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<p>The emergence of coronavirus variants that evade vaccine protection poses a serious threat to both human health and animal husbandry, including the novel SADS-CoV, an emerging bat-derived coronavirus. Herein, we introduce a "phylogenetic antigen reconstruction" strategy to design a trimeric ancestral spike (<sup>tA</sup>S) antigen sequence based on evolutionary spike protein analysis. Delivered via nucleoside-modified mRNA-LNP, the <sup>tA</sup>S mRNA vaccine induced robust and broad-spectrum immunity in mice and sows, conferring complete protection against lethal SADS-CoV challenges in their F1 offspring. Actively immunized piglets also exhibited full resistance to fatal infection. Importantly, the vaccine-elicited antibodies indicated efficient species cross-reactivity blocking SADS-CoV replication in human, monkey-derived cells, and chicken primary cells, and maintained efficacy for 140&#xa0;days. This study highlights the potential of integrating ancestral antigen design with mRNA-LNP technology to address coronavirus evolution, offering a scalable solution for livestock protection and proactive control of emerging zoonotic coronaviruses.</p> Graphical abstract <p></p>

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A trimer ancestral spike-based mRNA vaccine confers cross-generational protection against SADS-CoV

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年11月4日

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  • Teng Zhang,
  • Jiale Yao,
  • Xinchun Guo,
  • Chaoliang Leng,
  • Saige Liu,
  • Yaxin Chen,
  • Jucai Wang,
  • Mengsi Sun,
  • Hongfu Ma,
  • Longfa Li,
  • Kankan Yang,
  • Yong Wang,
  • Gaiping Zhang,
  • Lunguang Yao

摘要

The emergence of coronavirus variants that evade vaccine protection poses a serious threat to both human health and animal husbandry, including the novel SADS-CoV, an emerging bat-derived coronavirus. Herein, we introduce a "phylogenetic antigen reconstruction" strategy to design a trimeric ancestral spike (tAS) antigen sequence based on evolutionary spike protein analysis. Delivered via nucleoside-modified mRNA-LNP, the tAS mRNA vaccine induced robust and broad-spectrum immunity in mice and sows, conferring complete protection against lethal SADS-CoV challenges in their F1 offspring. Actively immunized piglets also exhibited full resistance to fatal infection. Importantly, the vaccine-elicited antibodies indicated efficient species cross-reactivity blocking SADS-CoV replication in human, monkey-derived cells, and chicken primary cells, and maintained efficacy for 140 days. This study highlights the potential of integrating ancestral antigen design with mRNA-LNP technology to address coronavirus evolution, offering a scalable solution for livestock protection and proactive control of emerging zoonotic coronaviruses.

Graphical abstract