The emergence of current SARS-CoV-2 variants of concern (VOCs) and potential future spillovers of SARS-like coronaviruses into humans pose a major threat to human health and the global economy 1-7 . Development of broadly effective coronavirus
vaccines that can mitigate these threats is needed 8, 9 . Notably, several recent studies have revealed that vaccination of recovered
COVID-19 donors results in enhanced nAb responses compared to
SARS-CoV-2 infection or vaccination alone 10-13 . Here, we utilized a targeted
donor selection strategy to isolate a large panel of
broadly neutralizing antibodies (
bnAbs) to sarbecoviruses from two such donors. Many of the
bnAbs are remarkably effective in neutralization against sarbecoviruses that use ACE2 for viral entry and a substantial fraction also show notable binding to non-ACE2-using sarbecoviruses. The
bnAbs are equally effective against most SARS-CoV-2 VOCs and many neutralize the Omicron variant. Neutralization breadth is achieved by
bnAb binding to
epitopes on a relatively conserved face of the receptor binding domain (RBD) as opposed to strain-specific nAbs to the receptor binding site that are commonly elicited in
SARS-CoV-2 infection and vaccination 14-18 . Consistent with targeting of conserved sites, select RBD
bnAbs exhibited in vivo protective efficacy against diverse SARS-like coronaviruses in a prophylaxis challenge model. The generation of a large panel of potent
bnAbs provides new opportunities and choices for next-generation antibody prophylactic and therapeutic applications and, importantly, provides a molecular basis for effective design of pan-sarbecovirus
vaccines.