Li Kangyin, Wu Yan, Zhang Hongqing, Chen Shaohong, Wu Bihao, Li Tingting, Li Entao, Luo Feiyang, Jin Aishun, Zhang Bo, Zhang Yanan, Gong Rui, Zhang Huajun, Chiu Sandra
Key Laboratory of Virology and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China.
University of the Chinese Academy of Sciences, Beijing, China.
J Med Virol. 2024 Dec;96(12):e70134. doi: 10.1002/jmv.70134.
SARS-CoV-2 continues to mutate, leading to breakthrough infections. The development of new vaccine strategies to combat various strains is crucial. Protein cyclization can enhance thermal stability and may improve immunogenicity. Here, we designed a cyclic tandem dimeric receptor-binding domain protein (cirRBD2) via the split intein Cth-Ter. Cyclization does not affect the antigen epitopes of RBD but results in better thermal stability than that of its linear counterpart (linRBD2). Compared with the mice immunized with linRBD2, those immunized with two doses of 5 μg of cirRBD2 produced significantly greater levels of broad-spectrum neutralizing antibodies, and generated a considerable cellular immune response. In the VEEV-VRP-hACE2-transduced mouse model, two doses of 5 μg of cirRBD2 provided protection against infection with BA.5, XBB.1.9, and partial protection against EG.5 which has more mutations. This study developed a novel circular RBD dimer subunit vaccine for SARS-CoV-2 that exhibits broad-spectrum neutralizing activity against various variants. A similar strategy can be applied to develop vaccines for other pathogens, especially for thermally stable vaccines.
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）持续变异，导致突破性感染。研发对抗各种毒株的新疫苗策略至关重要。蛋白质环化可增强热稳定性，并可能提高免疫原性。在此，我们通过裂合内含子Cth-Ter设计了一种环状串联二聚体受体结合域蛋白（cirRBD2）。环化不影响RBD的抗原表位，但与其线性对应物（linRBD2）相比，具有更好的热稳定性。与用linRBD2免疫的小鼠相比，用两剂5μg cirRBD2免疫的小鼠产生了显著更高水平的广谱中和抗体，并产生了可观的细胞免疫反应。在VEEV-VRP-hACE2转导的小鼠模型中，两剂5μg cirRBD2可提供针对BA.5、XBB.1.9感染的保护，并对具有更多突变的EG.5提供部分保护。本研究开发了一种新型的针对SARS-CoV-2的环状RBD二聚体亚单位疫苗，该疫苗对各种变体表现出广谱中和活性。类似的策略可应用于开发针对其他病原体的疫苗，特别是热稳定疫苗。
