{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T00:21:08Z","timestamp":1791937268853,"version":"4.3.4"},"reference-count":37,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2025,1,13]],"date-time":"2025-01-13T00:00:00Z","timestamp":1736726400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Guoke Ningbo Life Science and Health Industry Research Institute","award":["2022YJY0703"],"award-info":[{"award-number":["2022YJY0703"]}]},{"name":"Guoke Ningbo Life Science and Health Industry Research Institute","award":["KYCX22-0797"],"award-info":[{"award-number":["KYCX22-0797"]}]},{"name":"Jiangsu Province","award":["2022YJY0703"],"award-info":[{"award-number":["2022YJY0703"]}]},{"name":"Jiangsu Province","award":["KYCX22-0797"],"award-info":[{"award-number":["KYCX22-0797"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Vaccines"],"abstract":"<jats:p>Background\/Objectives: Approved mRNA vaccines commonly use sequences modified with pseudouridine to enhance translation efficiency and mRNA stability. However, this modification can result in ribosomal frameshifts, reduced immunogenicity, and higher production costs. This study aimed to explore the potential of unmodified mRNA sequences for varicella-zoster virus (VZV) and evaluate whether codon optimization could overcome the limitations of pseudouridine modification. Methods: We utilized artificial intelligence (AI) to design several unmodified gE mRNA sequences for VZV, considering factors such as codon preference and secondary structure. The optimized mRNA sequences were assessed for protein expression levels in vitro and were subsequently used to develop a vaccine, named Vac07, encapsulated in a lipid nanoparticle (LNP) delivery system. The immunogenicity of Vac07 was evaluated in mice. Results: Codon-optimized mRNA sequences showed significantly higher protein expression levels in vitro compared to wild-type (WT) sequences. Vaccination with Vac07 demonstrated immunogenicity in mice that was comparable to, or even superior to, the licensed Shingrix vaccine, characterized by a stronger Th1-biased antibody response and a slightly more robust Th1-type cellular response. Conclusions: Codon-optimized unmodified mRNA sequences may also represent a viable approach for mRNA vaccine development. These optimized sequences have the potential to lower production costs while possibly enhancing the immunogenicity of mRNA vaccines. Vac07, developed using this method, shows promise as a potentially more efficient and cost-effective mRNA vaccine candidate for VZV.<\/jats:p>","DOI":"10.3390\/vaccines13010068","type":"journal-article","created":{"date-parts":[[2025,1,13]],"date-time":"2025-01-13T09:49:17Z","timestamp":1736761757000},"page":"68","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Development and Evaluation of the Immunogenic Potential of an Unmodified Nucleoside mRNA Vaccine for Herpes Zoster"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3804-7475","authenticated-orcid":false,"given":"Shun","family":"Zhang","sequence":"first","affiliation":[{"name":"Ningbo No. 2 Hospital, Guoke Ningbo Life Science and Health Industry Research Institute, Ningbo 315099, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaojie","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China"},{"name":"Technology Center, Shandong Freda Pharmaceutical Group, Jinan 250101, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tongyi","family":"Zhao","sequence":"additional","affiliation":[{"name":"Vaccine Center, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7934-9269","authenticated-orcid":false,"given":"Chen","family":"Yang","sequence":"additional","affiliation":[{"name":"School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lulu","family":"Huang","sequence":"additional","affiliation":[{"name":"Vaccine Center, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,1,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1038\/nrd.2017.243","article-title":"mRNA vaccines\u2014A new era in vaccinology","volume":"17","author":"Pardi","year":"2018","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1038\/s41573-021-00283-5","article-title":"mRNA vaccines for infectious diseases: Principles, delivery and clinical translation","volume":"20","author":"Chaudhary","year":"2021","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1038\/s41392-022-01007-w","article-title":"mRNA-based therapeutics: Powerful and versatile tools to combat diseases","volume":"7","author":"Qin","year":"2022","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1016\/j.molmed.2019.10.002","article-title":"Tailoring mRNA Vaccine to Balance Innate\/Adaptive Immune Response","volume":"26","author":"Lacroix","year":"2020","journal-title":"Trends Mol. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1038\/nrd4278","article-title":"mRNA-based therapeutics\u2014Developing a new class of drugs","volume":"13","author":"Sahin","year":"2014","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1993","DOI":"10.1016\/j.immuni.2022.10.014","article-title":"Innate immune mechanisms of mRNA vaccines","volume":"55","author":"Verbeke","year":"2022","journal-title":"Immunity"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"100012","DOI":"10.1016\/j.crviro.2021.100012","article-title":"Translational regulation of viral RNA in the type I interferon response","volume":"2","author":"Hsu","year":"2021","journal-title":"Curr. Res. Virol. Sci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"eaaz6893","DOI":"10.1126\/sciadv.aaz6893","article-title":"Impact of mRNA chemistry and manufacturing process on innate immune activation","volume":"6","author":"Nelson","year":"2020","journal-title":"Sci. Adv."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1833","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":"Muramatsu","year":"2008","journal-title":"Mol. Ther."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"165","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":"Buckstein","year":"2005","journal-title":"Immunity"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1038\/s41586-023-06800-3","article-title":"N(1)-methylpseudouridylation of mRNA causes +1 ribosomal frameshifting","volume":"625","author":"Mulroney","year":"2024","journal-title":"Nature"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1038\/s41586-023-06127-z","article-title":"Algorithm for optimized mRNA design improves stability and immunogenicity","volume":"621","author":"Zhang","year":"2023","journal-title":"Nature"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"24075","DOI":"10.1073\/pnas.1908052116","article-title":"mRNA structure regulates protein expression through changes in functional half-life","volume":"116","author":"Mauger","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_14","unstructured":"Liu, Y., Gao, J., Zhang, X., and Fang, X. (2024). Joint Design of 5\u2032 Untranslated Region and Coding Sequence of mRNA. arXiv."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1038\/nrmicro3215","article-title":"Molecular mechanisms of varicella zoster virus pathogenesis","volume":"12","author":"Zerboni","year":"2014","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"6776","DOI":"10.1016\/j.vaccine.2019.09.031","article-title":"VZV-specific cell-mediated immunity, but not humoral immunity, correlates inversely with the incidence of herpes zoster and the severity of skin symptoms and zoster-associated pain: The SHEZ study","volume":"37","author":"Asada","year":"2019","journal-title":"Vaccine"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2704","DOI":"10.1128\/JVI.03445-13","article-title":"Analysis of T cell responses during active varicella-zoster virus reactivation in human ganglia","volume":"88","author":"Steain","year":"2014","journal-title":"J. Virol."},{"key":"ref_18","first-page":"341","article-title":"VZV T cell-mediated immunity","volume":"342","author":"Weinberg","year":"2010","journal-title":"Curr. Top. Microbiol. Immunol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"4245","DOI":"10.1172\/JCI123217","article-title":"Tale of two vaccines: Differences in response to herpes zoster vaccines","volume":"128","author":"Gershon","year":"2018","journal-title":"J. Clin. Investig."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1038\/nri3806","article-title":"Regulation of antiviral T cell responses by type I interferons","volume":"15","author":"Crouse","year":"2015","journal-title":"Nat. Rev. Immunol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1038\/nature18300","article-title":"Systemic RNA delivery to dendritic cells exploits antiviral defence for cancer immunotherapy","volume":"534","author":"Kranz","year":"2016","journal-title":"Nature"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Nord\u00e9n, R., Nilsson, J., Samuelsson, E., Risinger, C., Sihlbom, C., Blixt, O., Larson, G., Olofsson, S., and Bergstr\u00f6m, T. (2019). Recombinant Glycoprotein E of Varicella Zoster Virus Contains Glycan-Peptide Motifs That Modulate B Cell Epitopes into Discrete Immunological Signatures. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20040954"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1007\/s11427-022-2264-1","article-title":"Truncated glycoprotein E of varicella-zoster virus is an ideal immunogen for Escherichia coli-based vaccine design","volume":"66","author":"Chen","year":"2023","journal-title":"Sci. China Life Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1002\/iid3.297","article-title":"Evaluation of glycoprotein E subunit and live attenuated varicella-zoster virus vaccines formulated with a single-strand RNA-based adjuvant","volume":"8","author":"Lee","year":"2020","journal-title":"Immun. Inflamm. Dis."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2309985","DOI":"10.1080\/22221751.2024.2309985","article-title":"Herpes zoster mRNA vaccine induces superior vaccine immunity over licensed vaccine in mice and rhesus macaques","volume":"13","author":"Huang","year":"2024","journal-title":"Emerg. Microbes Infect."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"927","DOI":"10.1093\/genetics\/136.3.927","article-title":"Synonymous codon usage in Drosophila melanogaster: Natural selection and translational accuracy","volume":"136","author":"Akashi","year":"1994","journal-title":"Genetics"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1111","DOI":"10.1016\/j.cell.2015.02.029","article-title":"Codon optimality is a major determinant of mRNA stability","volume":"160","author":"Presnyak","year":"2015","journal-title":"Cell"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1038\/nsmb.2739","article-title":"Staufen1 senses overall transcript secondary structure to regulate translation","volume":"21","author":"Ricci","year":"2014","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1281","DOI":"10.1093\/nar\/15.3.1281","article-title":"The codon Adaptation Index\u2014A measure of directional synonymous codon usage bias, and its potential applications","volume":"15","author":"Sharp","year":"1987","journal-title":"Nucleic Acids Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"D280","DOI":"10.1093\/nar\/gkp892","article-title":"NNDB: The nearest neighbor parameter database for predicting stability of nucleic acid secondary structure","volume":"38","author":"Turner","year":"2010","journal-title":"Nucleic Acids Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.tim.2022.07.008","article-title":"T cell immunity in HSV-1- and VZV-infected neural ganglia","volume":"31","author":"Boeren","year":"2023","journal-title":"Trends Microbiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"997","DOI":"10.1016\/j.xphs.2020.12.006","article-title":"Addressing the Cold Reality of mRNA Vaccine Stability","volume":"110","author":"Crommelin","year":"2021","journal-title":"J. Pharm. Sci."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Uehata, T., and Takeuchi, O. (2020). RNA Recognition and Immunity-Innate Immune Sensing and Its Posttranscriptional Regulation Mechanisms. Cells, 9.","DOI":"10.3390\/cells9071701"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1526","DOI":"10.1126\/science.1093620","article-title":"Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8","volume":"303","author":"Heil","year":"2004","journal-title":"Science"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1529","DOI":"10.1126\/science.1093616","article-title":"Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA","volume":"303","author":"Diebold","year":"2004","journal-title":"Science"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"e970027","DOI":"10.4161\/21624011.2014.970027","article-title":"Chimeric antigen receptor T cells are vulnerable to immunosuppressive mechanisms present within the tumor microenvironment","volume":"3","author":"Beatty","year":"2014","journal-title":"Oncoimmunology"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2248","DOI":"10.1038\/s41467-023-38014-6","article-title":"Temperature sensitive liposome based cancer nanomedicine enables tumour lymph node immune microenvironment remodelling","volume":"14","author":"Fu","year":"2023","journal-title":"Nat. Commun."}],"container-title":["Vaccines"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-393X\/13\/1\/68\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T10:27:53Z","timestamp":1759919273000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-393X\/13\/1\/68"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,13]]},"references-count":37,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,1]]}},"alternative-id":["vaccines13010068"],"URL":"https:\/\/doi.org\/10.3390\/vaccines13010068","relation":{},"ISSN":["2076-393X"],"issn-type":[{"value":"2076-393X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1,13]]}}}