PLoS Pathogens (Sep 2023)

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

  • Yanfang Zhang,
  • Xinrui Kang,
  • Sheng Liu,
  • Pu Han,
  • Wenwen Lei,
  • Ke Xu,
  • Zepeng Xu,
  • Zhengrong Gao,
  • Xuemei Zhou,
  • Yaling An,
  • Yuxuan Han,
  • Kefang Liu,
  • Xin Zhao,
  • Lianpan Dai,
  • Peiyi Wang,
  • Guizhen Wu,
  • Jianxun Qi,
  • Kun Xu,
  • George F Gao

DOI
https://doi.org/10.1371/journal.ppat.1011659
Journal volume & issue
Vol. 19, no. 9
p. e1011659

Abstract

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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.