The human IGHD3-22 encoded motif contributes to broad reactivity of anti-SARS-CoV-2 antibodies

Abstract

Abstract The continuous evolution of SARS-CoV-2 coronavirus, the etiological agent of COVID-19, has resulted in the accumulation of mutations that may either escape from host immunity or increase its transmissibility. Cross-neutralizing antibodies targeting highly conserved sites of sarbecoviruses are critical to combat these SARS-CoV-2 variants and other related sarbecoviruses. However, these antibodies are apparently less frequently isolated, although robust antibody responses have been observed in many COVID-19 patients and vaccinees. Here, we describe a structural motif encoded by the human IGHD3-22 gene that targets a functionally conserved surface on the spike protein across sarbecoviruses. We compared antibody structures binding to this conserved site and found a recurrent YYDRxG motif within cross-neutralizing antibodies that mediates strong polar and hydrophobic interactions to the receptor-binding domain of SARS-CoV-2. A computational search using the YYDRxG pattern with publicly available antibody sequences yield over 100 such antibodies with many that broadly neutralize SARS-CoV-2 variants of concern, as well as other sarbecoviruses. Our analysis revealed a common convergent solution to counteract sarbecoviruses, but which seems to be elicited less frequently than other responses by the human humoral immune system. Nevertheless, statistical analysis shows that these YYDRxG sequences are commonly elicited in COVID-19 patients and vaccinees, providing a promising strategy that could be implemented in broad anti-sarbecovirus antibody identification and for pan-sarbecovirus vaccine development.