Omicron‐specific mRNA vaccine induced cross‐protective immunity against ancestral SARS‐CoV‐2 infection with low neutralizing antibodies

The major challenge in COVID‐19 vaccine effectiveness is immune escape by SARS‐CoV‐2 variants. To overcome this, an Omicron‐specific messenger RNA (mRNA) vaccine was designed. The extracellular domain of the spike of the Omicron variant was fused with a modified GCN4 trimerization domain with low immunogenicity (TSomi). After immunization with TSomi mRNA in hamsters, animals were challenged with SARS‐CoV‐2 virus. The raised nonneutralizing antibodies or cytokine secretion responses can recognize both Wuhan S and Omicron S. However, the raised antibodies neutralized SARS‐CoV‐2 Omicron virus infection but failed to generate Wuhan virus neutralizing antibodies. Surprisingly, TSomi mRNA immunization protected animals from Wuhan virus challenge. These data indicated that non‐neutralizing antibodies or cellular immunity may play a more important role in vaccine‐induced protection than previously believed. Next‐generation COVID‐19 vaccines using the Omicron S antigen may provide sufficient protection against ancestral or current SARS‐CoV‐2 variants.