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HSV-1 causes symptoms such as herpes labialis, herpetic keratitis, genital ulcers, and encephalitis, and primarily establishes latent infection in the trigeminal ganglion. The complexity of membrane fusion mechanisms and potential infection in nerves allow HSV to easily evade recognition and clearance by host immune cells. Therefore, developing a vaccine that can prevent both primary and reactivated HSV-1 infection is critical. Currently, no preventive or therapeutic HSV-1 vaccines have been approved for marketing. Methods: In this study, we utilized the gC, gD, and gE proteins of HSV-1, which are associated with viral fusion and immune escape, to design a trivalent antigen vaccine that is capable of inducing a cellular immune response. Two formulations of the vaccine are available: a subunit vaccine incorporating oligodeoxynucleotides with CpG motifs (CpG ODNs) and QS-21 as adjuvants, as well as an mRNA vaccine. Mice were immunized via intramuscular injection to evaluate and compare the immunological responses and protective efficacy of the two vaccines. Results: After the challenge, the viral load in the tissues of both vaccine groups was significantly lower than that in the positive control group, indicating that both vaccines were able to control viral proliferation in the tissues. Conclusions: The findings indicated that both mRNA and subunit vaccines were capable of eliciting comparable humoral and cellular immune responses.<\/jats:p>","DOI":"10.3390\/vaccines13090958","type":"journal-article","created":{"date-parts":[[2025,9,10]],"date-time":"2025-09-10T12:04:55Z","timestamp":1757505895000},"page":"958","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["A Comparative Study on Immune Protection Efficacy: An HSV-1 Trivalent Antigen Subunit Vaccine Formulated with a Cellular Immunity-Inducing Adjuvant Versus an mRNA Vaccine"],"prefix":"10.3390","volume":"13","author":[{"given":"Han","family":"Cao","sequence":"first","affiliation":[{"name":"Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming 650118, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingping","family":"Hu","sequence":"additional","affiliation":[{"name":"Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming 650118, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fengyuan","family":"Zeng","sequence":"additional","affiliation":[{"name":"Institute of Medical Biology, Chinese Academy of Medical Sciences 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":"Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming 650118, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dandan","family":"Gao","sequence":"additional","affiliation":[{"name":"Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming 650118, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhentao","family":"Lei","sequence":"additional","affiliation":[{"name":"Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming 650118, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0769-858X","authenticated-orcid":false,"given":"Jishuai","family":"Cheng","sequence":"additional","affiliation":[{"name":"Laboratory Animal Department, Kunming Medical University, Kunming 650500, 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":"Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming 650118, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Chang, J.Y., Balch, C., and Oh, H.S. 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