An elegant paper by Yuan et al., recently published in Science, provides novel insights into the molecular features of neutralizing antibody responses to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). 1ccording to the principles of the "reverse vaccinology 2.0" postulated by Burton et al., 2 the authors explore the interactions between potent neutralizing antibodies from naturally infected donors and their target epitopes, providing key information about structural motifs and binding mode that may facilitate the design of vaccine antigens capable to elicit the immune response against SARS-CoV-2.The vast majority of anti-CoV neutralizing antibodies have been found to specifically target the receptor-binding domain (RBD) of the viral spike (S) protein, thus hindering SARS-CoV-2 binding to the host angiotensin converting enzyme 2 (ACE2) receptor and viral entry. 3uan and collaborators analyzed 294 anti-SARS-CoV-2 antibodies from COVID-19 patients and demonstrated that among these antibodies the immunoglobulin heavy variable 3-53 (IGHV3-53) represents the most frequently used IGHV gene, with 10% encoded by IGHV3-53.In the cohort investigated by Yuan et al., IGHV3-53 antibodies have been reported to be more potent compared to other germlines, as well as to display lower somatic mutation rates.The authors determined the crystal structures of two antibodies, CC12.1 and CC12.3, encoded by a common IGHV3-53 gene, but belonging to different clonotypes, in order to define the structural features, and to add favorable properties for RBD recognition to IGHV3-53.Notably, among the antibodies tested against live replicating SARS-CoV-2 and pseudovirus, CC12.1 and CC12.3 (IC 50 ~20 ng/mL), isolated from COVID-19 patients, are among the top four highly potent neutralizing antibodies, with a binding affinity (K d ) of Fabs CC12.1 and CC12.3 to SARS-CoV-2 RBD of 17 and 14 nM, respectively. 1,4By performing competitions experiments, Yuan et al. demonstrated that both CC12.1 and CC12.3 bind to the ACE2 binding site on SARS-CoV-2 RBD with an identical angle of approach.Among 17 ACE2 binding residues on RBD, 15 and 11 are within the epitopes of CC12.1 and CC12.3, respectively.Remarkably, several epitope residues are not conserved between SARS-CoV-2 and SARS-CoV, thus explaining, at least in part, the absence of antibody cross-reactivity between these two CoVs. 5Such evidence is consistent with data, reported by Ju et al, showing the lack of antibody cross-reactivity with RBDs not only from SARS-CoV, but also from middle east respiratory syndrome coronavirus (MERS-CoV), thus suggesting that SARS-CoV, SARS-CoV-2, and MERS-CoV are immunologically distinct. 5As