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Striking antibody evasion by emerging circulating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants drives the identification of broadly neutralizing antibodies (bNAbs). However, how a bNAb acquires increased neutralization breadth during antibody evolution is still elusive. Here, we identify a clonally related antibody family from a convalescent individual. One of the members, XG005, exhibits potent and broad neutralizing activities against SARS-CoV-2 variants, while the other members show significant reductions in neutralization breadth and potency, especially against the Omicron sublineages. Structural analysis visualizing the XG005-Omicron spike binding interface reveals how crucial somatic mutations endow XG005 with greater neutralization potency and breadth. A single administration of XG005 with extended half-life, reduced antibody-dependent enhancement (ADE) effect, and increased antibody product quality exhibits a high therapeutic efficacy in BA.2- and BA.5-challenged mice. Our results provide a natural example to show the importance of somatic hypermutation during antibody evolution for SARS-CoV-2 neutralization breadth and potency. [Display omitted] • XG005 antibody is a potent and broad neutralizer against SARS-CoV-2 variants • XG005 family members exhibit reduced neutralization potency and breadth • Structure analysis and comparison identify the key amino acid residues of XG005 • Optimized XG005 exhibits a high therapeutic efficacy in vivo Wu et al. identify that XG005, but not its family members, is a potent and broad SARS-CoV-2 neutralizer and exhibits a high therapeutic efficacy. Structural analysis identifies the key residues of XG005. This provides a natural example to show the importance of somatic hypermutation for SARS-CoV-2 neutralization breadth and potency. [ABSTRACT FROM AUTHOR]

• A 4-aa insertion in the COE region of S protein forming an extra alpha helix was firstly identified in PEDV. • A 4-aa insertion in the COE region of S protein may influence the VN antibody reactivity. • PEDV LNsy was a natural recombination between GDS13 and GDS46 strains. In recent years, a novel, highly virulent variant of porcine epidemic diarrhea virus (PEDV) has emerged, causing substantial economic losses to the pork industry worldwide. In this study, a PEDV strain named LNsy was successfully isolated in China. Phylogenetic analysis based on the whole genome revealed that PEDV LNsy belonged to the G2 subtype. For the first time, a unique four amino acids (4-aa) insertion was identified in the COE region of the spike (S) protein (residues 499–640), resulting in an extra alpha helix in the spatial structure of the COE region. To determine changes in virus-neutralization (VN) antibody reactivity of the virus, polyclonal antibodies (PAbs) against the S protein of different subtypes were used in a VN test. Both PAbs against the S protein of the G1 and G2 subtype showed reduced VN reactivity to PEDV LNsy. Further, recombination analyses revealed that PEDV LNsy was the result of recombination between PEDV GDS13 and GDS46 strains at the genomic breakpoints (nt 17,959−20,594 in the alignment) in the ORF1b gene of the genomes. Pathological examination showed gross morphological pathological changes in the gut, including significant villus atrophy and shedding of the infected piglets. These results indicated that a 4-aa insertion in the COE region of the S protein may have partly altered the profiles of VN antibodies and thus it will be important to develop vaccine candidates to resist wild virus infection and to monitor the genetic diversity of PEDV. [ABSTRACT FROM AUTHOR]