Hong Qin, Wang Shuxia, Wang Xiaoli, Han Wenyu, Chen Tian, Liu Yan, Cheng Fei, Qin Song, Zhao Shengtao, Liu Qingwei, Cong Yao, Huang Zhong
Key Laboratory of RNA Innovation, Science and Engineering, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China.
Shanghai Institute of Infectious Disease and Biosecurity, Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Medical College, Fudan University, Shanghai 200032, China.
Vaccines (Basel). 2024 Sep 20;12(9):1077. doi: 10.3390/vaccines12091077.
Poliovirus (PV) is on the brink of eradication due to global vaccination programs utilizing live-attenuated oral and inactivated polio vaccines. Recombinant PV virus-like particles (VLPs) are emerging as a safe next-generation vaccine candidate for the impending polio-free era. In this study, we investigate the production, antigenicity, thermostability, immunogenicity, and structures of VLPs derived from PV serotype 2 (PV2) wildtype strain and thermally stabilized mutant (wtVLP and sVLP, respectively). Both PV2 wtVLP and sVLP are efficiently produced in yeast. The PV2 sVLP displays higher levels of D-antigen and significantly enhanced thermostability than the wtVLP. Unlike the wtVLP, the sVLP elicits neutralizing antibodies in mice at levels comparable to those induced by inactivated polio vaccine. The addition of an aluminum hydroxide adjuvant to sVLP results in faster induction and a higher magnitude of neutralizing antibodies. Furthermore, our cryo-EM structural study of both sVLP and wtVLP reveals a native conformation for the sVLP and a non-native expanded conformation for the wtVLP. Our work not only validates the yeast-produced PV2 sVLP as a promising vaccine candidate with high production potential but also sheds light on the structural mechanisms that underpin the assembly and immunogenicity of the PV2 sVLP. These findings may expedite the development of sVLP-based PV vaccines.
由于全球使用减毒活口服脊髓灰质炎疫苗和灭活脊髓灰质炎疫苗的免疫计划，脊髓灰质炎病毒（PV）已濒临根除。重组PV病毒样颗粒（VLP）正成为即将到来的无脊髓灰质炎时代的一种安全的下一代疫苗候选物。在本研究中，我们研究了源自2型PV（PV2）野生型菌株和热稳定突变体（分别为wtVLP和sVLP）的VLP的生产、抗原性、热稳定性、免疫原性和结构。PV2 wtVLP和sVLP均能在酵母中高效产生。与wtVLP相比，PV2 sVLP显示出更高水平的D抗原和显著增强的热稳定性。与wtVLP不同，sVLP在小鼠中诱导产生的中和抗体水平与灭活脊髓灰质炎疫苗诱导的水平相当。向sVLP中添加氢氧化铝佐剂可更快诱导产生中和抗体，且中和抗体水平更高。此外，我们对sVLP和wtVLP的冷冻电镜结构研究表明，sVLP具有天然构象，而wtVLP具有非天然的扩展构象。我们的工作不仅验证了酵母产生的PV2 sVLP作为一种具有高生产潜力的有前景的疫苗候选物，还揭示了支撑PV2 sVLP组装和免疫原性的结构机制。这些发现可能会加快基于sVLP的脊髓灰质炎疫苗的开发。
