A type of cryptic epitope-binding antibody on SARS-CoV-2 RBD retains the neutralization against SARS-CoV-2 variants and sarbecoviruses

The continuing emergence of SARS-CoV-2 variants has posed a great challenge to vaccination strategies. Therefore, the development of broad-spectrum protective antibodies and universal vaccines remains urgently needed. In this study, we isolated two broadly neutralizing mAbs, nCoV-R48 and nCoV-R70, from a vaccinated person. These two mAbs neutralize the SARS-CoV-2 prototype and variants, including Alpha, Beta, Gamma, Delta, BQ1.1, XBB, BF.7, and the recently emerged KP.2. Moreover, nCoV-R48 and nCoV-R70 also neutralize representative sarbecoviruses GD/1/2019 and SARS-CoV. We determined the epitopes of these two mAbs using X-ray crystallography and Cryo-EM. The structural analysis shows that nCoV-R48 and nCoV-R70 recognize the same cryptic epitope on the RBD. These antibodies belong to the RBD-8 class, which exhibits broad neutralizing potency by inducing S1 shedding. This cryptic epitope provides guidance for developing universal therapeutic antibodies against COVID-19.