A novel heterologous receptor-binding domain dodecamer universal mRNA vaccine against SARS-CoV-2 variants

Shugang Qin; Hai Huang; Wen Xiao; Kepan Chen; Xi He; Xiaoshan Tang; Zhiying Huang; Yupei Zhang; Xing Duan; Na Fan; Qian Zheng; Min Wu; Guangwen Lu; Yuqan Wei; Xiawei Wei; Xiangrong Song

doi:10.1016/j.apsb.2023.01.010

A novel heterologous receptor-binding domain dodecamer universal mRNA vaccine against SARS-CoV-2 variants

Acta Pharm Sin B. 2023 Jan 12;13(10):4291-4304. doi: 10.1016/j.apsb.2023.01.010. Online ahead of print.

Authors

Shugang Qin¹, Hai Huang¹, Wen Xiao¹, Kepan Chen¹, Xi He¹, Xiaoshan Tang¹, Zhiying Huang¹, Yupei Zhang¹, Xing Duan¹, Na Fan¹, Qian Zheng¹, Min Wu¹, Guangwen Lu¹, Yuqan Wei¹, Xiawei Wei¹, Xiangrong Song¹

Affiliation

¹ Department of Critical Care Medicine, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China.

Abstract

There are currently approximately 4,000 mutations in the SARS-CoV-2 S protein gene and emerging SARS-CoV-2 variants continue to spread rapidly worldwide. Universal vaccines with high efficacy and safety urgently need to be developed to prevent SARS-CoV-2 variants pandemic. Here, we described a novel self-assembling universal mRNA vaccine containing a heterologous receptor-binding domain (HRBD)-based dodecamer (HRBD^dodecamer) against SARS-CoV-2 variants, including Alpha (B.1.1.7), Beta (B.1.351), Gamma (B.1.1.28.1), Delta (B.1.617.2) and Omicron (B.1.1.529). HRBD containing four heterologous RBD (Delta, Beta, Gamma, and Wild-type) can form a stable dodecameric conformation under T4 trimerization tag (Flodon, FD). The HRBD^dodecamer -encoding mRNA was then encapsulated into the newly-constructed LNPs consisting of a novel ionizable lipid (4N4T). The obtained universal mRNA vaccine (4N4T-HRBD^dodecamer) presented higher efficiency in mRNA transfection and expression than the approved ALC-0315 LNPs, initiating potent immune protection against the immune escape of SARS-CoV-2 caused by evolutionary mutation. These findings demonstrated the first evidence that structure-based antigen design and mRNA delivery carrier optimization may facilitate the development of effective universal mRNA vaccines to tackle SARS-CoV-2 variants pandemic.

Keywords: Antigen design; Heterologous RBD; Immune escape; Ionizable lipids; Lipid nanoparticles; RBD dodecamer; SARS-CoV-2 variants pandemic; Universal mRNA vaccines.