Targeted isolation of panels of diverse human broadly neutralizing antibodies against SARS-like viruses

He, Wan-ting; Musharrafieh, Rami; Song, Ge; Dueker, Katharina; Callaghan, Sean; Yong, Peter; Beutler, Nathan; Torres, Jonathan L.; Volk, Reid M.; Zhou, Panpan; Yuan, Meng; Liu, Hejun; Anzanello, Fabio; Parren, Mara; Garcia, Elijah; Rawlings, Stephen A.; Smith, Davey M.; Wilson, Ian A.; Ward, Andrew B.; Rogers, Thomas F.; Burton, Dennis R.; Andrabi, Raiees

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 also show strong binding to non-ACE2-using sarbecoviruses. The bnAbs are equally effective against SARS-CoV-2 VOCs compared to the original virus. 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. 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 basis for effective design of pan-sarbecovirus vaccines.