{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T15:32:44Z","timestamp":1790609564015,"version":"4.1.0"},"reference-count":47,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,1,17]],"date-time":"2023-01-17T00:00:00Z","timestamp":1673913600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82071788"],"award-info":[{"award-number":["82071788"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Rabies is a lethal zoonotic disease that kills approximately 60,000 people each year. Although inactivated rabies vaccines are available, multiple-dose regimensare recommended for pre-exposure prophylaxis or post-exposure prophylaxis,which cuts down the cost- and time-effectiveness, especially in low- and middle incomecountries.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We developed a nucleoside-modified Rabies mRNA-lipid nanoparticle vaccine (RABV-G mRNA-LNP) encoding codon-optimized viral glycoprotein and assessed the immunogenicity and protective efficacy of this vaccine in mice comparing to a commercially available inactivated vaccine.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We first showed that, when evaluated in mice, a single vaccination of RABV-G mRNA with a moderate or high dose induces more potent humoral and T-cell immune responses than that elicited by three inoculations of the inactivated vaccine. Importantly, mice receiving a single immunization of RABV-G mRNA, even at low doses, showed full protection against the lethal rabies challenge. We further demonstrated that the humoral immune response induced by single RABV-G mRNA vaccination in mice could last for at least 25 weeks, while a two-dose strategy could extend the duration of the highly protective response to one year or even longer. In contrast, the three-dose regimen of inactivated vaccine failed to do so.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our study confirmed that it is worth developing a single-dose nucleoside-modified Rabies mRNA-LNP vaccine, which could confer much prolonged and more effective protection.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2022.1099991","type":"journal-article","created":{"date-parts":[[2023,1,17]],"date-time":"2023-01-17T05:20:37Z","timestamp":1673932837000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":26,"title":["A single vaccination of nucleoside-modified Rabies mRNA vaccine induces prolonged highly protective immune responses in mice"],"prefix":"10.3389","volume":"13","author":[{"given":"Shimeng","family":"Bai","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianhan","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cuisong","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meiqi","family":"Feng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziling","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiang","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinghao","family":"Pan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianqing","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,1,17]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0003709","article-title":"Estimating the global burden of endemic canine rabies","volume":"9","author":"Hampson","year":"2015","journal-title":"PLoS Negl Trop Dis"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-virology-100114-055157","article-title":"Everything you always wanted to know about rabies virus (But were afraid to ask)","volume":"2","author":"Davis","year":"2015","journal-title":"Annu Rev Virol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1038\/294275a0","article-title":"Structure of the glycoprotein gene in rabies virus","volume":"294","author":"Anilionis","year":"1981","journal-title":"Nature"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1099\/jgv.0.000998","article-title":"Antigenic site changes in the rabies virus glycoprotein dictates functionality and neutralizing capability against divergent lyssaviruses","volume":"99","author":"Evans","year":"2018","journal-title":"J Gen Virol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.4065\/79.5.671","article-title":"Overview, prevention, and treatment of rabies","volume":"79","author":"Hankins","year":"2004","journal-title":"Mayo Clin Proc"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.tim.2018.07.001","article-title":"Rabies virus","volume":"26","author":"Brunker","year":"2018","journal-title":"Trends Microbiol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2013.12.031","article-title":"Rabies: underused vaccines, unnecessary deaths","volume":"32","author":"Dodet","year":"2014","journal-title":"Vaccine"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2013.02.058","article-title":"A serum-free, purified vero cell rabies vaccine is safe and as immunogenic as the reference vaccine verorab for pre-exposure use in healthy adults: results from a randomized controlled phase-II trial","volume":"31","author":"Pichon","year":"2013","journal-title":"Vaccine"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2018.06.061","article-title":"Rabies vaccines: WHO position paper, April 2018\u2013Recommendations","volume":"36","year":"2018","journal-title":"Vaccine"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.15585\/mmwr.mm7118a2","article-title":"Use of a Modified Preexposure Prophylaxis Vaccination Schedule to Prevent Human Rabies: Recommendations of the Advisory Committee on Immunization Practices \u2014 United States, 2022","volume":"71","author":"Rao","year":"2022","journal-title":"MMWR Morb Mortal Wkly Rep"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2010.08.082","article-title":"Rabies vaccines: WHO position paper\u2013recommendations","volume":"28","year":"2010","journal-title":"Vaccine"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2005.06.008","article-title":"Suppression of RNA recognition by toll-like receptors: The impact of nucleoside modification and the evolutionary origin of RNA","volume":"23","author":"Kariko","year":"2005","journal-title":"Immunity"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1038\/mt.2008.200","article-title":"Incorporation of pseudouridine into mRNA yields superior nonimmunogenic vector with increased translational capacity and biological stability","volume":"16","author":"Kariko","year":"2008","journal-title":"Mol Ther"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1038\/mt.2015.103","article-title":"Sequence-engineered mRNA without chemical nucleoside modifications enables an effective protein therapy in Large animals","volume":"23","author":"Thess","year":"2015","journal-title":"Mol Ther"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(17)31665-3","article-title":"Safety and immunogenicity of a mRNA rabies vaccine in healthy adults: An open-label, non-randomised, prospective, first-in-human phase 1 clinical trial","volume":"390","author":"Alberer","year":"2017","journal-title":"Lancet"},{"key":"B16","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1038\/s41541-017-0032-6","article-title":"Unmodified mRNA in LNPs constitutes a competitive technology for prophylactic vaccines","volume":"2","author":"Lutz","year":"2017","journal-title":"NPJ Vaccines"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkr695","article-title":"Generating the optimal mRNA for therapy: HPLC purification eliminates immune activation and improves translation of nucleoside-modified, protein-encoding mRNA","volume":"39","author":"Kariko","year":"2011","journal-title":"Nucleic Acids Res"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1038\/nrd4278","article-title":"mRNA-based therapeutics\u2013developing a new class of drugs","volume":"13","author":"Sahin","year":"2014","journal-title":"Nat Rev Drug Discovery"},{"key":"B19","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1126\/sciimmunol.aaw7083","article-title":"Nucleoside-modified mRNA encoding HSV-2 glycoproteins C, D, and E prevents clinical and subclinical genital herpes","volume":"4","author":"Sita Awasthi","year":"2019","journal-title":"Sci Immunol"},{"key":"B20","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1038\/s41541-020-0163-z","article-title":"Modified mRNA\/lipid nanoparticle-based vaccines expressing respiratory syncytial virus f protein variants are immunogenic and protective in rodent models of RSV infection","volume":"5","author":"Espeseth","year":"2020","journal-title":"NPJ Vaccines"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2020.04.018","article-title":"A multi-targeting, nucleoside-modified mRNA influenza virus vaccine provides broad protection in mice","volume":"28","author":"Freyn","year":"2020","journal-title":"Mol Ther"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jix592","article-title":"Modified mRNA-based vaccines elicit robust immune responses and protect Guinea pigs from Ebola virus disease","volume":"217","author":"Meyer","year":"2018","journal-title":"J Infect Dis"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1038\/nature21428","article-title":"Zika virus protection by a single low-dose nucleoside-modified mRNA vaccination","volume":"543","author":"Pardi","year":"2017","journal-title":"Nature"},{"key":"B24","doi-asserted-by":"publisher","first-page":"1114","DOI":"10.1016\/j.cell.2017.02.017","article-title":"Modified mRNA vaccines protect against zika virus infection","volume":"168","author":"Richner","year":"2017","journal-title":"Cell"},{"key":"B25","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":"B26","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMc2036242","article-title":"Safety and efficacy of the BNT162b2 mRNA covid-19 vaccine","volume":"384","author":"Skowronski","year":"2021","journal-title":"New Engl J Med"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0004746","article-title":"An mRNA vaccine encoding rabies virus glycoprotein induces protection against lethal infection in mice and correlates of protection in adult and newborn pigs","volume":"10","author":"Schnee","year":"2016","journal-title":"PLoS Negl Trop Dis"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2020.12.070","article-title":"Proof-of-concept of a low-dose unmodified mRNA-based rabies vaccine formulated with lipid nanoparticles in human volunteers: A phase 1 trial","volume":"39","author":"Aldrich","year":"2021","journal-title":"Vaccine"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1007\/s12250-013-3321-x","article-title":"Establishment and preliminary application of a rapid fluorescent focus inhibition test (RFFIT) for rabies virus","volume":"28","author":"Yu","year":"2013","journal-title":"Virol Sin"},{"key":"B30","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1128\/jvi.01578-21","article-title":"A single vaccine protects against SARS-CoV-2 and influenza virus in mice","volume":"96","author":"Kangli Cao","year":"2022","journal-title":"J Virol"},{"key":"B31","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1016\/S0022-1759(97)00212-3","article-title":"Development of a fluorescent antibody virus neutralisation test (FAVN test) for the quantitation of rabies-neutralising antibody","volume":"212","author":"Cliquet MA","year":"1998","journal-title":"J Immunol Methods"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.aaz3381","article-title":"IFN-k suppresses the replication of influenza a viruses through the IFNAR-MAPK-Fos-CHD6 axis","volume":"13","author":"He","year":"2020","journal-title":"Sci Signal"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1016\/j.virs.2022.02.008","article-title":"A single dose of recombinant VSV-RABVG vaccine provides full protection against RABV challenge","volume":"37","author":"Liang","year":"2022","journal-title":"Virol Sin"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0008459","article-title":"A next generation vaccine against human rabies based on a single dose of a chimpanzee adenovirus vector serotype C","volume":"14","author":"Napolitano","year":"2020","journal-title":"PLoS Negl Trop Dis"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1080\/22221751.2022.2078226","article-title":"Recombinant adeno-associated virus serotype 9 AAV-RABVG expressing a rabies virus G protein confers long-lasting immune responses in mice and non-human primates","volume":"11","author":"Shi","year":"2022","journal-title":"Emerg Microbes Infect"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0006870","article-title":"A simian-adenovirus-vectored rabies vaccine suitable for thermostabilisation and clinical development for low-cost single-dose pre-exposure prophylaxis","volume":"12","author":"Wang","year":"2018","journal-title":"PLoS Negl Trop Dis"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2020.01070","article-title":"A bivalent human adenovirus type 5 vaccine expressing the rabies virus glycoprotein and canine distemper virus hemagglutinin protein confers protective immunity in mice and foxes","volume":"11","author":"Yan","year":"2020","journal-title":"Front Microbiol"},{"key":"B38","doi-asserted-by":"publisher","first-page":"102819","DOI":"10.1016\/j.ebiom.2020.102819","article-title":"A novel rabies vaccine based on infectious propagating particles derived from hybrid VEEV-rabies replicon","volume":"56","author":"Zhang","year":"2020","journal-title":"EBioMedicine"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.06699-11","article-title":"Postexposure treatment with the live-attenuated rabies virus (RV) vaccine TriGAS triggers the clearance of wild-type RV from the central nervous system (CNS) through the rapid induction of genes relevant to adaptive immunity in CNS tissues","volume":"86","author":"Li","year":"2012","journal-title":"J Virol"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2014.06.058","article-title":"A recombinant rabies vaccine expressing the trimeric form of the glycoprotein confers enhanced immunogenicity and protection in outbred mice","volume":"32","author":"Koraka","year":"2014","journal-title":"Vaccine"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abp9151","article-title":"Structure ofthe rabies virus glycoprotein trimer bound to a prefusion-specific neutralizing antibody","volume":"8","author":"Callaway","year":"2022","journal-title":"Sci Adv"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1501274","article-title":"T-Bet is required for the rapid clearance of attenuated rabies virus from central nervous system tissue","volume":"195","author":"Lebrun","year":"2015","journal-title":"J Immunol"},{"key":"B43","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1016\/B978-0-12-387040-7.00004-4","article-title":"Rabies virus clearance from the central nervous system","volume":"79","author":"Hooper","year":"2011","journal-title":"Adv Virus Res"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2814-7","article-title":"COVID-19 vaccine BNT162b1 elicits human antibody and TH1 T cell responses","volume":"586","author":"Sahin","year":"2020","journal-title":"Nature"},{"key":"B45","doi-asserted-by":"publisher","first-page":"1271","DOI":"10.1016\/j.cell.2020.07.024","article-title":"A thermostable mRNA vaccine against COVID-19","volume":"182","author":"Zhang","year":"2020","journal-title":"Cell"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1111\/j.1708-8305.2006.00097.x","article-title":"Duration of immunity: an anamnestic response 14 years after rabies vaccination with purified chick embryo cell rabies vaccine","volume":"14","author":"Malerczyk","year":"2007","journal-title":"J Travel Med"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(21)00677-0","article-title":"Efficacy and safety of the CVnCoV SARS-CoV-2 mRNA vaccine candidate in ten countries in Europe and Latin America (HERALD): A randomised, observer-blinded, placebo-controlled, phase 2b\/3 trial","volume":"22","author":"Kremsner","year":"2022","journal-title":"Lancet Infect Dis"}],"updated-by":[{"DOI":"10.3389\/fimmu.2023.1146466","type":"corrigendum","label":"Corrigendum","source":"publisher","updated":{"date-parts":[[2023,1,26]],"date-time":"2023-01-26T00:00:00Z","timestamp":1674691200000}}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.1099991\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,25]],"date-time":"2023-01-25T14:49:41Z","timestamp":1674658181000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.1099991\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,1,17]]},"references-count":47,"alternative-id":["10.3389\/fimmu.2022.1099991"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2022.1099991","relation":{"corrigendum":[{"id-type":"doi","id":"10.3389\/fimmu.2023.1146466","asserted-by":"object"}]},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,1,17]]},"article-number":"1099991"}}