Abstract The emergence of SARS-CoV in 2003 and SARS-CoV-2 in 2019 highlights the need to develop universal vaccination strategies against the broader Sarbecovirus subgenus. Using chimeric spike designs, we demonstrate protection against challenge from SARS-CoV, SARS-CoV-2, SARS-CoV-2 B.1.351, bat CoV (Bt-CoV) RsSHC014, and a heterologous Bt-CoV WIV-1 in vulnerable aged mice. Chimeric spike mRNAs induced high levels of broadly protective neutralizing antibodies against high-risk Sarbecoviruses. In contrast, SARS-CoV-2 mRNA vaccination not only showed a marked reduction in neutralizing titers against heterologous Sarbecoviruses, but SARS-CoV and WIV-1 challenge in mice resulted in breakthrough infection. Chimeric spike mRNA vaccines efficiently neutralized D614G, UK B.1.1.7., mink cluster five, and the South African B.1.351 variant of concern. Thus, multiplexed-chimeric spikes can prevent SARS-like zoonotic coronavirus infections with pandemic potential. Sentence Chimerized RBD, NTD, and S2 spike mRNA-LNPs protect mice against epidemic, zoonotic, and pandemic SARS-like viruses

Chimeric spike mRNA vaccines protect against Sarbecoviruschallenge in mice