Fusion protein pan-sarbecovirus vaccines elicit broadly protective immune responses targeting Clade 1a, 1b, and 3 sarbecoviruses

Broadly protective vaccines are needed to prevent health emergencies caused by emerging and circulating coronaviruses. Previously emerging viruses of the sarbecovirus subgenus (SARS-CoV (Severe Acute Respiratory Syndrome coronavirus) and SARS-CoV-2) have caused significant impacts on human and animal health and are anticipated to spillover again. We developed novel pan-sarbecovirus vaccines using next-generation technology producing plug-and-play fusion proteins. The scaffold of the platform links an N-terminal S1 domain with receptor binding domains (RBDs) from various targeted sarbecoviruses and is easily and quickly biomanufactured to be responsive to health emergencies. The design of our vaccines was guided by epitope prediction and molecular dynamic simulations. In vivo immunization studies showed the antigens induce broadly reactive T and B cell responses against several clades of sarbecoviruses including broadly neutralizing antibodies against pre-emergent sarbecoviruses using WIV16, PangGX, and PangGD pseudotyped viruses. Immunized Syrian hamsters were protected from mortality following heterologous challenge with SARS-CoV-2 Delta (Clade 1b) or SARS-CoV (Tor2) (Clade 1a). Significant reductions in tissue viral titer and lung pathology were observed in immunized animals compared to control groups (Pfizer BA4/5 vaccine and PBS). Taken together, our pan-sarbecovirus vaccines are protective against diverse sarbecoviruses and the platform is a strategy for addressing health emergencies.