Antisera and antivirals targeting the conserved domains in SARS-CoV-2 S2 subunit are effective against ACE2-using MERSr-CoVs with spillover potential

• S2 subunit remains high conserved throughout coronavirus evolution. • BA.5/BF.7-infection induces weak cross-immune response against MERS-related coronaviruses (MERSr-CoVs) in humans. • HR1LS based on conserved S2 elicits strong cross-immune response to MERSr-CoVs in mice. • Conserved domains in S2 represent ideal targets for pan-CoV vaccines and antivirals.