期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：9
DOI：10.1073/pnas.2119995119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
To contain the spread of SARS-CoV-2, the mRNA vaccine of viral spike protein has proven to be highly effective, although the efficacy against the emerging variants is decreasing. Here, we show that the mRNA of spike protein with deletion of glycosites in the RBD or especially the S2 domain to expose more conserved epitopes can be used as a broadly protective vaccine against the wild type and variants of concern. The spike protein translated from such mRNA was not properly folded, and thus induced cell apoptosis and a strong T cell response. Our findings demonstrate the importance of the glycosylation effect on the development of broadly protective mRNA vaccines.
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-eIF2α 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.
