Rabies is a lethal zoonotic infectious disease. Vaccines against the rabies virus have significantly reduced the number of deaths from the disease. However, all the licensed rabies vaccines are inactivated vaccines, which have limited immunogenicity and complicated immunization procedures. A novel vaccine that provides sustained and comprehensive protection is urgently needed. Here, we developed a novel rabies mRNA vaccine candidate containing sequence-optimized mRNAs encoding full-length glycoprotein encapsulated in ionizable lipid nanoparticles. In mice and rhesus macaques, the rabies mRNA exhibited superior immunogenicity over licensed vaccines, especially in inducing long-lasting neutralizing antibodies and memory B cells. A single administration of 1.5 μg mRNA vaccine could provide complete protection against a lethal rabies virus challenge in mice. Additionally, the mRNA vaccine could robustly activate cellular immune responses with moderate release of several cytokines. In summary, our data demonstrated that the rabies mRNA vaccine outperformed approved inactivated vaccines in both mice and rhesus macaques. This highlights the potential of the mRNA platform in developing next-generation rabies vaccines.
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