{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T15:24:54Z","timestamp":1782141894499,"version":"3.54.5"},"reference-count":59,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,3,16]],"date-time":"2023-03-16T00:00:00Z","timestamp":1678924800000},"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>The incidence of Lyme disease (LD) in Canada and the United States has risen over the last decade, nearing 480,000 cases each year. <jats:italic>Borrelia burgdorferi<\/jats:italic> sensu lato, the causative agent of LD, is transmitted to humans through the bite of an infected tick, resulting in flu-like symptoms and often a characteristic bull\u2019s-eye rash. In more severe cases, disseminated bacterial infection can cause arthritis, carditis and neurological impairments. Currently, no vaccine is available for the prevention of LD in humans.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In this study, we developed a lipid nanoparticle (LNP)-encapsulated DNA vaccine encoding outer surface protein C type A (OspC-type A) of <jats:italic>B. burgdorferi.<\/jats:italic><\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Vaccination of C3H\/HeN mice with two doses of the candidate vaccine induced significant OspC-type A-specific antibody titres and borreliacidal activity. Analysis of the bacterial burden following needle challenge with <jats:italic>B. burgdorferi<\/jats:italic> (OspC-type A) revealed that the candidate vaccine afforded effective protection against homologous infection across a range of susceptible tissues. Notably, vaccinated mice were protected against carditis and lymphadenopathy associated with Lyme borreliosis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>Overall, the results of this study provide support for the use of a DNA-LNP platform for the development of LD vaccines.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2023.1020134","type":"journal-article","created":{"date-parts":[[2023,3,16]],"date-time":"2023-03-16T05:27:44Z","timestamp":1678944464000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":27,"title":["DNA lipid nanoparticle vaccine targeting outer surface protein C affords protection against homologous Borrelia burgdorferi needle challenge in mice"],"prefix":"10.3389","volume":"14","author":[{"given":"Annabelle","family":"Pfeifle","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sathya N.","family":"Thulasi Raman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Casey","family":"Lansdell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanyue","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Levi","family":"Tamming","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathon","family":"Cecillon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emmanuel","family":"Laryea","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Devina","family":"Patel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianguo","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline","family":"Gravel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grant","family":"Frahm","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wangxue","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George","family":"Chaconas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon","family":"Sauve","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Rosu-Myles","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisheng","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J. W.","family":"Johnston","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuguang","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,3,16]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3201\/EID2702.202731","article-title":"Estimating the frequency of Lyme disease diagnoses, united states, 2010\u20132018","volume":"27","author":"Kugeler","year":"2021","journal-title":"Emerg Infect Dis"},{"key":"B2","unstructured":"Lyme Disease: Monitoring2022"},{"key":"B3","unstructured":"Climate change indicators: Lyme disease2022"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.21775\/CIMB.042.333","article-title":"Lyme Disease in humans","volume":"42","author":"Radolf","year":"2021","journal-title":"Curr Issues Mol Biol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM200306123482423","article-title":"The presenting manifestations of Lyme disease and the outcomes of treatment","volume":"348","author":"Steere","year":"2003","journal-title":"N Engl J Med"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1007\/S10096-018-3417-1","article-title":"Clinical spectrum of Lyme disease","volume":"38","author":"Cardenas-de la Garza","year":"2019","journal-title":"Eur J Clin Microbiol Infect Dis"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1084\/JEM.20031960","article-title":"Essential role for OspA\/B in the life cycle of the Lyme disease spirochete","volume":"199","author":"Yang","year":"2004","journal-title":"J Exp Med"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.01950-05","article-title":"Borrelia burgdorferi OspC protein required exclusively in a crucial early stage of mammalian infection","volume":"74","author":"Tilly","year":"2006","journal-title":"Infect Immun"},{"key":"B9","doi-asserted-by":"publisher","first-page":"3429","DOI":"10.1128\/JB.00085-08","article-title":"Reciprocal expression of ospA and ospC in single cells of borrelia burgdorferi","volume":"190","author":"Srivastava","year":"2008","journal-title":"J Bacteriol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1128\/JCM.38.1.382-388.2000","article-title":"Temporal changes in outer surface proteins a and c of the lyme disease-associated spirochete, borrelia burgdorferi, during the chain of infection in ticks and mice","volume":"38","author":"Schwan","year":"2000","journal-title":"J Clin Microbiol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1042\/BST0310108","article-title":"Temporal regulation of outer surface proteins of the Lyme-disease spirochaete borrelia burgdorferi","volume":"31","author":"Schwan","year":"2003","journal-title":"Biochem Soc Trans"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1038\/s41541-022-00429-5","article-title":"The year that shaped the outcome of the OspA vaccine for human Lyme disease","volume":"7","author":"Dattwyler","year":"2022","journal-title":"NPJ Vaccines"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1086\/515382","article-title":"Borreliacidal antibody production against outer surface protein c of borrelia burgdorferi","volume":"178","author":"Rousselle","year":"1998","journal-title":"J Infect Dis"},{"key":"B14","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1111\/J.1574-695X.2000.TB01499.X","article-title":"Specific immune response to a synthetic peptide derived from outer surface protein c of borrelia burgdorferi predicts protective borreliacidal antibodies","volume":"29","author":"Ikushima","year":"2000","journal-title":"FEMS Immunol Med Microbiol"},{"key":"B15","doi-asserted-by":"publisher","first-page":"1915","DOI":"10.1016\/J.VACCINE.2020.01.027","article-title":"Development and optimization of OspC chimeritope vaccinogens for Lyme disease","volume":"38","author":"Izac","year":"2020","journal-title":"Vaccine"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.3389\/FCELL.2021.633776\/BIBTEX","article-title":"A guide to nucleic acid vaccines in the prevention and treatment of infectious diseases and cancers: From basic principles to current applications","volume":"9","author":"Qin","year":"2021","journal-title":"Front Cell Dev Biol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/J.COI.2020.01.006","article-title":"DNA Vaccines: prime time is now","volume":"65","author":"Gary","year":"2020","journal-title":"Curr Opin Immunol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1093\/INFDIS\/175.1.91","article-title":"An OspA-based DNA vaccine protects mice against infection with borrelia burgdorferi","volume":"175","author":"Luke","year":"1997","journal-title":"J Infect Dis"},{"key":"B19","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":"B20","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":"B21","doi-asserted-by":"publisher","DOI":"10.1080\/21645515.2020.1789408","article-title":"Protection against borreliella burgdorferi infection mediated by a synthetically engineered DNA vaccine","volume":"16","author":"Guibinga","year":"2020","journal-title":"Human Vaccines Immunotherap"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.3389\/FIMMU.2021.615011\/FULL","article-title":"Tick-tattoo: DNA vaccination against b. burgdorferi or ixodes scapularis tick proteins","volume":"12","author":"Klouwens","year":"2021","journal-title":"Front Immunol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/J.NANO.2016.12.014","article-title":"Design of lipid nanoparticles for in vitro and in vivo delivery of plasmid DNA","volume":"13","author":"Kulkarni","year":"2017","journal-title":"Nanomedicine"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1016\/S0264-410X(00)00474-6","article-title":"DNA Vaccination against respiratory influenza virus infection","volume":"19","author":"Wong","year":"2001","journal-title":"Vaccine"},{"key":"B25","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41598-020-65059-0","article-title":"Lipid nanoparticle formulation increases efficiency of DNA-vectored Vaccines\/Immunoprophylaxis in animals including transchromosomic bovines","volume":"10","author":"Mucker","year":"2020","journal-title":"Sci Rep"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMOA2034577","article-title":"Safety and efficacy of the BNT162b2 mRNA covid-19 vaccine","volume":"383","author":"Polack","year":"2020","journal-title":"N Engl J Med"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMOA2035389","article-title":"Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine","volume":"384","author":"Baden","year":"2021","journal-title":"N Engl J Med"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.70.4.2139-2150.2002","article-title":"Clonal polymorphism of borrelia burgdorferi strain B31 MI: Implications for mutagenesis in an infectious strain background","volume":"70","author":"Elias","year":"2002","journal-title":"Infect Immun"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.01193-08","article-title":"OspC-independent infection and dissemination by host-adapted borrelia burgdorferi","volume":"77","author":"Tilly","year":"2009","journal-title":"Infect Immun"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.4049\/JIMMUNOL.1300093","article-title":"CD40 ligand preferentially modulates immune response and enhances protection against influenza virus","volume":"193","author":"Hashem","year":"2014","journal-title":"J Immunol"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1038\/SJ.GT.3302160","article-title":"Secretory heat-shock protein as a dendritic cell-targeting molecule: a new strategy to enhance the potency of genetic vaccines","volume":"11","author":"Hauser","year":"2004","journal-title":"Gene Ther"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1016\/J.IDC.2007.12.008","article-title":"Lyme Carditis","volume":"22","author":"Fish","year":"2008","journal-title":"Infect Dis Clin North Am"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.4269\/AJTMH.1992.47.249","article-title":"Carditis in Lyme disease susceptible and resistant strains of laboratory mice infected with borrelia burgdorferi","volume":"47","author":"Armstrong","year":"1992","journal-title":"Am J Trop Med Hyg"},{"key":"B34","doi-asserted-by":"publisher","first-page":"76","DOI":"10.7326\/0003-4819-99-1-76","article-title":"The early clinical manifestations of Lyme disease","volume":"99","author":"Steere","year":"1983","journal-title":"Ann Intern Med"},{"key":"B35","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/J.JCPA.2004.11.006","article-title":"Histopathological studies of experimental Lyme disease in the dog","volume":"133","author":"Summers","year":"2005","journal-title":"J Comp Pathol"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1371\/JOURNAL.PPAT.1002066","article-title":"Lymphoadenopathy during Lyme borreliosis is caused by spirochete migration-induced specific b cell activation","volume":"7","author":"Tunev","year":"2011","journal-title":"PloS Pathog"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.72.9.5063-5072.2004","article-title":"Temporal analysis of the antigenic composition of borrelia burgdorferi during infection in rabbit skin","volume":"72","author":"Crother","year":"2004","journal-title":"Infect Immun"},{"key":"B38","doi-asserted-by":"publisher","first-page":"415","DOI":"10.1084\/JEM.20011870","article-title":"An immune evasion mechanism for spirochetal persistence in Lyme borreliosis","volume":"195","author":"Liang","year":"2002","journal-title":"J Exp Med"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.71.9.5042-5055.2003","article-title":"Borrelia burgdorferi population dynamics and prototype gene expression during infection of immunocompetent and immunodeficient mice","volume":"71","author":"Hodzic","year":"2003","journal-title":"Infect Immun"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.69.4.2130-2136.2001","article-title":"DNA Vaccines expressing a fusion product of outer surface proteins a and c from borrelia burgdorferi induce protective antibodies suitable for prophylaxis but not for resolution of Lyme disease","volume":"69","author":"Wallich","year":"2001","journal-title":"Infect Immun"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1016\/J.VACCINE.2011.05.010","article-title":"A host-restricted viral vector for antigen-specific immunization against Lyme disease pathogen","volume":"29","author":"Xiao","year":"2011","journal-title":"Vaccine"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1371\/JOURNAL.PONE.0151850","article-title":"Oral immunization with OspC does not prevent tick-borne borrelia burgdorferi infection","volume":"11","author":"Melo","year":"2016","journal-title":"PloS One"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1038\/nri2868","article-title":"Vaccine delivery: a matter of size, geometry, kinetics and molecular patterns","volume":"10","author":"Bachmann","year":"2010","journal-title":"Nat Rev Immunol"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1016\/J.JCONREL.2021.05.021","article-title":"Impact of lipid nanoparticle size on mRNA vaccine immunogenicity","volume":"335","author":"Hassett","year":"2021","journal-title":"J Control Release"},{"key":"B45","doi-asserted-by":"publisher","first-page":"673","DOI":"10.2217\/NNM.16.5","article-title":"The effect of nanoparticle size on in vivo pharmacokinetics and cellular interaction","volume":"11","author":"Hoshyar","year":"2016","journal-title":"Nanomedicine"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.3389\/FIMMU.2018.00959\/BIBTEX","article-title":"The classical complement pathway is required to control borrelia burgdorferi levels during experimental infection","volume":"9","author":"Zhi","year":"2018","journal-title":"Front Immunol"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.69.3.1739-1746.2001","article-title":"Coiling phagocytosis of borrelia burgdorferi by primary human macrophages is controlled by CDC42Hs and Rac1 and involves recruitment of wiskott-Aldrich syndrome protein and Arp2\/3 complex","volume":"69","author":"Linder","year":"2001","journal-title":"Infect Immun"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1126\/SCITRANSLMED.ABJ9827","article-title":"mRNA vaccination induces tick resistance and prevents transmission of the Lyme disease agent","volume":"13","author":"Sajid","year":"2021","journal-title":"Sci Transl Med"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1371\/JOURNAL.PONE.0184357","article-title":"The novel Lyme borreliosis vaccine VLA15 shows broad protection against borrelia species expressing six different OspA serotypes","volume":"12","author":"Comstedt","year":"2017","journal-title":"PloS One"},{"key":"B50","unstructured":"RiveraOJ\n            NookalaV\n          StatPearlsLyme Carditis2022"},{"key":"B51","article-title":"Lyme Carditis: A can\u2019t miss diagnosis","volume":"62","author":"Young","year":"2020","journal-title":"BC Med J"},{"key":"B52","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":"B53","doi-asserted-by":"publisher","DOI":"10.1093\/INFDIS\/175.2.400","article-title":"Immunization with outer surface protein (Osp) a, but not OspC, provides cross-protection of mice challenged with north American isolates of borrelia burgdorferi","volume":"175","author":"Probert","year":"1997","journal-title":"J Infect Dis"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1371\/JOURNAL.PPAT.1006959","article-title":"Infection history of the blood-meal host dictates pathogenic potential of the Lyme disease spirochete within the feeding tick vector","volume":"14","author":"Bhatia","year":"2018","journal-title":"PloS Pathog"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1016\/J.MEEGID.2015.09.012","article-title":"Cross-reactive acquired immunity influences transmission success of the Lyme disease pathogen, borrelia afzelii","volume":"36","author":"Jacquet","year":"2015","journal-title":"Infect Genet Evol"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.7774\/CEVR.2015.4.1.1","article-title":"Improvement of DNA vaccination by adjuvants and sophisticated delivery devices: vaccine-platforms for the battle against infectious diseases","volume":"4","author":"Grunwald","year":"2015","journal-title":"Clin Exp Vaccine Res"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.3390\/MOLECULES25245995","article-title":"Nucleic acid delivery by solid lipid nanoparticles containing switchable lipids: Plasmid DNA vs. messenger RNA","volume":"25","author":"G\u00f3mez-Aguado","year":"2020","journal-title":"Molecules"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1007\/S11051-013-1960-3","article-title":"Microemulsion extrusion technique: a new method to produce lipid nanoparticles","volume":"15","author":"De Jesus","year":"2013","journal-title":"J Nanoparticle Res"},{"key":"B59","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3390\/VACCINES8030551","article-title":"Solid lipid nanoparticle carrier platform containing synthetic TLR4 agonist mediates non-viral DNA vaccine delivery","volume":"8","author":"Francis","year":"2020","journal-title":"Vaccines"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2023.1020134\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,3,16]],"date-time":"2023-03-16T05:27:50Z","timestamp":1678944470000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2023.1020134\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,16]]},"references-count":59,"alternative-id":["10.3389\/fimmu.2023.1020134"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2023.1020134","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,3,16]]},"article-number":"1020134"}}