A single immunization with core–shell structured lipopolyplex mRNA vaccine against rabies induces potent humoral immunity in mice and dogs

The persistence and clinical consequences of rabies virus (RABV) infection have prompted global efforts to develop a safe and effective vaccines against rabies. mRNA vaccines represent a promising option against emerging and re-emerging infectious diseases, gaining particular interest since the outbreak of COVID-19. Herein, we report the development of a highly efficacious rabies mRNA vaccine composed of sequence-modified mRNA encoding RABV glycoprotein (RABV-G) packaged in core–shell structured lipopolyplex (LPP) nanoparticles, named LPP-mRNA-G. The bilayer structure of LPP improves protection and delivery of RABV-G mRNA and allows gradual release of mRNA molecules as the polymer degrades. The unique core–shell structured nanoparticle of LPP-mRNA-G facilitates vaccine uptake and demonstrates a desirable biodistribution pattern with low liver targeting upon intramuscular immunization. Single administration of low-dose LPP-mRNA-G in mice elicited potent humoral immune response and provided complete protection against intracerebral challenge with lethal RABV. Similarly, single immunization of low-dose LPP-mRNA-G induced high levels of virus-neutralizing antibody titers in dogs. Collectively, our data demonstrate the potential of LPP-mRNA-G as a promising next-generation rabies vaccine used in human and companion animals.

狂犬病病毒（rabies virus，RABV）感染的持续存在及其临床危害，推动了全球范围内研发安全有效狂犬病疫苗的工作。信使核糖核酸（messenger RNA，mRNA）疫苗是应对新发与再发传染病的极具潜力的候选方案，自新冠疫情暴发以来愈发受到广泛关注。在此，我们报道一款高效狂犬病mRNA疫苗的研发进展：该疫苗由编码狂犬病病毒糖蛋白（rabies virus glycoprotein，RABV-G）的序列修饰mRNA组装而成，并封装于核壳结构脂质多聚体（lipopolyplex，LPP）纳米颗粒中，命名为LPP-mRNA-G。LPP的双层结构可提升RABV-G mRNA的保护效果与递送效率，并可在聚合物降解过程中实现mRNA分子的逐步释放。LPP-mRNA-G独特的核壳结构纳米颗粒可促进疫苗的细胞摄取，且在肌肉免疫后展现出理想的生物分布特征，肝脏靶向性较低。在小鼠模型中单次接种低剂量LPP-mRNA-G，即可诱发强效的体液免疫应答，并可完全抵御致死性RABV的脑内攻毒感染。同样地，在犬只中单次接种低剂量LPP-mRNA-G，可诱导产生高滴度的病毒中和抗体。综上，本研究数据证实，LPP-mRNA-G有望成为一款极具应用前景的下一代狂犬病疫苗，可用于人类与伴侣动物的免疫防护。