Halfmann_2026_Npj.Viruses_4_12

While vaccines against Middle East respiratory syndrome coronavirus (MERS-CoV) have had substantial preclinical and clinical development, few vaccine candidates target other related viruses with potential for human spillover within the Merbecovirus subgenus, like NL140422 and HKU4. We designed nanoparticle vaccines displaying the spike ectodomains of MERS-CoV, NL140422, and HKU4 and evaluated their immunogenicity and protective efficacy in mice. All vaccines elicited high IgG antibody titers against the corresponding vaccine spike protein with moderate cross-binding to mis-matched spike proteins as well. Only the MERS-CoV spike protein induced detectable neutralizing antibodies against MERS-CoV. In human dipeptidyl peptidase 4 (hDPP4) transgenic mice, vaccination with MERS-CoV spike protein completely inhibited MERS-CoV replication in the lungs and nasal turbinates. Vaccination with NL140422 and HKU4 spike proteins provided partial but significant reductions of lung viral loads after MERS-CoV challenge, highlighting their utility as components of a future pan-Merbecovirus vaccine.