Broad protective RBD heterotrimer vaccines neutralize SARS-CoV-2 including Omicron sub-variants XBB/BQ.1.1/BF.7

Zhang, Yanfang1; Kang, Xinrui2; Liu, Sheng3; Han, Pu1; Lei, Wenwen4; Xu, Ke4; Xu, Zepeng1,5; Gao, Zhengrong6,7; Zhou, Xuemei1,8; An, Yaling2; Han, Yuxuan2; Liu, Kefang1; Zhao, Xin1; Dai, Lianpan1; Wang, Peiyi3; Wu, Guizhen4; Qi, Jianxun1; Xu, Kun9; Gao, George F.1,2,9

2023-09-01

10.1371/journal.ppat.1011659

PLOS PATHOGENS   Impact Factor & Quartile

1553-7366

1553-7374

["SARS-CoV-2 variants with severe immune evasion are a major challenge for COVID-19 prevention, especially the circulating Omicron XBB/BQ.1.1/BF.7 strains. Thus, the next-generation of broad-spectrum vaccines are urgently needed. Previously, we developed a COVID-19 protein subunit vaccine, ZF2001, based on the RBD-homodimer as the immunogen. To adapt SARS-CoV-2 variants, we developed chimeric RBD-heterodimers to induce broad immune responses. In this study, we further explored the concept of tandem RBD homotrimer and heterotrimer. Prototype SARS-CoV-2 RBD-homotrimer, prototype-Delta-BA.1 (PDO) RBD-heterotrimer and Delta-BA.2-BA.5 (DBA2BA5) RBD-heterotrimer were designed. Biochemical and cryo-EM structural characterization demonstrated total epitope exposure of the RBD-trimers. In mouse experiments, PDO and DBA2BA5 elicited broad SARS-CoV-2 neutralization. Potent protection against SARS-CoV-2 variants was observed in challenge assays and was correlated with neutralizing antibody titer. This study validated the design strategy of tandem RBD-heterotrimers as multivalent immunogens and presented a promising vaccine candidate, DBA2BA5, eliciting broad-spectrum immune responses, including against the circulating XBB/BF.7/BQ.1.1.","SARS-CoV-2 variants continue to emerge and circulate. Omicron sub-variants show severe evasion of the immune response induced by early-approved vaccines. Bivalent mRNA vaccines (prototype and Omicron BA. 5) have been approved for use in the United States and other countries. However, the co-circulation of SARS-CoV-2 variants (such as BA. 5.2, BF. 7, BQ. 1.1 and XBB) poses a challenge to disease control. The next-generation of COVID-19 vaccines need to induce potent and broad-spectrum immune responses. Here, we demonstrate a design strategy for trivalent SARS-CoV-2 vaccines with RBD-heterotrimers, which are single protein molecules without any linker sequences or trimerization domain. Biochemical and cryo-EM structural characterization demonstrated the total epitope exposure of RBD-trimers. Animal experiments showed that RBD-heterotrimers induce broad-spectrum protective immune responses. As a proof-of-concept, this trivalent immunogen design strategy is promising and practical for preventing the continuous circulation of SARS-CoV-2. This study provides guidance for future vaccine design against coronavirus and other viruses such as the influenza and dengue viruses."]

SCI

English

Corresponding

Microbiology ; Parasitology ; Virology

Microbiology ; Parasitology ; Virology

WOS:001074571100002

PUBLIC LIBRARY SCIENCE

Web of Science

1.Chinese Acad Sci, Inst Microbiol, CAS Key Lab Pathogen Microbiol & Immunol, Beijing, Peoples R China
2.Univ Chinese Acad Sci, Savaid Med Sch, Beijing, Peoples R China
3.Southern Univ Sci & Technol, Cryo EM Ctr, Shenzhen, Peoples R China
4.Chinese Ctr Dis Control & Prevent, Natl Inst Viral Dis Control & Prevent, NHC Key Lab Biosafety, Beijing 102206, Peoples R China
5.Univ Macau, Fac Hlth Sci, Macau, Peoples R China
6.Chinese Acad Sci, Shenzhen Inst Adv Technol, Shenzhen, Peoples R China
7.Shenzhen Childrens Hosp, Shenzhen, Peoples R China
8.Hebei Univ, Sch Life Sci, Baoding, Peoples R China
9.Chinese Acad Sci, Beijing Inst Life Sci, Res Network Immun & Hlth RNIH, Beijing, Peoples R China

Zhang, Yanfang,Kang, Xinrui,Liu, Sheng,et al. Broad protective RBD heterotrimer vaccines neutralize SARS-CoV-2 including Omicron sub-variants XBB/BQ.1.1/BF.7[J]. PLOS PATHOGENS,2023,19(9).

Zhang, Yanfang.,Kang, Xinrui.,Liu, Sheng.,Han, Pu.,Lei, Wenwen.,...&Gao, George F..(2023).Broad protective RBD heterotrimer vaccines neutralize SARS-CoV-2 including Omicron sub-variants XBB/BQ.1.1/BF.7.PLOS PATHOGENS,19(9).

Zhang, Yanfang,et al."Broad protective RBD heterotrimer vaccines neutralize SARS-CoV-2 including Omicron sub-variants XBB/BQ.1.1/BF.7".PLOS PATHOGENS 19.9(2023).