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Current vaccine production faces challenges in manufacturing efficiency and cost-effectiveness. The RABV glycoprotein (RABV-G) serves as the key antigen for eliciting protective immunity. Methods: We developed a novel QS21+CpG-adjuvanted RABV-G subunit vaccine and systematically compared its performance against three control formulations: mRNA vaccine composed of H270P-targeted mutation packaged in lipid nanoparticles (LNP), named LNP-mRNA-G-H270P, commercial inactivated vaccine, and alum-adjuvanted RABV-G subunit vaccine. Results: The result show that the G+QS21+CpG subunit vaccine elicited superior humoral immunity, as evidenced by significantly higher RABV-G-specific IgG titers and virus-neutralizing antibody responses compared to all other groups. The LNP-mRNA-G-H270P vaccine maintained its expected cellular immunity advantage, with the G+QS21+CpG group exhibiting moderately reduced but still significant levels of IFN-\u03b3-secreting splenocytes and levels of IL-2 in the supernatant of spleen cells, as well as IFN-\u03b3-producing CD4+ T cells. Both LNP-mRNA-G-H270P and G+QS21+CpG vaccine groups provided 100% protection against lethal challenge (50LD50 RABV). Conclusions: These findings provide novel vaccine\/adjuvant strategies for rabies while elucidating platform-specific immunogenicity patterns, offering critical insights for pathogens requiring balanced humoral\/cellular immunity.<\/jats:p>","DOI":"10.3390\/vaccines13080887","type":"journal-article","created":{"date-parts":[[2025,8,22]],"date-time":"2025-08-22T07:41:45Z","timestamp":1755848505000},"page":"887","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["A QS21+ CpG-Adjuvanted Rabies Virus G Subunit Vaccine Elicits Superior Humoral and Moderate Cellular Immunity"],"prefix":"10.3390","volume":"13","author":[{"given":"Han","family":"Cao","sequence":"first","affiliation":[{"name":"Yunnan Key Laboratory of Vaccine Research and Development on Severe Infectious Diseases, Institute of Medical Biology, Chinese Academy of Medical Science and Peking Union Medical College, Kunming 650118, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Li","sequence":"additional","affiliation":[{"name":"Yunnan Key Laboratory of Vaccine Research and Development on Severe Infectious Diseases, Institute of Medical Biology, Chinese Academy of Medical Science and Peking Union Medical College, Kunming 650118, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenzhi","family":"Liu","sequence":"additional","affiliation":[{"name":"Yunnan Key Laboratory of Vaccine Research and Development on Severe Infectious Diseases, Institute of Medical Biology, Chinese Academy of Medical Science and Peking Union Medical College, Kunming 650118, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8559-7464","authenticated-orcid":false,"given":"Ning","family":"Luan","sequence":"additional","affiliation":[{"name":"Yunnan Key Laboratory of Vaccine Research and Development on Severe Infectious Diseases, Institute of Medical Biology, Chinese Academy of Medical Science and Peking Union Medical College, Kunming 650118, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingping","family":"Hu","sequence":"additional","affiliation":[{"name":"Yunnan Key Laboratory of Vaccine Research and Development on Severe Infectious Diseases, Institute of Medical Biology, Chinese Academy of Medical Science and Peking Union Medical College, Kunming 650118, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meijun","family":"Kong","sequence":"additional","affiliation":[{"name":"Yunnan Key Laboratory of Vaccine Research and Development on Severe Infectious Diseases, Institute of Medical Biology, Chinese Academy of Medical Science and Peking Union Medical College, Kunming 650118, China"},{"name":"NMPA Key Laboratory for Quality Control and Evaluation of Vaccines and Biological Products, Institute of Medical Biology, Chinese Academy of Medical Science and Peking Union Medical College, Kunming 650108, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-4331-2086","authenticated-orcid":false,"given":"Jie","family":"Song","sequence":"additional","affiliation":[{"name":"Yunnan Key Laboratory of Vaccine Research and Development on Severe Infectious Diseases, Institute of Medical Biology, Chinese Academy of Medical Science and Peking Union Medical College, Kunming 650118, China"},{"name":"NMPA Key Laboratory for Quality Control and Evaluation of Vaccines and Biological Products, Institute of Medical Biology, Chinese Academy of Medical Science and Peking Union Medical College, Kunming 650108, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2101-2612","authenticated-orcid":false,"given":"Cunbao","family":"Liu","sequence":"additional","affiliation":[{"name":"Yunnan Key Laboratory of Vaccine Research and Development on Severe Infectious Diseases, Institute of Medical Biology, Chinese Academy of Medical Science and Peking Union Medical College, Kunming 650118, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"7129","DOI":"10.1016\/j.vaccine.2023.10.019","article-title":"Immunogenicity of rabies virus G mRNA formulated with lipid nanoparticles and nucleic acid immunostimulators in mice","volume":"41","author":"Hongtu","year":"2023","journal-title":"Vaccine"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1893","DOI":"10.1016\/j.vaccine.2008.01.043","article-title":"A CpG oligodeoxynucleotide acts as a potent adjuvant for inactivated rabies virus vaccine","volume":"26","author":"Wang","year":"2008","journal-title":"Vaccine"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1139\/cjm-2024-0023","article-title":"The roles of rabies virus structural proteins in 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