A Comparison of Plasmid DNA and mRNA as Vaccine Technologies

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.

[1]  Michael Dallas,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 , 2015, The Lancet.

[2]  Khalid A. Hajj,et al.  Branched-Tail Lipid Nanoparticles Potently Deliver mRNA In Vivo due to Enhanced Ionization at Endosomal pH. , 2019, Small.

[3]  C. Andrews,et al.  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 , 2006, Toxicological sciences : an official journal of the Society of Toxicology.

[4]  T. Schlake,et al.  mRNA as novel technology for passive immunotherapy , 2018, Cellular and Molecular Life Sciences.

[5]  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 , 2018, Oncoimmunology.

[6]  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.

[7]  D. Dearnaley,et al.  DNA fusion-gene vaccination in patients with prostate cancer induces high-frequency CD8+ T-cell responses and increases PSA doubling time , 2012, Cancer Immunology, Immunotherapy.

[8]  Brian D. Carroll,et al.  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). , 2011, Vector borne and zoonotic diseases.

[9]  D. Tollervey,et al.  The Many Pathways of RNA Degradation , 2009, Cell.

[10]  Daniel G. Anderson,et al.  Advances in the delivery of RNA therapeutics: from concept to clinical reality , 2017, Genome Medicine.

[11]  J. Mascola,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. , 2011, The Journal of infectious diseases.

[12]  J. Ulmer,et al.  Further protection against antigenic drift of influenza virus in a ferret model by DNA vaccination. , 1997, Vaccine.

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

[14]  C. Mandl,et al.  Self-amplifying mRNA vaccines. , 2015, Advances in genetics.

[15]  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.

[16]  Houping Ni,et al.  Suppression of RNA recognition by Toll-like receptors: the impact of nucleoside modification and the evolutionary origin of RNA. , 2005, Immunity.

[17]  G. Chang,et al.  DNA Vaccination of the American Crow (Corvus brachyrhynchos) Provides Partial Protection Against Lethal Challenge with West Nile Virus , 2007, Avian diseases.

[18]  J. Burke,et al.  Quantitative Systems Pharmacology Model of hUGT1A1‐modRNA Encoding for the UGT1A1 Enzyme to Treat Crigler‐Najjar Syndrome Type 1 , 2018, CPT: pharmacometrics & systems pharmacology.

[19]  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.

[20]  Pengpeng Xia,et al.  RNA sensors of the innate immune system and their detection of pathogens , 2017, IUBMB life.

[21]  R. Hawkins,et al.  Idiotypic DNA Vaccines Against B‐cell Lymphoma , 1995, Immunological reviews.

[22]  B. Beutler,et al.  Type I interferons (alpha/beta) in immunity and autoimmunity. , 2005, Annual review of immunology.

[23]  A. Spielman,et al.  DNA Vaccine for West Nile Virus Infection in Fish Crows (Corvus ossifragus) , 2003, Emerging infectious diseases.

[24]  Mauro Ferrari,et al.  Lipopolyplex potentiates anti-tumor immunity of mRNA-based vaccination. , 2017, Biomaterials.

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

[26]  A. Stenzl,et al.  mRNA vaccine CV9103 and CV9104 for the treatment of prostate cancer , 2014, Human vaccines & immunotherapeutics.

[27]  D. Tang,et al.  Genetic immunization is a simple method for eliciting an immune response , 1992, Nature.

[28]  R. Levy,et al.  DNA immunization induces protective immunity against B–cell lymphoma , 1996, Nature Medicine.

[29]  S. Halford,et al.  Targeting Carcinoembryonic Antigen with DNA Vaccination: On-Target Adverse Events Link with Immunologic and Clinical Outcomes , 2016, Clinical Cancer Research.

[30]  M. Fiorotto,et al.  High‐efficiency growth hormone releasing hormone plasmid vector administration into skeletal muscle mediated by electroporation in pigs , 2003, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

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

[32]  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.

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

[34]  E. Radue,et al.  Phase 2 trial of a DNA vaccine encoding myelin basic protein for multiple sclerosis , 2008, Annals of neurology.

[35]  Daniel G. Anderson,et al.  Engineering circular RNA for potent and stable translation in eukaryotic cells , 2018, Nature Communications.

[36]  W. Robinson,et al.  Clinical optimization of antigen specific modulation of type 1 diabetes with the plasmid DNA platform. , 2013, Clinical immunology.

[37]  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.

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

[39]  Jie Liu,et al.  Toll-like receptor ligands enhance the protective effects of vaccination against porcine reproductive and respiratory syndrome virus in swine. , 2013, Veterinary microbiology.

[40]  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.

[41]  L. Holdt,et al.  Circular RNAs as Therapeutic Agents and Targets , 2018, Front. Physiol..

[42]  J. Ulmer,et al.  Heterologous protection against influenza by injection of DNA encoding a viral protein. , 1993, Science.

[43]  M. Fotin‐Mleczek,et al.  Adjuvant effects of a sequence-engineered mRNA vaccine: translational profiling demonstrates similar human and murine innate response , 2017, Journal of Translational Medicine.

[44]  G. Moyle Toxicity of Antiretroviral Nucleoside and Nucleotide Analogues , 2000, Drug safety.

[45]  R. Houston,et al.  Assessment of the potential integration of the DNA plasmid vaccine CLYNAV into the salmon genome , 2017, EFSA journal. European Food Safety Authority.

[46]  Khalid A. Hajj,et al.  Tools for translation: non-viral materials for therapeutic mRNA delivery , 2017 .

[47]  G. Weinstein,et al.  Immunotherapy Targeting HPV16/18 Generates Potent Immune Responses in HPV-Associated Head and Neck Cancer , 2018, Clinical Cancer Research.

[48]  R. K. Evans,et al.  Analysis of plasmid DNA from a pharmaceutical perspective. , 1998, Journal of pharmaceutical sciences.

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

[50]  Chao Shan,et al.  Vaccine Mediated Protection Against Zika Virus-Induced Congenital Disease , 2017, Cell.

[51]  F. Bloom,et al.  Reversal of diabetes insipidus in Brattleboro rats: intrahypothalamic injection of vasopressin mRNA. , 1992, Science.

[52]  Kenneth A. Johnson,et al.  Insights into the Molecular Mechanism of Mitochondrial Toxicity by AIDS Drugs* , 2001, The Journal of Biological Chemistry.

[53]  Minghua Wu,et al.  The Potential Role of circRNA in Tumor Immunity Regulation and Immunotherapy , 2018, Front. Immunol..

[54]  Margaret A. Liu DNA vaccines: an historical perspective and view to the future , 2011, Immunological reviews.

[55]  P. Mason,et al.  Self-Amplifying RNA Vaccines for Venezuelan Equine Encephalitis Virus Induce Robust Protective Immunogenicity in Mice. , 2019, Molecular therapy : the journal of the American Society of Gene Therapy.

[56]  J. Ulmer,et al.  Protective cellular immunity: cytotoxic T-lymphocyte responses against dominant and recessive epitopes of influenza virus nucleoprotein induced by DNA immunization , 1997, Journal of virology.

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

[58]  C. Coban,et al.  Novel strategies to improve DNA vaccine immunogenicity. , 2011, Current gene therapy.

[59]  David J Griffiths,et al.  Endogenous retroviruses in the human genome sequence , 2001, Genome Biology.

[60]  K. Anderson,et al.  Toxicity of Antiviral Nucleoside Analogs and the Human Mitochondrial DNA Polymerase* , 2001, The Journal of Biological Chemistry.

[61]  R. Dalmo DNA vaccines for fish: Review and perspectives on correlates of protection. , 2018, Journal of fish diseases.

[62]  John D Campbell,et al.  Development of the CpG Adjuvant 1018: A Case Study. , 2017, Methods in molecular biology.

[63]  M. Viljoen WHO Expert Committee on Specifications for Pharmaceutical Preparations. , 2012, World Health Organization technical report series.

[64]  A. Schmid Considerations for Producing mRNA Vaccines for Clinical Trials. , 2017, Methods in molecular biology.

[65]  K. Tomonaga,et al.  Endogenous non-retroviral RNA virus elements evidence a novel type of antiviral immunity , 2016, Mobile genetic elements.

[66]  P. Rothwell,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 , 2018, Cancer Immunology, Immunotherapy.

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

[68]  W. W. Nichols,et al.  Plasmid DNA Vaccines: Investigation of Integration into Host Cellular DNA following Intramuscular Injection in Mice , 2001, Intervirology.

[69]  J. Mascola,et al.  Safety, tolerability, and immunogenicity of two Zika virus DNA vaccine candidates in healthy adults: randomised, open-label, phase 1 clinical trials , 2017, The Lancet.

[70]  Kylie M. Quinn,et al.  Coadministration of Polyinosinic:Polycytidylic Acid and Immunostimulatory Complexes Modifies Antigen Processing in Dendritic Cell Subsets and Enhances HIV Gag-Specific T Cell Immunity , 2013, The Journal of Immunology.

[71]  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.

[72]  Tae Jin Kim,et al.  Clearance of persistent HPV infection and cervical lesion by therapeutic DNA vaccine in CIN3 patients , 2014, Nature Communications.

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

[74]  D. McDonald,et al.  Distribution of DNA Vaccines Determines Their Immunogenicity After Intramuscular Injection in Mice1 , 2000, The Journal of Immunology.

[75]  Philipp Reautschnig,et al.  The notorious R.N.A. in the spotlight - drug or target for the treatment of disease , 2016, RNA biology.

[76]  S. Koch,et al.  RNA-based adjuvant CV8102 enhances the immunogenicity of a licensed rabies vaccine in a first-in-human trial. , 2019, Vaccine.

[77]  Kimberly J. Hassett,et al.  Multi-antigenic human cytomegalovirus mRNA vaccines that elicit potent humoral and cell-mediated immunity. , 2018, Vaccine.

[78]  J. Ulmer,et al.  Characterization of humoral immune responses induced by an influenza hemagglutinin DNA vaccine. , 1997, Vaccine.

[79]  A. Nath,et al.  Human endogenous retroviruses and the nervous system. , 2014, Handbook of clinical neurology.

[80]  M. Fay,et al.  A West Nile virus DNA vaccine induces neutralizing antibody in healthy adults during a phase 1 clinical trial. , 2007, The Journal of infectious diseases.

[81]  B. Beutler,et al.  TYPE I INTERFERONS (/) IN IMMUNITY AND AUTOIMMUNITY , 2005 .

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

[83]  L. Kramer,et al.  DNA vaccination of American robins (Turdus migratorius) against West Nile virus. , 2010, Vector borne and zoonotic diseases.

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

[85]  J. Martinez-Picado,et al.  Phase I clinical trial of an intranodally administered mRNA-based therapeutic vaccine against HIV-1 infection , 2018, AIDS.

[86]  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.

[87]  G. Chang,et al.  Prospective immunization of the endangered California condors (Gymnogyps californianus) protects this species from lethal West Nile virus infection. , 2007, Vaccine.

[88]  P. Romero,et al.  Intravaginal TLR agonists increase local vaccine-specific CD8 T-cells and human papillomavirus-associated genital-tumor regression in mice , 2012, Mucosal Immunology.

[89]  J. Ulmer,et al.  Priming of Cytotoxic T Lymphocytes by DNA Vaccines: Requirement for Professional Antigen Presenting Cells and Evidence for Antigen Transfer from Myocytes , 1997, Molecular medicine.

[90]  M. Schmeer,et al.  Plasmid DNA Manufacturing for Indirect and Direct Clinical Applications. , 2017, Human gene therapy.

[91]  H. Rammensee,et al.  The European Regulatory Environment of RNA-Based Vaccines. , 2017, Methods in molecular biology.