PDF(Pubmed)
Abstract：
Human respiratory syncytial virus (RSV) poses a significant human health threat, particularly to infants and the elderly. While efficacious vaccines based on the F protein have recently received market authorization, uncertainties remain regarding the future need for vaccine updates to counteract potential viral drift. The attachment protein G has long been ignored as a vaccine target due to perceived non-essentiality and ineffective neutralization on immortalized cells. Here, we show strong G-based neutralization in fully differentiated human airway epithelial cell (hAEC) cultures that is comparable to F-based neutralization. Next, we designed an RSV vaccine component based on the central conserved domain (CCD) of G fused to self-assembling lumazine synthase (LS) nanoparticles from the thermophile Aquifex aeolicus as a multivalent antigen presentation scaffold. These nanoparticles, characterized by high particle expression and assembly through the introduction of N-linked glycans, showed exceptional thermal and storage stability and elicited potent RSV neutralizing antibodies in a mouse model. In conclusion, our results emphasize the pivotal role of RSV G in the viral lifecycle and culminate in a promising next-generation RSV vaccine candidate characterized by excellent manufacturability and immunogenic properties. This candidate could function independently or synergistically with current F-based vaccines.
摘要：
人呼吸道合胞病毒(RSV)对人类健康构成重大威胁,特别是婴儿和老人。虽然基于F蛋白的有效疫苗最近获得了市场授权，未来是否需要更新疫苗以抵消潜在的病毒漂移仍存在不确定性.由于感知到的非必需性和对永生化细胞的无效中和,附着蛋白G长期以来一直被忽略为疫苗靶标。这里,我们在完全分化的人气道上皮细胞（hAEC）培养物中显示出强的基于G的中和，与基于F的中和相当。接下来,我们设计了一种基于G的中心保守域（CCD）的RSV疫苗组件，该组件与来自嗜热菌Aquifexaeolicus的自组装lumazine合酶（LS）纳米颗粒融合，作为多价抗原呈递支架。这些纳米粒子，其特征在于通过引入N-连接聚糖的高颗粒表达和组装，在小鼠模型中显示出优异的热和储存稳定性，并引起有效的RSV中和抗体。总之,我们的研究结果强调了RSVG在病毒生命周期中的关键作用,并最终形成了具有优异可制造性和免疫原性的下一代RSV候选疫苗.该候选物可以与当前的基于F的疫苗独立地或协同地起作用。
