Rationally Designed Immunogens Enable Immune Focusing Following SARS-CoV-2 Spike Imprinting

Eliciting antibodies to surface-exposed viral glycoproteins can generate protective responses that control and prevent future infections. Targeting conserved sites may reduce the likelihood of escape limit spread related viruses with pandemic potential. Here, we leveraged rational immunogen design focus humoral on epitopes. Using glycan engineering epitope scaffolding, directed murine serum antibody receptor binding motif (RBM) domain (RBD) epitopes in context SARS-CoV-2 spike imprinting. Whereas all engineered immunogens elicited a robust SARS-CoV-2-neutralizing response, RBM-focusing exhibited increased potency against sarbecoviruses, SARS-CoV, WIV1-CoV, RaTG13-CoV, SHC014-CoV;structural characterization representative defined epitope. Furthermore, RBM-focused sera conferred protection challenge. Thus, RBM focusing is promising strategy elicit breadth across emerging sarbecoviruses without compromising protection. Broadly, these strategies are adaptable other for targeting