Advances in mRNA Vaccines for Infectious Diseases

During the last two decades, there has been broad interest in RNA-based technologies for the development of prophylactic and therapeutic vaccines. Preclinical and clinical trials have shown that mRNA vaccines provide a safe and long-lasting immune response in animal models and humans. In this review, we summarize current research progress on mRNA vaccines, which have the potential to be quick-manufactured and to become powerful tools against infectious disease and we highlight the bright future of their design and applications.

[1]  D. Burgess RNA stability: Remember your driver , 2012, Nature Reviews Genetics.

[2]  C. Heirman,et al.  Preclinical evaluation of TriMix and antigen mRNA-based antitumor therapy. , 2012, Cancer research.

[3]  Margaret M. Billingsley,et al.  Biomaterials for vaccine‐based cancer immunotherapy , 2018, Journal of controlled release : official journal of the Controlled Release Society.

[4]  Lisa C. Zaba,et al.  Resident and "inflammatory" dendritic cells in human skin. , 2009, The Journal of investigative dermatology.

[5]  G. Acsadi,et al.  Direct gene transfer into mouse muscle in vivo. , 1990, Science.

[6]  G. Rhodes,et al.  Self-replicating Semliki Forest virus RNA as recombinant vaccine. , 1994, Vaccine.

[7]  Edith Jasny,et al.  New Vaccine Technologies to Combat Outbreak Situations , 2018, Front. Immunol..

[8]  Hiroki Kato,et al.  Incorporation of pseudouridine into mRNA yields superior nonimmunogenic vector with increased translational capacity and biological stability. , 2008, Molecular therapy : the journal of the American Society of Gene Therapy.

[9]  R. Deering,et al.  Nucleic acid vaccines: prospects for non-viral delivery of mRNA vaccines , 2014, Expert opinion on drug delivery.

[10]  V. Flamand,et al.  Intratumoral Delivery of TriMix mRNA Results in T-cell Activation by Cross-Presenting Dendritic Cells , 2015, Cancer Immunology Research.

[11]  P. Gupta,et al.  Induction of immune responses and protection in mice against rabies using a self-replicating RNA vaccine encoding rabies virus glycoprotein. , 2009, Veterinary microbiology.

[12]  Bernard Verrier,et al.  Poly(lactic acid) nanoparticles and cell-penetrating peptide potentiate mRNA-based vaccine expression in dendritic cells triggering their activation. , 2019, Biomaterials.

[13]  T. Daemen,et al.  Tattoo Delivery of a Semliki Forest Virus-Based Vaccine Encoding Human Papillomavirus E6 and E7 , 2015, Vaccines.

[14]  Kimberly J. Hassett,et al.  Induction of Robust B Cell Responses after Influenza mRNA Vaccination Is Accompanied by Circulating Hemagglutinin-Specific ICOS+ PD-1+ CXCR3+ T Follicular Helper Cells , 2017, Front. Immunol..

[15]  K. Ljungberg,et al.  Self-replicating alphavirus RNA vaccines , 2015, Expert review of vaccines.

[16]  J. Bryers,et al.  Scaffold-mediated delivery for non-viral mRNA vaccines , 2018, Gene Therapy.

[17]  Kathryn L. Jones,et al.  Long-term storage of DNA-free RNA for use in vaccine studies. , 2007, BioTechniques.

[18]  D. Weissman,et al.  Administration of nucleoside-modified mRNA encoding broadly neutralizing antibody protects humanized mice from HIV-1 challenge , 2017, Nature Communications.

[19]  P. Coulie,et al.  Tumour antigens recognized by T lymphocytes: at the core of cancer immunotherapy , 2014, Nature Reviews Cancer.

[20]  Sanyog Jain,et al.  &egr;‐Poly‐L‐Lysine/plasmid DNA nanoplexes for efficient gene delivery in vivo , 2018, International journal of pharmaceutics.

[21]  J. Wilschut,et al.  Alphavirus-based vaccines encoding nonstructural proteins of hepatitis C virus induce robust and protective T-cell responses. , 2014, Molecular therapy : the journal of the American Society of Gene Therapy.

[22]  Ö. Türeci,et al.  Improving mRNA-Based Therapeutic Gene Delivery by Expression-Augmenting 3' UTRs Identified by Cellular Library Screening. , 2019, Molecular therapy : the journal of the American Society of Gene Therapy.

[23]  D. Weissman,et al.  Generating the optimal mRNA for therapy: HPLC purification eliminates immune activation and improves translation of nucleoside-modified, protein-encoding mRNA , 2011, Nucleic acids research.

[24]  D. Weissman,et al.  In vitro transcription of long RNA containing modified nucleosides. , 2013, Methods in molecular biology.

[25]  D. Voss,et al.  An mRNA Vaccine Encoding Rabies Virus Glycoprotein Induces Protection against Lethal Infection in Mice and Correlates of Protection in Adult and Newborn Pigs , 2016, PLoS neglected tropical diseases.

[26]  A. García-Sastre,et al.  A Sendai Virus-Derived RNA Agonist of RIG-I as a Virus Vaccine Adjuvant , 2012, Journal of Virology.

[27]  R. Weiss,et al.  DNA and mRNA vaccination against allergies , 2018, Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology.

[28]  A. Di Nardo,et al.  Plasmacytoid dendritic cells sense skin injury and promote wound healing through type I interferons , 2010, The Journal of experimental medicine.

[29]  R. Weiss,et al.  N(1)-methylpseudouridine-incorporated mRNA outperforms pseudouridine-incorporated mRNA by providing enhanced protein expression and reduced immunogenicity in mammalian cell lines and mice. , 2015, Journal of controlled release : official journal of the Controlled Release Society.

[30]  G. Vanham,et al.  Type I IFN counteracts the induction of antigen-specific immune responses by lipid-based delivery of mRNA vaccines. , 2013, Molecular therapy : the journal of the American Society of Gene Therapy.

[31]  Özlem Türeci,et al.  Systemic RNA delivery to dendritic cells exploits antiviral defence for cancer immunotherapy , 2016, Nature.

[32]  H. Liao,et al.  Potent immune responses in rhesus macaques induced by nonviral delivery of a self-amplifying RNA vaccine expressing HIV type 1 envelope with a cationic nanoemulsion. , 2015, The Journal of infectious diseases.

[33]  Yuhua Wang,et al.  Systemic delivery of modified mRNA encoding herpes simplex virus 1 thymidine kinase for targeted cancer gene therapy. , 2013, Molecular therapy : the journal of the American Society of Gene Therapy.

[34]  A. Jestin,et al.  Biosafety of DNA vaccines: New generation of DNA vectors and current knowledge on the fate of plasmids after injection. , 2010, Vaccine.

[35]  D. G. Gibson,et al.  Rapidly produced SAM® vaccine against H7N9 influenza is immunogenic in mice , 2013, Emerging Microbes & Infections.

[36]  Pedro Romero,et al.  Exhaustion of tumor-specific CD8⁺ T cells in metastases from melanoma patients. , 2011, The Journal of clinical investigation.

[37]  S. Xiao,et al.  Recombination in Vaccine and Circulating Strains of Porcine Reproductive and Respiratory Syndrome Viruses , 2009, Emerging infectious diseases.

[38]  Qian Feng,et al.  MDA5 Detects the Double-Stranded RNA Replicative Form in Picornavirus-Infected Cells , 2012, Cell Reports.

[39]  Kelly Servick,et al.  On message. , 2017, Science.

[40]  D. Weissman mRNA transcript therapy , 2015, Expert review of vaccines.

[41]  R. Steinman,et al.  Synthetic double-stranded RNA induces innate immune responses similar to a live viral vaccine in humans , 2011, The Journal of experimental medicine.

[42]  Rolf Suter,et al.  Polyethylenimine-based polyplex delivery of self-replicating RNA vaccines. , 2016, Nanomedicine : nanotechnology, biology, and medicine.

[43]  K. Lundstrom Replicon RNA Viral Vectors as Vaccines , 2016, Vaccines.

[44]  I. Hoerr A successful founder off the beaten path , 2017, Nature Biotechnology.

[45]  L. Defrancesco The 'anti-hype' vaccine , 2017, Nature Biotechnology.

[46]  Yi-Ling Lin,et al.  Japanese encephalitis virus replicon-based vaccine expressing enterovirus-71 epitope confers dual protection from lethal challenges , 2015, Journal of Biomedical Science.

[47]  Justin M. Richner,et al.  Cellular and Humoral Immunity Protect against Vaginal Zika Virus Infection in Mice , 2018, Journal of Virology.

[48]  R. Langer,et al.  mRNA vaccine delivery using lipid nanoparticles. , 2016, Therapeutic delivery.

[49]  M. Avci-Adali,et al.  In vitro synthesis of modified mRNA for induction of protein expression in human cells. , 2014, Journal of visualized experiments : JoVE.

[50]  T. Schlake,et al.  A novel, disruptive vaccination technology , 2013, Human vaccines & immunotherapeutics.

[51]  A. Raj,et al.  Identification of a Natural Viral RNA Motif That Optimizes Sensing of Viral RNA by RIG-I , 2015, mBio.

[52]  D. Weissman,et al.  Nucleoside-modified mRNA vaccines induce potent T follicular helper and germinal center B cell responses , 2018, The Journal of experimental medicine.

[53]  C. Mandl,et al.  Humoral and Cellular Immune Response to RNA Immunization with Flavivirus Replicons Derived from Tick-Borne Encephalitis Virus , 2005, Journal of Virology.

[54]  K. Fiedler,et al.  mRNA Cancer Vaccines. , 2016, Recent results in cancer research. Fortschritte der Krebsforschung. Progres dans les recherches sur le cancer.

[55]  U. Şahin,et al.  Self-Amplifying RNA Vaccines Give Equivalent Protection against Influenza to mRNA Vaccines but at Much Lower Doses , 2017, Molecular therapy : the journal of the American Society of Gene Therapy.

[56]  F. Zohra,et al.  Effective delivery with enhanced translational activity synergistically accelerates mRNA-based transfection. , 2007, Biochemical and biophysical research communications.

[57]  Santiago Garcia-Vallvé,et al.  Working toward a new NIOSH. , 1996, Nucleic Acids Res..

[58]  J. Grooten,et al.  Type I Interferons Modulate CD8+ T Cell Immunity to mRNA Vaccines. , 2017, Trends in molecular medicine.

[59]  P. Eilers,et al.  A phase I/IIa immunotherapy trial of HIV-1-infected patients with Tat, Rev and Nef expressing dendritic cells followed by treatment interruption. , 2012, Clinical immunology.

[60]  D. Weissman,et al.  Expression kinetics of nucleoside-modified mRNA delivered in lipid nanoparticles to mice by various routes. , 2015, Journal of controlled release : official journal of the Controlled Release Society.

[61]  T. Decker,et al.  The Yin and Yang of type I interferon activity in bacterial infection , 2005, Nature Reviews Immunology.

[62]  J. Ulmer,et al.  Recent innovations in mRNA vaccines. , 2016, Current opinion in immunology.

[63]  J. Ross,et al.  mRNA stability in mammalian cells. , 1995, Microbiological reviews.

[64]  D. Weissman,et al.  Nucleoside Modified mRNA Vaccines for Infectious Diseases. , 2017, Methods in molecular biology.

[65]  M. Tatematsu,et al.  Extracellular RNA Sensing by Pattern Recognition Receptors , 2018, Journal of Innate Immunity.

[66]  D. Harrich,et al.  Kunjin Virus Replicon Vaccine Vectors Induce Protective CD8+ T-Cell Immunity , 2002, Journal of Virology.

[67]  Robert Langer,et al.  Lipid Nanoparticle Assisted mRNA Delivery for Potent Cancer Immunotherapy. , 2017, Nano letters.

[68]  Shubiao Zhang,et al.  Toxicity of cationic lipids and cationic polymers in gene delivery. , 2006, Journal of controlled release : official journal of the Controlled Release Society.

[69]  J. Rosenecker,et al.  Expression of therapeutic proteins after delivery of chemically modified mRNA in mice , 2011, Nature Biotechnology.

[70]  Daniel G. Anderson,et al.  Silencing or stimulation? siRNA delivery and the immune system. , 2011, Annual review of chemical and biomolecular engineering.

[71]  L. Ivashkiv,et al.  Regulation of type I interferon responses , 2013, Nature Reviews Immunology.

[72]  Florian Krammer,et al.  Nucleoside-modified mRNA immunization elicits influenza virus hemagglutinin stalk-specific antibodies , 2018, Nature Communications.

[73]  Özlem Türeci,et al.  mRNA-based therapeutics — developing a new class of drugs , 2014, Nature Reviews Drug Discovery.

[74]  R. Johnston,et al.  A tetravalent alphavirus-vector based dengue vaccine provides effective immunity in an early life mouse model. , 2014, Vaccine.

[75]  F. Sobrino,et al.  RNA immunization can protect mice against foot-and-mouth disease virus. , 2010, Antiviral research.

[76]  Ruth Hershberg,et al.  Selection on codon bias. , 2008, Annual review of genetics.

[77]  R. Waymouth,et al.  Enhanced mRNA delivery into lymphocytes enabled by lipid-varied libraries of charge-altering releasable transporters , 2018, Proceedings of the National Academy of Sciences.

[78]  H. Schild,et al.  Correction: Increased Antigen Presentation Efficiency by Coupling Antigens to MHC Class I Trafficking Signals , 2012, The Journal of Immunology.

[79]  Daniel G. Anderson,et al.  Dendrimer-RNA nanoparticles generate protective immunity against lethal Ebola, H1N1 influenza, and Toxoplasma gondii challenges with a single dose , 2016, Proceedings of the National Academy of Sciences.

[80]  A. Thess,et al.  A development that may evolve into a revolution in medicine: mRNA as the basis for novel, nucleotide-based vaccines and drugs , 2014, Therapeutic advances in vaccines.

[81]  R. Koup,et al.  Dissociation of skeletal muscle for flow cytometric characterization of immune cells in macaques. , 2015, Journal of immunological methods.

[82]  Daniel G. Anderson,et al.  Materials for non-viral intracellular delivery of messenger RNA therapeutics. , 2016, Journal of controlled release : official journal of the Controlled Release Society.

[83]  A. Webber,et al.  Function of 3′ non-coding sequences and stop codon usage in expression of the chloroplast psaB gene in Chlamydomonas reinhardtii , 1996, Plant Molecular Biology.

[84]  Isabelle Bassi,et al.  Self-replicating Replicon-RNA Delivery to Dendritic Cells by Chitosan-nanoparticles for Translation In Vitro and In Vivo , 2014, Molecular therapy. Nucleic acids.

[85]  A. Mondal,et al.  The role of follicular helper T cells and the germinal center in HIV-1 gp120 DNA prime and gp120 protein boost vaccination , 2014, Human vaccines & immunotherapeutics.

[86]  G. Ebel,et al.  An mRNA Vaccine Protects Mice against Multiple Tick-Transmitted Flavivirus Infections , 2018, Cell Reports.

[87]  Man Li,et al.  Induction of HIV-1 gag specific immune responses by cationic micelles mediated delivery of gag mRNA , 2016, Drug delivery.

[88]  T. Schlake,et al.  Sequence-engineered mRNA Without Chemical Nucleoside Modifications Enables an Effective Protein Therapy in Large Animals , 2015, Molecular therapy : the journal of the American Society of Gene Therapy.

[89]  M. Fotin‐Mleczek,et al.  Unmodified mRNA in LNPs constitutes a competitive technology for prophylactic vaccines , 2017, npj Vaccines.

[90]  D. Harrich,et al.  Kunjin Virus Replicon Vectors for Human Immunodeficiency Virus Vaccine Development , 2003, Journal of Virology.

[91]  Jack Cuzick,et al.  Preventive therapy for cancer. , 2017, The Lancet. Oncology.

[92]  N. Sardesai,et al.  Immunotherapy Against HPV16/18 Generates Potent TH1 and Cytotoxic Cellular Immune Responses , 2012, Science Translational Medicine.

[93]  D. Weissman,et al.  Zika virus protection by a single low dose nucleoside modified mRNA vaccination , 2017, Nature.

[94]  A. Oxenius,et al.  Regulation of antiviral T cell responses by type I interferons , 2015, Nature Reviews Immunology.

[95]  R. Schreiber,et al.  Blocking monoclonal antibodies specific for mouse IFN-alpha/beta receptor subunit 1 (IFNAR-1) from mice immunized by in vivo hydrodynamic transfection. , 2006, Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research.

[96]  Thomas Krucker,et al.  Nonviral delivery of self-amplifying RNA vaccines , 2012, Proceedings of the National Academy of Sciences.

[97]  P. Mason,et al.  Induction of Broad-Based Immunity and Protective Efficacy by Self-amplifying mRNA Vaccines Encoding Influenza Virus Hemagglutinin , 2015, Journal of Virology.

[98]  M. Fotin‐Mleczek,et al.  Self-adjuvanted mRNA vaccines induce local innate immune responses that lead to a potent and boostable adaptive immunity. , 2016, Vaccine.

[99]  T. Schlake,et al.  Protective efficacy of in vitro synthesized, specific mRNA vaccines against influenza A virus infection , 2012, Nature Biotechnology.

[100]  D. Weissman,et al.  HPLC purification of in vitro transcribed long RNA. , 2013, Methods in molecular biology.

[101]  H. Schild,et al.  Increased Antigen Presentation Efficiency by Coupling Antigens to MHC Class I Trafficking Signals1 , 2008, The Journal of Immunology.

[102]  D. Curiel,et al.  A Sindbis virus mRNA polynucleotide vector achieves prolonged and high level heterologous gene expression in vivo. , 1995, Nucleic acids research.

[103]  A. Helwak,et al.  High Guanine and Cytosine Content Increases mRNA Levels in Mammalian Cells , 2006, PLoS biology.

[104]  M. Murphy,et al.  Self-replicative RNA vaccines elicit protection against influenza A virus, respiratory syncytial virus, and a tickborne encephalitis virus. , 2001, The Journal of infectious diseases.

[105]  J. Routy,et al.  Immunologic activity and safety of autologous HIV RNA-electroporated dendritic cells in HIV-1 infected patients receiving antiretroviral therapy. , 2010, Clinical immunology.

[106]  M. Schlee Master sensors of pathogenic RNA – RIG-I like receptors , 2013, Immunobiology.

[107]  Tao Gong,et al.  Enhanced intranasal delivery of mRNA vaccine by overcoming the nasal epithelial barrier via intra- and paracellular pathways. , 2016, Journal of controlled release : official journal of the Controlled Release Society.

[108]  C. K. Kiya,et al.  Immunocastration of goats using anti-gonadotrophin releasing hormone vaccine. , 2018, Theriogenology.

[109]  H. Shan,et al.  Microneedle Patches as Drug and Vaccine Delivery Platform. , 2017, Current medicinal chemistry.

[110]  Wing‐Fu Lai,et al.  Design of Polymeric Gene Carriers for Effective Intracellular Delivery. , 2018, Trends in biotechnology.

[111]  Seth J. Zost,et al.  Contemporary H3N2 influenza viruses have a glycosylation site that alters binding of antibodies elicited by egg-adapted vaccine strains , 2017, Proceedings of the National Academy of Sciences.

[112]  U. Şahin,et al.  Intranodal vaccination with naked antigen-encoding RNA elicits potent prophylactic and therapeutic antitumoral immunity. , 2010, Cancer research.

[113]  D. Voss,et al.  A thermostable messenger RNA based vaccine against rabies , 2017, PLoS neglected tropical diseases.

[114]  R. Levy,et al.  mRNA vaccination with charge-altering releasable transporters elicits human T cell responses and cures established tumors in mice , 2018, Proceedings of the National Academy of Sciences.

[115]  S. Bertholet,et al.  Self-Amplifying mRNA Vaccines Expressing Multiple Conserved Influenza Antigens Confer Protection against Homologous and Heterosubtypic Viral Challenge , 2016, PloS one.

[116]  D. Gallie The cap and poly(A) tail function synergistically to regulate mRNA translational efficiency. , 1991, Genes & development.

[117]  Philip C. Bevilacqua,et al.  Incorporation of pseudouridine into mRNA enhances translation by diminishing PKR activation , 2010, Nucleic acids research.

[118]  C. Zurla,et al.  Proximity Ligation Assays for In Situ Detection of Innate Immune Activation: Focus on In Vitro-Transcribed mRNA , 2018, Molecular therapy. Nucleic acids.

[119]  H. Rammensee,et al.  Spontaneous cellular uptake of exogenous messenger RNA in vivo is nucleic acid-specific, saturable and ion dependent , 2007, Gene Therapy.

[120]  G. Hartmann,et al.  Antiviral immunity via RIG-I-mediated recognition of RNA bearing 5′-diphosphates , 2014, Nature.

[121]  V. Volchkova,et al.  A Kunjin Replicon Virus-like Particle Vaccine Provides Protection Against Ebola Virus Infection in Nonhuman Primates. , 2015, The Journal of infectious diseases.

[122]  Bernard Verrier,et al.  Efficient stimulation of HIV-1-specific T cells using dendritic cells electroporated with mRNA encoding autologous HIV-1 Gag and Env proteins. , 2006, Blood.

[123]  P. Fechter,et al.  Recognition of mRNA cap structures by viral and cellular proteins. , 2005, The Journal of general virology.

[124]  Birke Andrea Tews,et al.  Self-Replicating RNA , 2016, Methods in molecular biology.

[125]  Kenneth Lundstrom,et al.  Latest development on RNA-based drugs and vaccines , 2018, Future science OA.

[126]  J. Rosenecker,et al.  Nanotechnologies in delivery of mRNA therapeutics using nonviral vector-based delivery systems , 2017, Gene Therapy.

[127]  Justin M. Richner,et al.  Modified mRNA Vaccines Protect against Zika Virus Infection , 2017, Cell.

[128]  M. Zeng,et al.  T-cell-mediated cross-strain protective immunity elicited by prime-boost vaccination with a live attenuated influenza vaccine. , 2014, International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases.

[129]  C. Grunwitz,et al.  mRNA Cancer Vaccines-Messages that Prevail. , 2017, Current topics in microbiology and immunology.

[130]  Gunther Hartmann,et al.  Selection of Molecular Structure and Delivery of RNA Oligonucleotides to Activate TLR7 versus TLR8 and to Induce High Amounts of IL-12p70 in Primary Human Monocytes1 , 2009, The Journal of Immunology.

[131]  R. Flavell,et al.  Recognition of double-stranded RNA and activation of NF-κB by Toll-like receptor 3 , 2001, Nature.

[132]  B. Walker,et al.  Immunization of HIV-1-Infected Persons With Autologous Dendritic Cells Transfected With mRNA Encoding HIV-1 Gag and Nef: Results of a Randomized, Placebo-Controlled Clinical Trial , 2016, Journal of acquired immune deficiency syndromes.

[133]  G. Lenzen,et al.  Induction of virus‐specific cytotoxic T lymphocytes in vivo by liposome‐entrapped mRNA , 1993, European journal of immunology.

[134]  B. Neyns,et al.  Intravenous and intradermal TriMix-dendritic cell therapy results in a broad T-cell response and durable tumor response in a chemorefractory stage IV-M1c melanoma patient , 2012, Cancer Immunology, Immunotherapy.

[135]  Kimberly J. Hassett,et al.  Preclinical and Clinical Demonstration of Immunogenicity by mRNA Vaccines against H10N8 and H7N9 Influenza Viruses , 2017, Molecular therapy : the journal of the American Society of Gene Therapy.

[136]  A. Masuda,et al.  Results of a randomized, placebo-controlled clinical trial of famvir for active Meniere’s disease , 2003 .

[137]  G. B. Robb,et al.  mRNA capping: biological functions and applications , 2016, Nucleic acids research.

[138]  J. Bolen,et al.  Safety Evaluation of Lipid Nanoparticle–Formulated Modified mRNA in the Sprague-Dawley Rat and Cynomolgus Monkey , 2018, Veterinary pathology.

[139]  C. Mandl,et al.  A cationic nanoemulsion for the delivery of next-generation RNA vaccines. , 2014, Molecular therapy : the journal of the American Society of Gene Therapy.

[140]  Jason C Debasitis,et al.  Induction of an IFN-Mediated Antiviral Response by a Self-Amplifying RNA Vaccine: Implications for Vaccine Design , 2017, The Journal of Immunology.

[141]  D. Weissman,et al.  mRNA Is an Endogenous Ligand for Toll-like Receptor 3* , 2004, Journal of Biological Chemistry.

[142]  C. Heirman,et al.  Particle-mediated Intravenous Delivery of Antigen mRNA Results in Strong Antigen-specific T-cell Responses Despite the Induction of Type I Interferon. , 2016, Molecular therapy. Nucleic acids.

[143]  D. Weissman,et al.  mRNA vaccines — a new era in vaccinology , 2018, Nature Reviews Drug Discovery.

[144]  S. Buus,et al.  Efficient Induction of T Cells against Conserved HIV-1 Regions by Mosaic Vaccines Delivered as Self-Amplifying mRNA , 2018, Molecular therapy. Methods & clinical development.

[145]  I. Wilson,et al.  A structural explanation for the low effectiveness of the seasonal influenza H3N2 vaccine , 2017, PLoS pathogens.

[146]  R. Schreiber,et al.  Blocking monoclonal antibodies specific for mouse IFN-alpha/beta receptor subunit 1 (IFNAR-1) from mice immunized by in vivo hydrodynamic transfection. , 2006, Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research.

[147]  C. D. de Haan,et al.  Evaluation of nonspreading Rift Valley fever virus as a vaccine vector using influenza virus hemagglutinin as a model antigen. , 2014, Vaccine.

[148]  Yan Zhou,et al.  Influenza A Virus Panhandle Structure Is Directly Involved in RIG-I Activation and Interferon Induction , 2015, Journal of Virology.

[149]  Timothy B. Stockwell,et al.  Reversion of Cold-Adapted Live Attenuated Influenza Vaccine into a Pathogenic Virus , 2016, Journal of Virology.

[150]  K. Miller,et al.  Self-adjuvanted mRNA vaccination in advanced prostate cancer patients: a first-in-man phase I/IIa study , 2015, Journal of Immunotherapy for Cancer.

[151]  Zhaolin Hua,et al.  TLR signaling in B-cell development and activation , 2012, Cellular and Molecular Immunology.

[152]  T. Fujita,et al.  RIG-I-Like Receptors and Type I Interferonopathies. , 2017, Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research.

[153]  M. Kozak An analysis of 5'-noncoding sequences from 699 vertebrate messenger RNAs. , 1987, Nucleic acids research.

[154]  H. Goossens,et al.  Induction of Cytomegalovirus-Specific T Cell Responses in Healthy Volunteers and Allogeneic Stem Cell Recipients Using Vaccination With Messenger RNA–Transfected Dendritic Cells , 2014, Transplantation.

[155]  Shizuo Akira,et al.  Signaling to NF-?B by Toll-like receptors , 2007 .

[156]  U. Şahin,et al.  Modification of antigen-encoding RNA increases stability, translational efficacy, and T-cell stimulatory capacity of dendritic cells. , 2006, Blood.

[157]  R. Gottardo,et al.  Safety and immunogenicity of a mRNA rabies vaccine in healthy adults: an open-label, non-randomised, prospective, first-in-human phase 1 clinical trial , 2017, The Lancet.

[158]  Holger Laux,et al.  Expression of the human cytomegalovirus pentamer complex for vaccine use in a CHO system , 2015, Biotechnology and bioengineering.

[159]  Michele A. Kutzler,et al.  DNA vaccines: ready for prime time? , 2008, Nature Reviews Genetics.

[160]  T. Schlake,et al.  Developing mRNA-vaccine technologies , 2012, RNA biology.

[161]  A. Cascante,et al.  mRNA Delivery System for Targeting Antigen‐Presenting Cells In Vivo , 2018, Advanced healthcare materials.

[162]  C. Mandl,et al.  RNA: the new revolution in nucleic acid vaccines. , 2013, Seminars in immunology.

[163]  S. Pascolo Vaccination with messenger RNA. , 2006, Methods in molecular medicine.

[164]  Olga Yuzhakov,et al.  Modified mRNA-Based Vaccines Elicit Robust Immune Responses and Protect Guinea Pigs From Ebola Virus Disease , 2018, The Journal of infectious diseases.

[165]  G. Bensi,et al.  Immunogenicity and protective efficacy induced by self-amplifying mRNA vaccines encoding bacterial antigens. , 2017, Vaccine.

[166]  C. Rudolph,et al.  Maximizing the Translational Yield of mRNA Therapeutics by Minimizing 5'-UTRs. , 2019, Tissue engineering. Part A.

[167]  C. Reis e Sousa,et al.  Cytosolic Sensing of Viruses , 2013, Immunity.

[168]  D. Weissman,et al.  Increased Erythropoiesis in Mice Injected With Submicrogram Quantities of Pseudouridine-containing mRNA Encoding Erythropoietin , 2012, Molecular therapy : the journal of the American Society of Gene Therapy.

[169]  R. Steinman,et al.  Dendritic cells and the control of immunity , 1998, Nature.

[170]  Nicole C. Robb,et al.  RIG-I Detects Viral Genomic RNA during Negative-Strand RNA Virus Infection , 2010, Cell.

[171]  F. Scorza,et al.  New Kids on the Block: RNA-Based Influenza Virus Vaccines , 2018, Vaccines.

[172]  J. Ulmer,et al.  Mechanism of action of mRNA-based vaccines , 2017, Expert review of vaccines.