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

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.