A Comparison of Plasmid DNA and mRNA as Vaccine Technologies

Margaret A Liu, Margaret A Liu

Abstract

This review provides a comparison of the theoretical issues and experimental findings for plasmid DNA and mRNA vaccine technologies. While both have been under development since the 1990s, in recent years, significant excitement has turned to mRNA despite the licensure of several veterinary DNA vaccines. Both have required efforts to increase their potency either via manipulating the plasmid DNA and the mRNA directly or through the addition of adjuvants or immunomodulators as well as delivery systems and formulations. The greater inherent inflammatory nature of the mRNA vaccines is discussed for both its potential immunological utility for vaccines and for the potential toxicity. The status of the clinical trials of mRNA vaccines is described along with a comparison to DNA vaccines, specifically the immunogenicity of both licensed veterinary DNA vaccines and select DNA vaccine candidates in human clinical trials.

Keywords: Cytolytic T Lymphocytes; DNA vaccine; antibodies; formulations; immune responses; in vitro transcribed mRNA; innate immunity; mRNA vaccine; plasmid DNA.

Conflict of interest statement

“The author declares no conflict of interest.”

References

    1. Liu M.A. DNA vaccines: An historical perspective and view to the future. Immunol. Rev. 2011;239:62–84. doi: 10.1111/j.1600-065X.2010.00980.x.
    1. Pardi N., Hogan M.J., Porter F.W., Weissman D. mRNA vaccines––A new era in vaccinology. Nat. Rev. Drug Discov. 2018;17:261–279. doi: 10.1038/nrd.2017.243.
    1. Stevenson F.K., Zhu D., King C.A., Ashworth L.J., Kumar S., Hawkins R.E. Idiotypic DNA vaccines against B-cell lymphoma. Immunol. Rev. 1995;145:211–228. doi: 10.1111/j.1600-065X.1995.tb00083.x.
    1. Syrengelas A.D., Chen T.T., Levy R. DNA immunization induces protective immunity against B-cell lymphoma. Nat. Med. 1996;2:1038–1041. doi: 10.1038/nm0996-1038.
    1. Sahin U., Karikó K., Türeci Ö. mRNA-based therapeutics––Developing a new class of drugs. Nat. Rev. Drug Discov. 2014;13:759–780. doi: 10.1038/nrd4278.
    1. Wolff J.A., Malone R.W., Williams P., Chong W., Acsadi G., Jani A., Felgner P.L. Direct gene transfer into mouse muscle in vivo. Science. 1990;247:1465–1468. doi: 10.1126/science.1690918.
    1. Ulmer J.B., Donnelly J.J., Parker S.E., Rhodes G.H., Felgner P.L., Dwarki V.J., Gromkowski S.H., Deck R.R., DeWitt C.M., Friedman A., et al. Heterologous protection against influenza by injection of DNA encoding a viral protein. Science. 1993;259:1745–1749. doi: 10.1126/science.8456302.
    1. Jirikowski G.F., Sanna P.P., Maciejewski-Lenoir D., Bloom F.E. Reversal of diabetes insipidus in Brattleboro rats: Intrahypothalamic injection of vasopressin mRNA. Science. 1992;255:996–998. doi: 10.1126/science.1546298.
    1. Martinon F., Krishnan S., Lenzen G., Magné R., Gomard E., Guillet J.G., Lévy J.P., Meulien P. Induction of virus-specific cytotoxic T lymphocytes in vivo by liposome-entrapped mRNA. Eur. J. Immunol. 1993;23:1719–1722. doi: 10.1002/eji.1830230749.
    1. Deck R.R., DeWitt C.M., Donnelly J.J., Liu M.A., Ulmer J.B. Characterization of humoral immune responses induced by an influenza hemagglutinin DNA vaccine. Vaccine. 1997;15:71–78. doi: 10.1016/S0264-410X(96)00101-6.
    1. Hajj K.A., Whitehead K.A. Tools for translation: Non-viral materials for therapeutic mRNA delivery. Nat. Rev. Mater. 2017;2:17056. doi: 10.1038/natrevmats.2017.56.
    1. Houseley J., Tollervey D. The many pathways of RNA degradation. Cell. 2009;136:763–776. doi: 10.1016/j.cell.2009.01.019.
    1. Quinn K.M., Yamamoto A., Costa A., Darrah P.A., Lindsay R.W., Hegde S.T., Johnson T.R., Flynn B.J., Loré K., Seder R.A. Coadministration of polyinosinic:polycytidylic acid and immunostimulatory complexes modifies antigen processing in dendritic cell subsets and enhances HIV gag-specific T cell immunity. J. Immunol. 2013;191:5085–5096. doi: 10.4049/jimmunol.1301730.
    1. Domingos-Pereira S., Decrausaz L., Derré L., Bobst M., Romero P., Schiller J.T., Jichlinski P., Nardelli-Haefliger D. Intravaginal TLR agonists increase local vaccine-specific CD8 T cells and human papillomavirus-associated genital-tumor regression in mice. Mucosal Immunol. 2013;6:393–404. doi: 10.1038/mi.2012.83.
    1. Zhang L., Bai J., Liu J., Wang X., Li Y., Jiang P. Toll-like receptor ligands enhance the protective effects of vaccination against porcine reproductive and respiratory syndrome virus in swine. Vet. Microbiol. 2013;164:253–260. doi: 10.1016/j.vetmic.2013.02.016.
    1. Karikó K., Buckstein M., Ni H., Weissman D. Suppression of RNA recognition by Toll-like receptors: The impact of nucleoside modification and the evolutionary origin of RNA. Immunity. 2005;23:165–175. doi: 10.1016/j.immuni.2005.06.008.
    1. Karikó K., Muramatsu H., Welsh F.A., Ludwig J., Kato H., Akira S., Weissman D. Incorporation of pseudouridine into mRNA yields superior nonimmunogenic vector with increased translational capacity and biological stability. Mol. Ther. 2008;16:1833–1840. doi: 10.1038/mt.2008.200.
    1. Ledwith B.J., Manam S., Troilo P.J., Barnum A.B., Pauley C.J., Griffiths T.G., 2nd., Harper L.B., Beare C.M., Bagdon W.J., Nichols W.W. Plasmid DNA vaccines: Investigation of integration into host cellular DNA following intramuscular injection in mice. Intervirology. 2000;43:258–272. doi: 10.1159/000053993.
    1. Schmeer M., Buchholz T., Schleef M. Plasmid DNA Manufacturing for Indirect and Direct Clinical Applications. Hum. Gene Ther. 2017;28:856–861. doi: 10.1089/hum.2017.159.
    1. Reautschnig P., Vogel P., Stafforst T. The notorious R.N.A. in the spotlight––Drug or target for the treatment of disease. RNA Biol. 2017;14:651–668. doi: 10.1080/15476286.2016.1208323.
    1. Whisenand J.M., Azizian K.T., Henderson J.M., Shore S., Shin D., Lebedev A., McCaffrey A.P., Hogrefe R.I. Considerations for the Design and cGMP Manufacturing of mRNA Therapeutics. [(accessed on 21 February 2019)]; Available online: .
    1. Schmid A. Considerations for Producing mRNA Vaccines for Clinical Trials. Methods Mol. Biol. 2017;1499:237–251.
    1. WHO Expert Committee on Specifications for Pharmaceutical Preparations WHO Technical Report Series, No. 908. Thirty-Seventh Report: Annex 4 Good Manufacturing Practices for Pharmaceutical Products: Main Principles. [(accessed on 21 February 2019)]; Available online: .
    1. Good Manufacturing Practices for Biological Products. In WHO Expert Committee on Biological Standardization. Forty-Second Report. Geneva, World Health Organization, 1992, Annex 1.WHO Technical Report Series, No. 822. [(accessed on 21 February 2019)]; Available online: .
    1. Middaugh C.R., Evans R.K., Montgomery D.L., Casimiro D.R. Analysis of plasmid DNA from a pharmaceutical perspective. J. Pharm. Sci. 1998;87:130–146. doi: 10.1021/js970367a.
    1. Stitz L., Vogel A., Schnee M., Voss D., Rauch S., Mutzke T., Ketterer T., Kramps T., Petsch B. A thermostable messenger RNA based vaccine against rabies. PLoS Negl. Trop. Dis. 2017;11:e0006108. doi: 10.1371/journal.pntd.0006108.
    1. Fu T.M., Ulmer J.B., Caulfield M.J., Deck R.R., Friedman A., Wang S., Liu X., Donnelly J.J., Liu M.A. Priming of cytotoxic T lymphocytes by DNA vaccinequirement for professional antigen presenting cells and evidence for antigen transfer from myocytes. Mol. Med. 1997;3:362–371. doi: 10.1007/BF03401683.
    1. Fu T.M., Friedman A., Ulmer J.B., Liu M.A., Donnelly J.J. Protective cellular immunity: Cytotoxic T-lymphocyte responses against dominant and recessive epitopes of influenza virus nucleoprotein induced by DNA immunization. J. Virol. 1997;71:2715–2721.
    1. Dupuis M., Denis-Mize K., Woo C., Goldbeck C., Selby M.J., Chen M., Otten G.R., Ulmer J.B., Donnelly J.J., Ott G., et al. Distribution of DNA vaccines determines their immunogenicity after intramuscular injection in mice. J. Immunol. 2000;165:2850–2858. doi: 10.4049/jimmunol.165.5.2850.
    1. Donnelly J.J., Friedman A., Ulmer J.B., Liu M.A. Further protection against antigenic drift of influenza virus in a ferret model by DNA vaccination. Vaccine. 1997;15:865–868. doi: 10.1016/S0264-410X(96)00268-X.
    1. Probst J., Weide B., Scheel B., Pichler B.J., Hoerr I., Rammensee H.G., Pascolo S. Spontaneous cellular uptake of exogenous messenger RNA in vivo is nucleic acid-specific, saturable and ion dependent. Gene Ther. 2007;14:1175–1180. doi: 10.1038/sj.gt.3302964.
    1. Tang D.C., DeVit M., Johnston S.A. Genetic immunization is a simple method for eliciting an immune response. Nature. 1992;356:152–154. doi: 10.1038/356152a0.
    1. Hajj K.A., Ball R.L., Deluty S.B., Singh S.R., Strelkova D., Knapp C.M., Whitehead K.A. Branched-Tail Lipid Nanoparticles Potently Deliver mRNA In Vivo due to Enhanced Ionization at Endosomal pH. Small. 2019;15:e1805097. doi: 10.1002/smll.201805097.
    1. Iavarone C., O’Hagan D.T., Yu D., Delahaye N.F., Ulmer J.B. Mechanism of action of mRNA-based vaccines. Expert Rev. Vaccines. 2017;16:871–881. doi: 10.1080/14760584.2017.1355245.
    1. Kaczmarek J.C., Kowalski P.S., Anderson D.G. Advances in the delivery of RNA therapeutics: From concept to clinical reality. Genome Med. 2017;9:60. doi: 10.1186/s13073-017-0450-0.
    1. Persano S., Guevara M.L., Li Z., Mai J., Ferrari M., Pompa P.P., Shen H. Lipopolyplex potentiates anti-tumor immunity of mRNA-based vaccination. Biomaterials. 2017;125:81–89. doi: 10.1016/j.biomaterials.2017.02.019.
    1. Rauch S., Jasny E., Schmidt K.E., Petsch B. New Vaccine Technologies to Combat Outbreak Situations. Front. Immunol. 2018;9:1963. doi: 10.3389/fimmu.2018.01963.
    1. Pascolo S. Vaccination with messenger RNA. Methods Mol. Med. 2006;127:23–40.
    1. Xu Z., Li P., Fan L., Wu M. The Potential Role of circRNA in Tumor Immunity Regulation and Immunotherapy. Front Immunol. 2018 doi: 10.3389/fimmu.2018.00009.
    1. Wesselhoeft R.A., Kowalski P.S., Anderson D.G. Engineering circular RNA for potent and stable translation in eukaryotic cells. Nat. Commun. 2018;9 doi: 10.1038/s41467-018-05096-6.
    1. Holdt L.M., Kohlmaier A., Teupser D. Circular RNAs as Therapeutic Agents and Targets. Front. Physiol. 2018 doi: 10.3389/fphys.2018.01262.
    1. Ljungberg K., Liljeström P. Self-replicating alphavirus RNA vaccines. Expert Rev. Vaccines. 2015;14:177–194. doi: 10.1586/14760584.2015.965690.
    1. Brazzoli M., Magini D., Bonci A., Buccato S., Giovani C., Kratzer R., Zurli V., Mangiavacchi S., Casini D., Brito L.M., et al. Induction of Broad-Based Immunity and Protective Efficacy by Self-amplifying mRNA Vaccines Encoding Influenza Virus Hemagglutinin. J. Virol. 2016;90:332–344. doi: 10.1128/JVI.01786-15.
    1. Brito L.A., Kommareddy S., Maione D., Uematsu Y., Giovani C., Berlanda Scorza F., Otten G.R., Yu D., Mandl C.W., Mason P.W., et al. Self-amplifying mRNA vaccines. Adv. Genet. 2015;89:179–233.
    1. Samsa M.M., Dupuy L.C., Beard C.W., Six C.M., Schmaljohn C.S., Mason P.W., Geall A.J., Ulmer J.B., Yu D. Self-Amplifying RNA Vaccines for Venezuelan Equine Encephalitis Virus Induce Robust Protective Immunogenicity in Mice. Mol Ther. 2019;27:850–865. doi: 10.1016/j.ymthe.2018.12.013.
    1. Campbell J.D. Development of the CpG Adjuvant 1018: A Case Study. Methods Mol. Biol. 2017;1494:15–27.
    1. Gottlieb P., Utz P.J., Robinson W., Steinman L. Clinical optimization of antigen specific modulation of type 1 diabetes with the plasmid DNA platform. Clin. Immunol. 2013;149:297–306. doi: 10.1016/j.clim.2013.08.010.
    1. Coban C., Kobiyama K., Aoshi T., Takeshita F., Horii T., Akira S., Ishii K.J. Novel strategies to improve DNA vaccine immunogenicity. Curr. Gene Ther. 2011;11:479–484. doi: 10.2174/156652311798192815.
    1. Coban C., Kobiyama K., Jounai N., Tozuka M., Ishii K.J. DNA vaccines––A simple DNA sensing matter? Hum. Vaccin. Immunother. 2013;9 doi: 10.4161/hv.25893.
    1. Allen A., Wang C., Caproni L.J., Sugiyarto G., Harden E., Douglas L.R., Duriez P.J., Karbowniczek K., Extance J., Rothwell P.J., et al. Linear doggybone DNA vaccine induces similar immunological responses to conventional plasmid DNA independently of immune recognition by TLR9 in a pre-clinical model. Cancer Immunol. Immunother. 2018;67:627–638. doi: 10.1007/s00262-017-2111-y.
    1. Chen N., Xia P., Li S., Zhang T., Wang T.T., Zhu J. RNA sensors of the innate immune system and their detection of pathogens. IUBMB Life. 2017;69:297–304. doi: 10.1002/iub.1625.
    1. Pollard C., Rejman J., De Haes W., Verrier B., Van Gulck E., Naessens T., De Smedt S., Bogaert P., Grooten J., Vanham G., et al. Type I IFN counteracts the induction of antigen-specific immune responses by lipid-based delivery of mRNA vaccines. Mol. Ther. 2013;21:251–259. doi: 10.1038/mt.2012.202.
    1. Karikó K., Muramatsu H., Ludwig J., Weissman D. Generating the optimal mRNA for therapy: HPLC purification eliminates immune activation and improves translation of nucleoside-modified, protein-encoding mRNA. Nucleic Acids Res. 2011;39:e142. doi: 10.1093/nar/gkr695.
    1. Doener F., Hong H.S., Meyer I., Tadjalli-Mehr K., Daehling A., Heidenreich R., Koch S.D., Fotin-Mleczek M., Gnad-Vogt U. RNA-based adjuvant CV8102 enhances the immunogenicity of a licensed rabies vaccine in a first-in-human trial. Vaccine. 2019 doi: 10.1016/j.vaccine.2019.02.024.
    1. Alberer M., Gnad-Vogt U., Hong H.S., Mehr K.T., Backert L., Finak G., Gottardo R., Bica M.A., Garofano A., Koch S.D., 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. Lancet. 2017;390:1511–1520. doi: 10.1016/S0140-6736(17)31665-3.
    1. Feng J.Y., Johnson A.A., Johnson K.A., Anderson K.S. Insights into the Molecular Mechanism of Mitochondrial Toxicity by AIDS Drugs. J. Biol. Chem. 2001;276:23832–23837. doi: 10.1074/jbc.M101156200.
    1. Johnson A.A., Ray A.S., Hanes J., Suo Z., Colacino J.M., Anderson K.S., Johnson K.A. Toxicity of Antiviral Nucleoside Analogs and the Human Mitochondrial DNA Polymerase. J. Biol. Chem. 2001;276:40847–40857. doi: 10.1074/jbc.M106743200.
    1. Moyle G. Toxicity of antiretroviral nucleoside and nucleotide analogues: Is mitochondrial toxicity the only mechanism? Drug Saf. 2000;23:467–481. doi: 10.2165/00002018-200023060-00001.
    1. Moderna Hits Safety Problems in Bold Bid to Reinvent Medicine. STAT (2017) [(accessed on 27 February 2019)]; Available online:
    1. Apgar J.F., Tang J.P., Singh P., Balasubramanian N., Burke J., Hodges M.R., Lasaro M.A., Lin L., Miliard B.L., Moore K., et al. Quantitative Systems Pharmacology Model of hUGT1A1-modRNA Encoding for the UGT1A1 Enzyme to Treat Crigler-Najjar Syndrome Type 1. CPT Pharmacomet. Syst. Pharmacol. 2018;7:404–412. doi: 10.1002/psp4.12301.
    1. Schlake T., Thess A., Thran M., Jordan I. mRNA as novel technology for passive immunotherapy. Cell. Mol. Life Sci. 2019;76:301–328. doi: 10.1007/s00018-018-2935-4.
    1. Garren H., Robinson W.H., Krasulová E., Havrdová E., Nadj C., Selmaj K., Losy J., Nadj I., Radue E.W., Kidd B.A., et al. Phase 2 trial of a DNA vaccine encoding myelin basic protein for multiple sclerosis. Ann. Neurol. 2008;63:611–620. doi: 10.1002/ana.21370.
    1. Pepini T., Pulichino A.M., Carsillo T., Carlson A.L., Sari-Sarraf F., Ramsauer K., Debasitis J.C., Maruggi G., Otten G.R., Geall A.J., et al. Induction of an IFN-Mediated Antiviral Response by a Self-Amplifying RNA Vaccine: Implications for Vaccine Design. J. Immunol. 2017;198:4012–4024. doi: 10.4049/jimmunol.1601877.
    1. Theofilopoulos A.N., Baccala R., Beutler B., Kono D.H. Type I interferons (alpha/beta) in immunity and autoimmunity. Annu. Rev. Immunol. 2005;23:307–336. doi: 10.1146/annurev.immunol.23.021704.115843.
    1. Edwards D.K., Jasny E., Yoon H., Horscroft N., Schanen B., Geter T., Fotin-Mleczek M., Petsch B., Wittman V., et al. Adjuvant effects of a sequence-engineered mRNA vaccine: Translational profiling demonstrates similar human and murine innate response. J. Transl. Med. 2017;15:1. doi: 10.1186/s12967-016-1111-6.
    1. Sheets R.L., Stein J., Manetz T.S., Duffy C., Nason M., Andrews C., Kong W.P., Nabel G.J., Gomez P.L. Biodistribution of DNA Plasmid Vaccines against HIV-1, Ebola, Severe Acute Respiratory Syndrome, or West Nile Virus Is Similar, without Integration, despite Differing Plasmid Backbones or Gene Inserts. Toxicol. Sci. 2006;91:610–619. doi: 10.1093/toxsci/kfj169.
    1. European Food Safety Authority (EFSA) Houston R., Moxon S., Nogué F., Papadopoulou N., Ramon M., Waigmann E. Assessment of the potential integration of the DNA plasmid vaccine CLYNAV into the salmon genome. EFSA J. 2017;15:e04689.
    1. Griffiths D.J. Endogenous retroviruses in the human genome sequence. Genome Biol. 2001;2:PMC138943. doi: 10.1186/gb-2001-2-6-reviews1017.
    1. Honda T., Tomonaga K. Endogenous non-retroviral RNA virus elements evidence a novel type of antiviral immunity. Mob. Genet. Elem. 2016;6:e1165785. doi: 10.1080/2159256X.2016.1165785.
    1. Douville R.N., Nath A. Human endogenous retroviruses and the nervous system. Handb. Clin. Neurol. 2014;123:465–485.
    1. Hinz T., Kallen K., Britten C.M., Flamion B., Granzer U., Hoos A., Huber C., Khleif S., Kreiter S., Rammensee H.G., et al. The European Regulatory Environment of RNA-Based Vaccines. Methods Mol. Biol. 2017;1499:203–222.
    1. Dalmo R.A. DNA vaccines for fish: Review and perspectives on correlates of protection. J. Fish Dis. 2018;41:1–9. doi: 10.1111/jfd.12727.
    1. . Oncept Melanoma: Withdrawn Application. European Medicines Agency––Commission (2018) [(accessed on 21 February 2019)]; Available online: .
    1. CDC-Media Relations-Press Release-July 18 2005. [(accessed on 21 February 2019)]; Available online: .
    1. Wheeler S.S., Langevin S., Woods L., Carroll B.D., Vickers W., Morrison S.A., Chang G.-J.J., Reisen W.K., Boyce W.M. Efficacy of three vaccines in protecting Western Scrub-Jays (Aphelocoma californica) from experimental infection with West Nile virus: implications for vaccination of Island Scrub-Jays (Aphelocoma insularis) Vector Borne Zoonotic Dis. 2011;11:1069–1080. doi: 10.1089/vbz.2010.0173.
    1. Kilpatrick A.M., Dupuis A.P., Chang G.-J.J., Kramer L.D. DNA vaccination of American robins (Turdus migratorius) against West Nile virus. Vector Borne Zoonotic Dis. 2010;10:377–380. doi: 10.1089/vbz.2009.0029.
    1. Bunning M.L., Fox P.E., Bowen R.A., Komar N., Chang G.J., Speaker T.J., Stephens M.R., Nemeth N., Panella N.A., Langevin S.A., et al. DNA vaccination of the American crow (Corvus brachyrhynchos) provides partial protection against lethal challenge with West Nile virus. Avian Dis. 2007;51:573–577. doi: 10.1637/0005-2086(2007)51[573:DVOTAC];2.
    1. Turell M.J., Bunning M., Ludwig G.V., Ortman B., Chang J., Speaker T., Spielman A., McLean R., Komar N., Gates R., et al. DNA vaccine for West Nile virus infection in fish crows (Corvus ossifragus) Emerg. Infect. Dis. 2003;9:1077–1081. doi: 10.3201/eid0909.030025.
    1. Chang G.-J.J., Davis B.S., Stringfield C., Lutz C. Prospective immunization of the endangered California condors (Gymnogyps californianus) protects this species from lethal West Nile virus infection. Vaccine. 2007;25:2325–2330. doi: 10.1016/j.vaccine.2006.11.056.
    1. Draghia-Akli R., Ellis K.M., Hill L.-A., Malone P.B., Fiorotto M.L. High-efficiency growth hormone-releasing hormone plasmid vector administration into skeletal muscle mediated by electroporation in pigs. FASEB J. 2003;17:526–528. doi: 10.1096/fj.02-0671fje.
    1. VGX Animal Health Announces Approval of LifeTideTM SW 5-World’s First and Only Approved DNA Therapy for Food Animals. [(accessed on 21 February 2019)]; Available online: .
    1. Martin J.E., Pierson T.C., Hubka S., Rucker S., Gordon I.J., Enama M.E., Andrews C.A., Xu Q., Davis B.S., Nason M., et al. A West Nile virus DNA vaccine induces neutralizing antibody in healthy adults during a phase 1 clinical trial. J. Infect. Dis. 2007;196:1732–1740. doi: 10.1086/523650.
    1. Ledgerwood J.E., Pierson T.C., Hubka S.A., Desai N., Rucker S., Gordon I.J., Enama M.E., Nelson S., Nason M., Gu W., et al. A West Nile virus DNA vaccine utilizing a modified promoter induces neutralizing antibody in younger and older healthy adults in a phase I clinical trial. J. Infect. Dis. 2011;203:1396–1404. doi: 10.1093/infdis/jir054.
    1. Sarwar U.N., Costner P., Enama M.E., Berkowitz N., Hu Z., Hendel C.S., Sitar S., Plummer S., Mulangu S., Bailer R.T., et al. Safety and immunogenicity of DNA vaccines encoding Ebolavirus and Marburgvirus wild-type glycoproteins in a phase I clinical trial. J. Infect. Dis. 2015;211:549–557. doi: 10.1093/infdis/jiu511.
    1. Gaudinski M.R., Houser K.V., Morabito K.M., Hu Z., Yamshchikov G., Rothwell R.S., Berkowitz N., Mendoza F., Saunders J.G., Novik L., et al. Safety, tolerability, and immunogenicity of two Zika virus DNA vaccine candidates in healthy adults: Randomised, open-label, phase 1 clinical trials. Lancet. 2018;391:552–562. doi: 10.1016/S0140-6736(17)33105-7.
    1. Kim T.J., Jin H.T., Hur S.Y., Yang H.G., Seo Y.B., Hong S.R., Lee C.W., Kim S., Woo J.W., Park K.S., et al. Clearance of persistent HPV infection and cervical lesion by therapeutic DNA vaccine in CIN3 patients. Nat. Commun. 2014;5:5317. doi: 10.1038/ncomms6317.
    1. Trimble C.L., Morrow M.P., Kraynyak K.A., Shen X., Dallas M., Yan J., Edwards L., Parker R.L., Denny L., Giffear M., Brown A.S., et al. Safety, efficacy, and immunogenicity of VGX-3100, a therapeutic synthetic DNA vaccine targeting human papillomavirus 16 and 18 E6 and E7 proteins for cervical intraepithelial neoplasia 2/3: A randomised, double-blind, placebo-controlled phase 2b trial. Lancet. 2015;386:2078–2088. doi: 10.1016/S0140-6736(15)00239-1.
    1. Aggarwal C., Cohen R.B., Morrow M.P., Kraynak K.A., Sylvester A.J., Knoblock D.M., Bauml J., Weinstein G.S., Lin A., Boyer J., et al. Immunotherapy targeting HPV 16/18 generates potent immune responses in HPV-Associated Head and Neck Cancer. Clin. Cancer Res. 2018 doi: 10.1158/1078-0432.CCR-18-1763.
    1. Chudley L., McCann K., Mander A., Tjelle T., Campos-Perez J., Godeseth R., Creak A., Dobbyn J., Johnson B., Bass P., et al. DNA fusion-gene vaccination in patients with prostate cancer induces high-frequency CD8+ T-cell responses and increases PSA doubling time. Cancer Immunol. Immunother. 2012;61:2161–2170. doi: 10.1007/s00262-012-1270-0.
    1. McCann K.J., Mander A., Cazaly A., Chudley L., Stasakova J., Thirdborough S.M., King A., Lloyd-Evans P., Buxton E., Edwards C., et al. Targeting Carcinoembryonic Antigen with DNA Vaccination: On-Target Adverse Events Link with Immunologic and Clinical Outcomes. Clin. Cancer Res. 2016 doi: 10.1158/1078-0432.CCR-15-2507.
    1. Patel P.M., Ottensmeier C.H., Mulatero C., Lorigan P., Plummer R., Pandha H., Elsheikh S., Hadjimichael E., Villasanti N., Adams S.E., et al. Targeting gp100 and TRP-2 with a DNA vaccine: Incorporating T cell epitopes with a human IgG1 antibody induces potent T cell responses that are associated with favourable clinical outcome in a phase I/II trial. Oncoimmunology. 2018;7:e1433516. doi: 10.1080/2162402X.2018.1433516.
    1. Leal L., Guardo A.C., Morón-López S., Salgado M., Mothe B., Heirman C., Pannus P., Vanham G., van den Ham H.J., Gruters R., et al. Phase I clinical trial of an intranodally administered mRNA-based therapeutic vaccine against HIV-1 infection. AIDS. 2018;32:2533–2545. doi: 10.1097/QAD.0000000000002026.
    1. Moderna Announces Dosing of the First Monoclonal Antibody Encoded by mRNA in a Clinical Trial. Moderna, Inc. [(accessed on 23 February 2019)]; Available online: .
    1. Bahl K., Senn J.J., Yuzhakov O., Bulychev A., Brito L.A., Hassett K.J., Laska M.E., Smith M., Almarsson Ö., Thompson J., et al. Preclinical and Clinical Demonstration of Immunogenicity by mRNA Vaccines against H10N8 and H7N9 Influenza Viruses. Mol. Ther. 2017;25:1316–1327. doi: 10.1016/j.ymthe.2017.03.035.
    1. Richner J.M., Jagger B.W., Shan C., Fontes C.R., Dowd K.A., Cao B., Himansu S., Caine E.A., Nunes B.T.D., Medeiros D.B.A., et al. Vaccine Mediated Protection Against Zika Virus-Induced Congenital Disease. Cell. 2017;170:273–283. doi: 10.1016/j.cell.2017.06.040.
    1. Richner J.M., Himansu S., Dowd K.A., Butler S.L., Salazar V., Fox J.M., Julander J.G., Tang W.W., Shresta S., Pierson T.C., et al. Modified mRNA Vaccines Protect against Zika Virus Infection. Cell. 2017;168:1114–1125. doi: 10.1016/j.cell.2017.02.017.
    1. John S., Yuzhakov O., Woods A., Deterling J., Hassett K., Shaw C.A., Ciaramella G. Multi-antigenic human cytomegalovirus mRNA vaccines that elicit potent humoral and cell-mediated immunity. Vaccine. 2018;36:1689–1699. doi: 10.1016/j.vaccine.2018.01.029.
    1. Rausch S., Schwentner C., Stenzl A., Bedke J. mRNA vaccine CV9103 and CV9104 for the treatment of prostate cancer. Hum. Vaccines Immunother. 2014;10:3146–3152. doi: 10.4161/hv.29553.
    1. Kübler H., Scheel B., Gnad-Vogt U., Miller K., Schultze-Seemann W., Vom Dorp F., Parmiani G., Hampel C., Wedel S., Trojan L., et al. Self-adjuvanted mRNA vaccination in advanced prostate cancer patients: A first-in-man phase I/IIa study. J. Immunother. Cancer. 2015;3:26. doi: 10.1186/s40425-015-0068-y.

Source: PubMed

Patrocinadores e Colaboradores

Condições médicas

Intervenções de drogas

3
Se inscrever