R1-32-like public antibodies, characterized by shared IGHV1-69/IGLV1-40 usage, are elicited in more than 50% of individuals with COVID-19 and have been implicated in driving recurrent mutations at L452SARS2 and F490SARS2 within their convergent epitope in the SARS-CoV-2 spike receptor-binding domain. These mutations effectively mediate escape from non-affinity-matured R1-32-like antibodies with germline-like sequences. Here, we characterize four affinity-matured human R1-32-like antibodies, C092, C807, BD56-104, and BD56-597, that tolerate L452SARS2 and F490SARS2 mutations. We show that this tolerance arises from residues introduced by somatic hypermutation at convergent positions across multiple CDR loops and surrounding regions, thereby creating additional contacts that reinforce epitope binding. An unusual N354SARS2 glycosylation site, which emerged in BA.2.86 and became fixed in its descendants, is linked to escape from affinity-matured R1-32-like antibodies, implying ongoing selection by this public antibody class. Using an AI model trained on extensive neutralization data, we further identified ZL525, an ultrapotent human R1-32-like antibody with pan-SARS-CoV-2 variant activity, including against the highly evasive KP.3 variant carrying the N354SARS2 glycosylation, and broad sarbecovirus cross-reactivity extending to SARS-CoV-1. Together, these findings show how affinity maturation enables public antibodies to adapt to viral antigenic drift, reveal their role in shaping SARS-CoV-2 antigenic evolution, and demonstrate the potential of AI-empowered strategies for discovering broadly neutralizing antibodies.
Chuan-Ying Niu, Xiao-Han Huang, Qi-Hong Yan et al.· PLoS Biology· 0 citations
ABSTRACT The rapid spread of immune‐evasive viral variants, exemplified by SARS‐CoV‐2, highlights the urgent need for broad‐spectrum coronavirus vaccines. Although multimeric display of the receptor‐binding domain (RBD) using exogenous scaffolds improve immune responses, such approaches may elicit off‐target immune responses against the scaffolds themselves and remain limited by rapid RBD antigenic drift. Here, we report the rational design of a self‐assembling trimeric subunit vaccine, termed RBD‐heptad repeat 1 (HR1)‐stem helix (SH)‐heptad repeat 2 (HR2) (RHS), which integrates the JN.1 RBD with a highly conserved SH epitope from SARS‐CoV‐2 within a native HR1‐HR2 trimeric scaffold via optimized linkers. RHS exhibits high structural stability, efficient trimerization, and enhanced antigen presentation. In mice, RHS elicits robust humoral and cellular immune responses, including potent cross‐ neutralizing antibodies against diverse SARS‐CoV‐2 variants and pan‐betacoronavirus SH‐specific antibodies. In K18‐hACE2 mice, RHS confers strong protection against both antigen‐matched and antigen‐mismatched Omicron variants, while intranasal immunization induces potent mucosal IgA and IgG responses. Furthermore, the modular RHS platform is readily adaptable to antigens from SARS‐CoV and MERS‐CoV, underscoring its versatility for pan‐coronavirus vaccine development. Together, these findings establish RHS as a generalizable strategy for overcoming viral immune evasion and advancing next‐generation vaccine design.
Xi-Kui Sun, Junhao Fan, Xiaolu Xie et al.· Advancement of science· 0 citations
We use cookies to run the site and, with your consent, for analytics and to show ads.
See our Cookie Policy.
