural Language Processing (NLP) pipeline for automated knowledge extraction retrieved key biological evidences that were joined into an interactive mechanistic graphical model representing the chain of immune events induced by mRNA vaccines administration. The achieved mechanistic graphical model will help the design of future experiments, foster the generation of new hypotheses and set the basis for the development of mathematical models capable of simulating and predicting the immune response to mRNA vaccines.

          Related collections

          Most cited references32

          • Record: found
          • Abstract: found
          • Article: not found

          mRNA vaccines — a new era in vaccinology

          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.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA.

            Interferons (IFNs) are critical for protection from viral infection, but the pathways linking virus recognition to IFN induction remain poorly understood. Plasmacytoid dendritic cells produce vast amounts of IFN-alpha in response to the wild-type influenza virus. Here, we show that this requires endosomal recognition of influenza genomic RNA and signaling by means of Toll-like receptor 7 (TLR7) and MyD88. Single-stranded RNA (ssRNA) molecules of nonviral origin also induce TLR7-dependent production of inflammatory cytokines. These results identify ssRNA as a ligand for TLR7 and suggest that cells of the innate immune system sense endosomal ssRNA to detect infection by RNA viruses.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Incorporation of pseudouridine into mRNA yields superior nonimmunogenic vector with increased translational capacity and biological stability.

              In vitro-transcribed mRNAs encoding physiologically important proteins have considerable potential for therapeutic applications. However, in its present form, mRNA is unfeasible for clinical use because of its labile and immunogenic nature. Here, we investigated whether incorporation of naturally modified nucleotides into transcripts would confer enhanced biological properties to mRNA. We found that mRNAs containing pseudouridines have a higher translational capacity than unmodified mRNAs when tested in mammalian cells and lysates or administered intravenously into mice at 0.015-0.15 mg/kg doses. The delivered mRNA and the encoded protein could be detected in the spleen at 1, 4, and 24 hours after the injection, where both products were at significantly higher levels when pseudouridine-containing mRNA was administered. Even at higher doses, only the unmodified mRNA was immunogenic, inducing high serum levels of interferon-alpha (IFN-alpha). These findings indicate that nucleoside modification is an effective approach to enhance stability and translational capacity of mRNA while diminishing its immunogenicity in vivo. Improved properties conferred by pseudouridine make such mRNA a promising tool for both gene replacement and vaccination.
                Bookmark

                Author and article information

                Contributors
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                07 September 2021
                2021
                : 12
                : 738388
                Affiliations
                [1] 1Fondazione The Microsoft Research – University of Trento Centre for Computational and Systems Biology (COSBI) , Rovereto, Italy
                [2] 2Preclinical, GSK , Rockville, MD, United States
                [3] 3Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento , Povo, Italy
                [4] 4Department of Computer Science, University of Pisa , Pisa, Italy
                [5] 5Toscana Life Sciences Foundation , Siena, Italy
                [6] 6Data Science and Computational Vaccinology, GSK , Siena, Italy
                Author notes

                Edited by: Jurjen Tel, Eindhoven University of Technology, Netherlands

                Reviewed by: Kashish Chetal, Massachusetts General Hospital and Harvard Medical School, United States; Jennifer Oyler-Yaniv, Harvard Medical School, United States

                *Correspondence: Duccio Medini, d.medini@ 123456toscanalifesciences.org

                This article was submitted to Systems Immunology, a section of the journal Frontiers in Immunology

                ‡These authors share first authorship

                §These authors share last authorship

                Article
                10.3389/fimmu.2021.738388
                8454234
                34557200
                e07edf94-13fe-4e93-ab00-eafd1e61adcd
                Copyright © 2021 Leonardelli, Lofano, Selvaggio, Parolo, Giampiccolo, Tomasoni, Domenici, Priami, Song, Medini, Marchetti and Siena

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 08 July 2021
                : 23 August 2021
                Page count
                Figures: 2, Tables: 1, Equations: 0, References: 32, Pages: 6, Words: 3031
                Categories
                Immunology
                Perspective

                Immunology
                mrna vaccines,natural language processing,graphical modeling,scientific literature mining,mechanisms of action

                Comments

                Comment on this article