Understanding vaccine-elicited protection against SARS-CoV-2 variants and other sarbecoviruses is
key for guiding public health policies. We show that a clinical stage multivalent SARS-CoV-2 spike
receptor-binding domain nanoparticle vaccine (RBD-NP) protects mice from SARS-CoV-2 challenge
after a single immunization, indicating a potential dose-sparing strategy. We benchmarked serum
neutralizing activity elicited by RBD-NP in non-human primates against a lead prefusion-stabilized
SARS-CoV-2 spike (HexaPro) using a panel of circulating mutants. Polyclonal antibodies elicited by
both vaccines are similarly resilient to many RBD residue substitutions tested although mutations at
and surrounding position 484 have negative consequences for neutralization. Mosaic and cocktail
nanoparticle immunogens displaying multiple sarbecovirus RBDs elicit broad neutralizing activity in
mice and protect mice against SARS-CoV challenge even in the absence of SARS-CoV RBD in the
vaccine. This study provides proof of principle that multivalent sarbecovirus RBD-NPs induce
heterotypic protection and motivates advancing such broadly protective sarbecovirus vaccines to the
clinic