Glycosite-deleted mRNA of SARS-CoV-2 spike protein as a broad-spectrum vaccine

Development of the messenger RNA (mRNA) vaccine has emerged as an effective and speedy strategy to control the spread of new pathogens. After vaccination, the mRNA is translated into the real protein vaccine, and there is no need to manufacture the protein in vitro. However, the fate of mRNA and its posttranslational modification inside the cell may affect immune response. Here, we showed that the mRNA vaccine of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein with deletion of glycosites in the receptor-binding domain (RBD) or especially the subunit 2 (S2) domain to expose more conserved epitopes elicited stronger antibody and CD8(+) T cell responses with broader protection against the alpha, beta, gamma, delta, and omicron variants, compared to the unmodified mRNA. Immunization of such mRNA resulted in accumulation of misfolded spike protein in the endoplasmic reticulum, causing the up-regulation of BiP/GRP78, XBP1, and p-eIF2 alpha to induce cell apoptosis and strong CD8(+) T cell response. In addition, dendritic cells (DCs) incubated with S2-glysosite deleted mRNA vaccine increased class I major histocompatibility complex (MHC I) expression. This study provides a direction for the development of broad-spectrum mRNA vaccines which may not be achieved with the use of expressed proteins as antigens.

Automated summary

The development of mRNA vaccines has proven to be an effective and rapid strategy to control the spread of new pathogens. mRNA vaccines with deleted glycosites in the SARS-CoV-2 spike protein elicited stronger immune responses and broader protection compared to unmodified mRNA. This study suggests that development of broad-spectrum mRNA vaccines may not be achieved with the use of expressed proteins as antigens.