Development of Glycan-masked SARS-CoV-2 RBD vaccines against SARS-related coronaviruses

Liang, Zuxin1,2,3; Li, Chunhui4,5,6; Gong, Xiaohua7,8; Ye, Guoguo7; Jiang, Yushan1,2,3; Shi, Huiping4,5,6; Hussain, Abid4,5,6; Zhao, Mengyuan4,5,6; Li, Mengjun1,2,3; Tian, Yuxin4,5,6; Zhao, Wei1,2,3; Yang, Yang7; Huang, Yuanyu4,5,6; Shen, Chenguang1,2,3; Yang, Minghui4,5,6

2024-09-01

10.1371/journal.ppat.1012599

PLOS PATHOGENS   影响因子和分区

1553-7366

1553-7374

["Emerging and recurrent infectious diseases caused by coronaviruses remain a significant public health concern. Here, we present a targeted approach to elicit antibodies capable of neutralizing SARS-CoV-2 variants and other SARS-related coronaviruses. By introducing amino acid mutations at mutation-prone sites, we engineered glycosylation modifications to the Receptor Binding Domain (RBD) of SARS-CoV-2, thereby exposing more conserved, yet less accessible epitopes. We developed both messenger RNA (mRNA) and recombination subunit vaccines using these engineered-RBDs (M1, M2) and the wild-type RBD as immunogens. The engineered-RBD vaccines elicited robust neutralizing responses against various SARS-CoV-2 variants as well as SARS-CoV and WIV1-CoV, and conferred protection in mice challenged with the XBB.1.16 strain. Furthermore, We highlighted that glycan masking is a decisive factor in antibody binding changes and RBD-conserved antibody response. Additionally, the glycan-engineered RBD mRNA vaccines stimulated stronger cell-mediated immune responses. Our glycan modification strategy significantly enhances broad-spectrum neutralizing efficacy and cellular immunity, providing valuable insights for the development of vaccines against a wide range of SARS-related coronaviruses.","Since late 2020, numerous SARS-CoV-2 variants have emerged across different regions, with the Omicron variant and its subvariants (e.g., BA.5, XBB, JN.1, etc.) posing significant challenges to ongoing efforts in controlling the pandemic. This highlights the urgent need for broadly protective vaccines that target both SARS-CoV-2 variants and other SARS-related coronaviruses that could cause future outbreaks. In this study, we developed a glycan modification strategy based on N-glycosylation by introducing amino acid mutations in the RBD. Using these engineered RBDs (M1, M2) and wild-type RBD as immunogens, we created thermostable mRNA vaccines and recombinant subunit vaccines. Our results demonstrate that these engineered-RBD vaccines elicit potent neutralizing responses against notonly various SARS-CoV-2 variants, but also other coronaviruses like SARS-CoV and WIV1-CoV, surpassing the immune response triggered by the wild-type RBD. Furthermore, glycan-engineered RBD mRNA vaccines stimulated stronger cell-mediated immune responses and provided effective protection against XBB strain challenge in mice. We identified key glycosylation modifications at residues K417, L452, R457, and Q493 that play a critical role in inducing broad-spectrum neutralizing antibodies. In particular, the glycosylation of residues R457 and Q493 was especially effective in enhancing this immune response. These findings offer valuable insights for the design of broad-spectrum vaccines against SARS-related coronaviruses."]

SCI

英语

通讯

Microbiology ; Parasitology ; Virology

Microbiology ; Parasitology ; Virology

WOS:001320728800006

PUBLIC LIBRARY SCIENCE

Web of Science

1.Zhujiang Hosp, Sch Publ Hlth, BSL 3 Lab Guangdong, Guangdong Prov Key Lab Trop Dis Res, Guangzhou, Peoples R China
2.Zhujiang Hosp, Dept Lab Med, Guangzhou, Peoples R China
3.Southern Med Univ, Guangzhou, Peoples R China
4.Beijing Inst Technol, Sch Life Sci, Beijing, Peoples R China
5.Beijing Inst Technol, Adv Res Inst Multidisciplinary Sci, Beijing, Peoples R China
6.Beijing Inst Technol, Key Lab Mol Med & Biotherapy, Beijing, Peoples R China
7.Southern Univ Sci & Technol, Shenzhen Peoples Hosp 3, Natl Clin Res Ctr Infect Dis, Affiliated Hosp 2, Shenzhen, Peoples R China
8.Anhui Med Univ, Lab Anim Ctr, Hefei, Peoples R China

Liang, Zuxin,Li, Chunhui,Gong, Xiaohua,et al. Development of Glycan-masked SARS-CoV-2 RBD vaccines against SARS-related coronaviruses[J]. PLOS PATHOGENS,2024,20(9).

Liang, Zuxin.,Li, Chunhui.,Gong, Xiaohua.,Ye, Guoguo.,Jiang, Yushan.,...&Yang, Minghui.(2024).Development of Glycan-masked SARS-CoV-2 RBD vaccines against SARS-related coronaviruses.PLOS PATHOGENS,20(9).

Liang, Zuxin,et al."Development of Glycan-masked SARS-CoV-2 RBD vaccines against SARS-related coronaviruses".PLOS PATHOGENS 20.9(2024).