An mRNA-LNP vaccine expressing TP0435 provides protective immunity in rabbits against Treponema pallidum challenge.

Syphilis, a sexually transmitted disease caused by Treponema pallidum (T. pallidum), is a major public health concern globally. Although syphilis can be easily diagnosed and treated with an inexpensive antibiotic, it continues to be a significant global health problem. Vaccination is the most cost-effective public health intervention to prevent and control infections. Therefore, a safe and effective syphilis vaccine is urgently needed. T. pallidum surface exposed antigens are regarded as the most promising vaccine candidates. In recent years, mRNA-LNP (lipid nanoparticles) vaccines also showed promising protective results for bacterial diseases. TP0435, encoding the highly immunogenic T. pallidum 17-kDa lipoprotein, is a periplasmic antigen that has also been shown on the pathogen surface. In this study, we successfully constructed the TP0435 mRNA-LNP vaccine, which was stable, effectively expressed, and exhibited no acute toxicity. In BALB/c mice, a 5 µg dose elicited strong antigen-specific humoral responses, Th1-biased cellular immunity, and enhanced CD4+ central memory T-cell formation. In New Zealand White (NZW) rabbits, both TP0435 mRNA-LNP and protein vaccines delayed lesion formation and reduced T. pallidum burden; moreover, the mRNA-LNP vaccine provided superior protection, completely preventing ulcer formation and showing lower T. pallidum loads at lesion sites than the protein vaccine, while effectively limiting pathogen dissemination. Histopathological analysis revealed that, at nodular lesions, the mRNA vaccine group exhibited reduced neutrophil infiltration and increased proportions of macrophages and lymphocytes compared with ulcerative lesions in the LNP group. Therefore, we successfully constructed an mRNA-LNP vaccine targeting TP0435, which might be a promising syphilis vaccine candidate.