Design of a mutation-integrated trimeric RBD with broad protection against SARS-CoV-2
Yu Liang, Jing Zhang, Run Yu Yuan, Mei Yu Wang, Peng He, Ji Guo Su, Zi Bo Han, Yu Jin, Jun Hou, Hao Zhang, Xuefeng Zhang, Shuai Shao, Ya Nan Hou, Zhao Ming Liu, Li Fang Du, Fu Jie Shen, Wei Zhou, Ke Xu, Ru Gao, Fang Tang, Ze Hua Lei, Shuo Liu, Wei Zhen, Jin Juan Wu, Xiang Zheng, Ning Liu, Shi Chen, Zhi Jing, Fan Zheng, Si Yu Ren, Zhong Hu, Weijin Huang, Gui Zhen Wu, Ke Chang, Qi Ming Li
Abstract
The continuous emergence of SARS-CoV-2 variants highlights the need of developing vaccines with broad protection. Here, according to the immune-escape capability and evolutionary convergence, the representative SARS-CoV-2 strains carrying the hotspot mutations were selected. Then, guided by structural and computational analyses, we present a mutation-integrated trimeric form of spike receptor-binding domain (mutI-tri-RBD) as a broadly protective vaccine candidate, which combined heterologous RBDs from different representative strains into a hybrid immunogen and integrated immune-escape hotspots into a single antigen. When compared with a homo-tri-RBD vaccine candidate in the stage of phase II trial, of which all three RBDs are derived from the SARS-CoV-2 prototype strain, mutI-tri-RBD induced significantly higher neutralizing antibody titers against the Delta and Beta variants, and maintained a similar immune response against the prototype strain. Pseudo-virus neutralization assay demonstrated that mutI-tri-RBD also induced broadly strong neutralizing activities against all tested 23 SARS-CoV-2 variants. The in vivo protective capability of mutI-tri-RBD was further validated in hACE2-transgenic mice challenged by the live virus, and the results showed that mutI-tri-RBD provided potent protection not only against the SARS-CoV-2 prototype strain but also against the Delta and Beta variants.