A Tetravalent Dengue prM-E mRNA-LNP Vaccine Protects via Antibodies in Susceptible Mice 2255808

Abstract Introduction Dengue virus (DENV) remains a major global health threat, with no optimal vaccine available against its four distinct serotypes: DENV1, DENV2, DENV3, and DENV4. A central challenge in dengue vaccine development is achieving balanced and durable immunity against all serotypes, as partial protection can lead to antibody-dependent enhancement (ADE), increasing the risk of severe disease upon secondary infection. Methods We developed a tetravalent mRNA vaccine encoding the prM-E proteins from each DENV serotype, formulated in lipid nanoparticles (LNPs). The vaccine was administered intramuscularly to C57BL/6J mice. Each dose contained a total of 5 µg mRNA (1.25 µg per serotype) and was given at 4-week intervals for three immunizations. Germinal center (GC) B cell responses and tissue-resident memory T (Trm) cell induction were analyzed in comparison with recombinant Envelope (rE) protein formulated with Alum. Results The tetravalent prM-E mRNA-LNP vaccine elicited strong neutralizing antibody responses against all four serotypes, producing titers of 5481, 4632, 12,179, and 5006 for DENV1-4, respectively. Passive transfer of sera from vaccinated mice conferred complete protection in AG129 mice (IFN-α/β/γR-/-) challenged with lethal DENV2, resulting in 100% survival. By day 14, the prM-E mRNA-LNP group exhibited a two-fold higher frequency of CD38^lowGL7+ GC B cells than the rE + Alum group, indicating enhanced GC B cell activity. Intradermal (ID) vaccination induced significantly higher Trm cell formation in the skin compared to intramuscular delivery, showing approximately four-fold increases following ID prime-boost immunization. Conclusion These findings show that the tetravalent prM-E mRNA-LNP vaccine elicits strong humoral and tissue-resident cellular immunity against all DENV serotypes. The results underscore its robust immunogenicity and protective efficacy, supporting further development of mRNA-based dengue vaccines for broad and durable protection. Funding Source n/a Topic Categories Vaccines and Immunotherapy (VAC)