Title: A universal design of betacoronavirus vaccines against COVID-19, MERS and SARS
Author: Lianpan Dai, Tianyi Zheng, Kun Xu, Yuxuan Han, Lili Xu, Enqi Huang, Yaling An, Yingjie Cheng, Shihua Li, Mei Liu, Mi Yang, Yan Li, Huijun Cheng, Yuan Yuan, Wei Zhang, Changwen Ke, Gary Wong, Jianxun Qi, Chuan Qin, Jinghua Yan, George F. Gao
Abstract: Vaccines are urgently needed to control the ongoing pandemic COVID-19 and previously-emerging MERS/SARS caused by coronavirus (CoV) infections. The CoV spike receptor-binding domain (RBD) is an attractive vaccine target but is undermined by limited immunogenicity. We describe a dimeric form of MERS-CoV RBD that overcomes this limitation. The RBD-dimer significantly increased neutralizing antibody (NAb) titers compared to conventional monomeric form and protected mice against MERS-CoV infection. Crystal structure showed RBD-dimer fully exposed dual receptor-binding motifs, the major target for NAbs. Structure-guided design further yielded a stable version of RBD-dimer as a tandem repeat single-chain (RBD-sc-dimer) which retained the vaccine potency. We generalized this strategy to design vaccines against COVID-19 and SARS, achieving 10-100-fold enhancement of NAb titers. RBD-sc-dimers in pilot scale production yielded high yields, supporting their scalability for further clinical development. The framework of immunogen design can be universally applied to other beta-CoV vaccines to counter emerging threats.