{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T15:25:01Z","timestamp":1782141901026,"version":"3.54.5"},"reference-count":37,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,2,25]],"date-time":"2021-02-25T00:00:00Z","timestamp":1614211200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p><jats:italic>Borrelia burgdorferi<\/jats:italic> sensu lato (sl) is the causative agent of Lyme borreliosis. Currently there is no human vaccine against Lyme borreliosis, and most research focuses on recombinant protein vaccines. DNA tattoo vaccination with <jats:italic>B. afzelii<\/jats:italic> strain PKo OspC in mice has proven to be fully protective against <jats:italic>B. afzelii<\/jats:italic> syringe challenge and induces a favorable humoral immunity compared to recombinant protein vaccination. Alternatively, several recombinant protein vaccines based on tick proteins have shown promising effect in tick-bite infection models. In this study, we evaluated the efficacy of DNA vaccines against <jats:italic>Borrelia<\/jats:italic> OspC or tick antigens in a tick-bite infection model.<\/jats:p><\/jats:sec><jats:sec><jats:title>Method<\/jats:title><jats:p>We vaccinated C3H\/HeN mice with OspC using a codon-optimized DNA vaccine or with recombinant protein. We challenged these mice with <jats:italic>B. burgdorferi<\/jats:italic> sensu stricto (ss)-infected <jats:italic>Ixodes scapularis<\/jats:italic> nymphs. Subsequently, we vaccinated C3H\/HeN mice with DNA vaccines coding for tick proteins for which recombinant protein vaccines have previously resulted in interference with tick feeding and\/or <jats:italic>Borrelia<\/jats:italic> transmission: Salp15, tHRF, TSLPI, and Tix-5. These mice were also challenged with <jats:italic>B. burgdorferi<\/jats:italic> ss infected <jats:italic>Ixodes scapularis<\/jats:italic> nymphs.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>DNA tattoo and recombinant OspC vaccination both induced total IgG responses. <jats:italic>Borrelia<\/jats:italic> cultures and DNA loads of skin and bladder remained negative in the mice vaccinated with OspC DNA vaccination, except for one culture. DNA vaccines against tick antigens Salp15 and Tix-5 induced IgG responses, while those against tHRF and TSLPI barely induced any IgG response. In addition, <jats:italic>Borrelia<\/jats:italic> cultures, and DNA loads from mice tattooed with DNA vaccines against tick proteins TSLPI, Salp15, tHRF, and Tix-5 were all positive.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>A DNA tattoo vaccine against OspC induced high specific IgG titers and provided near total protection against <jats:italic>B. burgdorferi<\/jats:italic> ss infection by tick challenge. In contrast, DNA tattoo vaccines against tick proteins TSLPI, Salp15, tHRF, and Tix-5 induced low to moderate IgG titers and did not provide protection. Therefore, DNA tattoo vaccination does not seem a suitable vaccine strategy to identify, or screen for, tick antigens for anti-tick vaccines. However, DNA tattoo vaccination is a straightforward and effective vaccination platform to assess novel <jats:italic>B. burgdorferi<\/jats:italic> sl antigen candidates in a relevant tick challenge model.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2021.615011","type":"journal-article","created":{"date-parts":[[2021,2,25]],"date-time":"2021-02-25T04:25:34Z","timestamp":1614227134000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":15,"title":["Tick-Tattoo: DNA Vaccination Against B. burgdorferi or Ixodes scapularis Tick Proteins"],"prefix":"10.3389","volume":"12","author":[{"given":"Michelle J.","family":"Klouwens","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos J. A.","family":"Trentelman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alex","family":"Wagemakers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jasmin I.","family":"Ersoz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adriaan D.","family":"Bins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joppe W.","family":"Hovius","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,2,25]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciz872","article-title":"Protective Immunity and New Vaccines for Lyme Disease","volume":"70","author":"Gomes-Solecki","year":"2020","journal-title":"Clin Infect Dis"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1128\/cvi.00406-14","article-title":"A Novel multivalent OspA vaccine against Lyme borreliosis is safe and immunogenic in an adult population previously infected with Borrelia burgdorferi sensu lato","volume":"21","author":"Wressnigg","year":"2014","journal-title":"Clin Vaccine Immunol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1128\/iai.00917-19","article-title":"Broadly Protective Multivalent OspA Vaccine against Lyme Borreliosis, Developed Based on Surface Shaping of the C-Terminal Fragment","volume":"88","author":"Nayak","year":"2020","journal-title":"Infect Immun"},{"key":"B4","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3855\/jidc.7999","article-title":"Safety, immunogenicity, and efficacy of Borrelia burgdorferi outer surface protein A (OspA) vaccine: A meta-analysis","volume":"11","author":"Zhao","year":"2017","journal-title":"J Infect Dev Ctries"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1056\/nejm199807233390401","article-title":"Vaccination against Lyme disease with recombinant Borrelia burgdorferi outer-surface lipoprotein A with adjuvant. Lyme Disease Vaccine Study Group","volume":"339","author":"Steere","year":"1998","journal-title":"N Engl J Med"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1056\/nejm199807233390402","article-title":"A vaccine consisting of recombinant Borrelia burgdorferi outer-surface protein A to prevent Lyme disease. Recombinant Outer-Surface Protein A Lyme Disease Vaccine Study Consortium","volume":"339","author":"Sigal","year":"1998","journal-title":"N Engl J Med"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1007\/bf01713341","article-title":"Immunological and molecular variability of OspA and OspC. Implications for Borrelia vaccine development","volume":"24","author":"Wilske","year":"1996","journal-title":"Infection"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1128\/iai.73.12.7869-7877.2005","article-title":"Demonstration of OspC type diversity in invasive human lyme disease isolates and identification of previously uncharacterized epitopes that define the specificity of the OspC murine antibody response","volume":"73","author":"Earnhart","year":"2005","journal-title":"Infect Immun"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.2741\/3363","article-title":"The role of saliva in tick feeding","volume":"14","author":"Francischetti","year":"2009","journal-title":"Front Biosci (Landmark Ed)"},{"key":"B10","doi-asserted-by":"publisher","first-page":"e43","DOI":"10.1371\/journal.pmed.0050043","article-title":"Salivating for knowledge: potential pharmacological agents in tick saliva","volume":"5","author":"Hovius","year":"2008","journal-title":"PLoS Med"},{"key":"B11","doi-asserted-by":"publisher","first-page":"296","DOI":"10.1089\/vbz.2006.0624","article-title":"Identification of Salp15 homologues in Ixodes ricinus ticks","volume":"7","author":"Hovius","year":"2007","journal-title":"Vector Borne Zoonotic Dis (Larchmont NY)"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1086\/591917","article-title":"Preferential protection of Borrelia burgdorferi sensu stricto by a Salp15 homologue in Ixodes ricinus saliva","volume":"198","author":"Hovius","year":"2008","journal-title":"J Infect Dis"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1038\/nature03812","article-title":"The Lyme disease agent exploits a tick protein to infect the mammalian host","volume":"436","author":"Ramamoorthi","year":"2005","journal-title":"Nature"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2009.10.006","article-title":"Antibodies against a tick protein, Salp15, protect mice from the Lyme disease agent","volume":"6","author":"Dai","year":"2009","journal-title":"Cell Host Microbe"},{"key":"B15","doi-asserted-by":"publisher","first-page":"e31","DOI":"10.1371\/journal.ppat.0040031","article-title":"Salp15 binding to DC-SIGN inhibits cytokine expression by impairing both nucleosome remodeling and mRNA stabilization","volume":"4","author":"Hovius","year":"2008","journal-title":"PLoS Pathog"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1016\/s1074-7613(02)00325-4","article-title":"Salp15, an ixodes scapularis salivary protein, inhibits CD4(+) T cell activation","volume":"16","author":"Anguita","year":"2002","journal-title":"Immunity"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.pt.2007.07.001","article-title":"Tick-host-pathogen interactions in Lyme borreliosis","volume":"23","author":"Hovius","year":"2007","journal-title":"Trends Parasitol"},{"key":"B18","doi-asserted-by":"publisher","first-page":"e1001205","DOI":"10.1371\/journal.ppat.1001205","article-title":"Tick histamine release factor is critical for Ixodes scapularis engorgement and transmission of the lyme disease agent","volume":"6","author":"Dai","year":"2010","journal-title":"PLoS Pathog"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2011.06.010","article-title":"A tick mannose-binding lectin inhibitor interferes with the vertebrate complement cascade to enhance transmission of the lyme disease agent","volume":"10","author":"Schuijt","year":"2011","journal-title":"Cell Host Microbe"},{"key":"B20","doi-asserted-by":"publisher","first-page":"e15926","DOI":"10.1371\/journal.pone.0015926","article-title":"Identification and characterization of Ixodes scapularis antigens that elicit tick immunity using yeast surface display","volume":"6","author":"Schuijt","year":"2011","journal-title":"PLoS One"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1161\/circulationaha.113.003191","article-title":"Factor Xa activation of factor V is of paramount importance in initiating the coagulation system: lessons from a tick salivary protein","volume":"128","author":"Schuijt","year":"2013","journal-title":"Circulation"},{"key":"B22","doi-asserted-by":"publisher","first-page":"20061","DOI":"10.1038\/s41598-020-76268-y","article-title":"A combined transcriptomic approach to identify candidates for an anti-tick vaccine blocking B. afzelii transmission","volume":"10","author":"Trentelman","year":"2020","journal-title":"Sci Rep"},{"key":"B23","doi-asserted-by":"publisher","first-page":"e27","DOI":"10.1371\/journal.ppat.0020027","article-title":"An antivector vaccine protects against a lethal vector-borne pathogen","volume":"2","author":"Labuda","year":"2006","journal-title":"PLoS Pathog"},{"key":"B24","doi-asserted-by":"publisher","first-page":"899","DOI":"10.1038\/nm1264","article-title":"A rapid and potent DNA vaccination strategy defined by in vivo monitoring of antigen expression","volume":"11","author":"Bins","year":"2005","journal-title":"Nat Med"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.7326\/0003-4819-138-7-200304010-00011","article-title":"Gene vaccines","volume":"138","author":"Srivastava","year":"2003","journal-title":"Ann Intern Med"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1126\/science.abc6284","article-title":"DNA vaccine protection against SARS-CoV-2 in rhesus macaques","volume":"369","author":"Yu","year":"2020","journal-title":"Science (New York NY)"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2022483","article-title":"An mRNA Vaccine against SARS-CoV-2 - Preliminary Report","volume":"383","author":"Jackson","year":"2020","journal-title":"N Engl J Med"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2639-4","article-title":"Phase\u00a01\/2 study of COVID-19 RNA vaccine BNT162b1 in adults","volume":"586","author":"Mulligan","year":"2020","journal-title":"Nature"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1038\/gt.2014.87","article-title":"Rapid outer-surface protein C DNA tattoo vaccination protects against Borrelia afzelii infection","volume":"21","author":"Wagemakers","year":"2014","journal-title":"Gene Ther"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.1701","article-title":"SignalP 4.0: discriminating signal peptides from transmembrane regions","volume":"8","author":"Petersen","year":"2011","journal-title":"Nat Methods"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gki376","article-title":"JCat: a novel tool to adapt codon usage of a target gene to its potential expression host","volume":"33","author":"Grote","year":"2005","journal-title":"Nucleic Acids Res"},{"key":"B32","doi-asserted-by":"publisher","first-page":"e45","DOI":"10.1093\/nar\/gkp045","article-title":"Amplification efficiency: linking baseline and bias in the analysis of quantitative PCR data","volume":"37","author":"Ruijter","year":"2009","journal-title":"Nucleic Acids Res"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.94.23.12533","article-title":"Therapeutic passive vaccination against chronic Lyme disease in mice","volume":"94","author":"Zhong","year":"1997","journal-title":"Proc Natl Acad Sci U S A"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1002\/(sici)1521-4141(199903)29:03<946::Aid-immu946>3.0.Co;2-p","article-title":"Resolution of experimental and tick-borne Borrelia burgdorferi infection in mice by passive, but not active immunization using recombinant OspC","volume":"29","author":"Zhong","year":"1999","journal-title":"Eur J Immunol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1016\/s1286-4579(03)00182-5","article-title":"A DNA vaccine encoding the outer surface protein C from Borrelia burgdorferi is able to induce protective immune responses","volume":"5","author":"Scheiblhofer","year":"2003","journal-title":"Microbes Infect"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1007\/s11259-008-9040-3","article-title":"DNA vaccines and their applications in veterinary practice: current perspectives","volume":"32","author":"Dhama","year":"2008","journal-title":"Vet Res Commun"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1016\/s0264-410x(00)00495-3","article-title":"Genetic adjuvants for DNA vaccines","volume":"19","author":"Scheerlinck","year":"2001","journal-title":"Vaccine"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.615011\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,2,25]],"date-time":"2021-02-25T04:25:39Z","timestamp":1614227139000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.615011\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,25]]},"references-count":37,"alternative-id":["10.3389\/fimmu.2021.615011"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2021.615011","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,2,25]]},"article-number":"615011"}}