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However, we lack effective drugs and vaccines to control toxoplasmosis, representing a clinical challenge. Therefore, safe and effective vaccines are urgently needed. In this study, a self-replicating mRNA vaccine comprising four <jats:italic>T. gondii<\/jats:italic> antigens: ROP18, TGME49_237490, TGME49_268230, and MIC13, named 4x-mRNA-LNP (lipid nanoparticle), was developed, and its protective efficacy was evaluated in mice. <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>The expression of this vaccine in eukaryotic Human embryonic kidney 293\u00a0T (HEK-293\u00a0T) cells and mouse myoblast (C2C12) cells were analyzed, followed by enzyme-linked immunosorbent assay (ELISA) evaluation of the elicited humoral immune response. Subsequently, the vaccine-triggered immune responses in mice were detected, including antibody titers, T lymphocyte subsets, and cytokine levels. Finally, its immunoprotective effects were evaluated after challenging mice with <jats:italic>T. gondii<\/jats:italic> PRU oocysts or tachyzoites of different strains and analyzing the pathological changes, parasite loads, and mouse survival time. Western blotting and ELISA confirmed the successful eukaryotic expression and immunogenicity of 4x-mRNA, respectively. Statistical analyses, including the log-rank (Mantel\u2013Cox) test, Student\u2019s<jats:italic> t<\/jats:italic>-test, and one-way ANOVA, were performed using GraphPad Prism software. <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>Mice vaccinated with 4x-mRNA-LNP generated higher levels of IgG1 and IgG2a antibodies (<jats:italic>P<\/jats:italic>\u2009&lt;\u20090.05) and cytokines (IL-2, IL-4, IL-10, IL-12, IFN-\u03b3) (<jats:italic>P<\/jats:italic>\u2009&lt;\u20090.05) compared with the control group. The high specific IgG titer was maintained for at least 10\u00a0weeks after the last vaccination. The proportion of CD3<jats:sup>+<\/jats:sup>CD4<jats:sup>+<\/jats:sup> T cells and CD3<jats:sup>+<\/jats:sup>CD8<jats:sup>+<\/jats:sup> T cells also increased significantly (<jats:italic>P<\/jats:italic>\u2009&lt;\u20090.05), along with increased spleen cell proliferation in 4x-mRNA-LNP-vaccinated mice. Notably, limited pathological changes and\u2009&lt;\u200910\u00a0fg of parasites\/mg were found in the immunized mice tissues post-pathogen challenge. During observation for 30\u00a0days, 4x-mRNA-LNP-immunized mice survived significantly longer under challenge with lethal doses of RH, ME49, or WH6 tachyzoites (survival rates\u2009=\u200960%, 80%, and 60%, respectively). Following PRU oocyst challenge, vaccinated mice had notably decreased cyst burdens (72.5%, <jats:italic>P<\/jats:italic>\u2009&lt;\u20090.05) compared with control mice.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>The 4x-mRNA-LNP vaccine triggered effective long-term antibody levels in mice, thus representing a promising candidate to further develop anti-toxoplasmosis vaccines.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Graphical Abstract<\/jats:title>\n          <\/jats:sec>","DOI":"10.1186\/s40249-025-01332-6","type":"journal-article","created":{"date-parts":[[2025,6,23]],"date-time":"2025-06-23T03:56:41Z","timestamp":1750651001000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["A novel combined quadrivalent self-amplifying mRNA-LNP vaccine provokes protective immunity against acute and chronic toxoplasmosis in mice"],"prefix":"10.1186","volume":"14","author":[{"given":"Qinli","family":"Wu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhongao","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongkun","family":"Chu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bing","family":"Xia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiqi","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianzu","family":"Ding","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haojie","family":"Ding","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youru","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eman E.","family":"El Shanawany","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Tan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huayue","family":"Ye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5805-0711","authenticated-orcid":false,"given":"Xunhui","family":"Zhuo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9855-7154","authenticated-orcid":false,"given":"Shaohong","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,6,23]]},"reference":[{"issue":"3","key":"1332_CR1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0090203","volume":"9","author":"J Flegr","year":"2014","unstructured":"Flegr J, Prandota J, Sovi\u010dkov\u00e1 M, Israili ZH. 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The experimental protocols were reviewed and approved by the Animal Care and Use Committee of Hangzhou Medical College (Approval No. 2023\u2013017).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"Dr Shaohong Lu serves as a guest editor of Infectious Diseases of Poverty-Role for the special issue\u00a0\"Role of Vaccines in the Elimination of Infectious Diseases of Poverty: Need for Innovation and Development.\"\u00a0She was not involved in the peer-review process or editorial handling of this manuscript. All other authors declare that they have no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"55"}}