1. Academic Validation
  2. Glycosite-deleted mRNA of SARS-CoV-2 spike protein as a broad-spectrum vaccine

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

  • Proc Natl Acad Sci U S A. 2022 Mar 1;119(9):e2119995119. doi: 10.1073/pnas.2119995119.
Chung-Yi Wu 1 Cheng-Wei Cheng 1 2 Chih-Chuan Kung 1 Kuo-Shiang Liao 1 Jia-Tsrong Jan 1 Che Ma 1 Chi-Huey Wong 3 4
Affiliations

Affiliations

  • 1 Genomics Research Center, Academia Sinica, Taipei 11529, Taiwan.
  • 2 The Master Program of AI Application in Health Industry, Kaohsiung Medical University, Kaohsiung City 80708, Taiwan.
  • 3 Genomics Research Center, Academia Sinica, Taipei 11529, Taiwan; wong@scripps.edu.
  • 4 Department of Chemistry, Scripps Research, La Jolla, CA 92037.
Abstract

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.

Keywords

COVID-19; broad spectrum; glycosite deletion; mRNA vaccine.

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