A universal design of betacoronavirus vaccines against COVID-19, MERS and SARS

Dai, Lianpan; Zheng, Tianyi; Xu, Kun; Han, Yuxuan; Xu, Lili; Huang, Enqi; An, Yaling; Cheng, Yingjie; Li, Shihua; Liu, Mei; Yang, Mi; Li, Yan; Cheng, Huijun; Yuan, Yuan; Zhang, Wei; Ke, Changwen; Wong, Gary; Qi, Jianxun; Qin, Chuan; Yan, Jinghua; Gao, George F.

Summary 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.