Jul 2026· Advancement of science· 0 citations· 58 references
Medicine
TL;DR
The structural basis by which specific mutations enhance cross‐variant recognition of SARS‐CoV‐2 is defined, highlighting the underappreciated breadth encoded within the naïve B‐cell repertoire and providing a conceptual framework for engineering and eliciting antibody responses resilient to future antigenic drift.
Abstract
ABSTRACT Rapid antigenic drift of the SARS‐CoV‐2 receptor‐binding domain (RBD) underlies immune escape and continues to challenge the durability of antibody‐mediated protection. Among the major classes of RBD‐directed antibodies, germline‐encoded IGHV3‐53 responses are highly potent against early SARS‐CoV‐2 variants but are generally compromised by Omicron‐associated mutations. Here, we identify an intrinsically cross‐reactive IGHV3‐53 germline antibody that recognizes multiple pre‐Omicron variants, including SARS‐CoV‐2 wild‐type, Alpha, and Delta. Notably, we demonstrate that targeted somatic evolution can further expand this breadth to overcome the immune escape of different Omicron variants. Guided by integrated structural and sequence analyses, we introduce four somatic mutations (G26E, T28I, S53P, and Y58F) into the germline antibody, resulting in markedly enhanced binding and neutralization of Omicron BA.1, and BA.4/5. High‐resolution crystal structures reveal that these mutations re‐establish interactions disrupted by substitutions in the Omicron RBD and improve binding at a remodeled epitope interface. Collectively, our findings define the structural basis by which specific mutations enhance cross‐variant recognition of SARS‐CoV‐2. This work highlights the underappreciated breadth encoded within the naïve B‐cell repertoire and provides a conceptual framework for engineering and eliciting antibody responses resilient to future antigenic drift.
ABSTRACT Objective Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) continuously evolves to evade antibodies elicited by prior infection or vaccination. Most IGHV3‐53/3‐66 public antibodies potently neutralize the prototype strain, but show limited activity against recent variants. However, some acquire broad neutralizing activity through accumulation of somatic hypermutations. We assessed whether non‐broadly neutralizing IGHV3‐53/3‐66 antibodies could mature into broadly neutralizing antibodies. Methods A series of mutant antibodies was constructed based on the IGHV3‐53/3‐66 antibodies, 9‐105 and K4‐66. Neutralizing and binding activities were compared with the original antibodies. Results Introducing six mutations frequently observed in broadly neutralizing antibodies markedly improved the neutralization and binding of 9‐105 against Omicron variants. Introducing Y66F into K4‐66 enhanced neutralization of variants including BA.4/5 and JN.1. Conclusion These findings show that mutations within the IGHV3‐53/3‐66 gene can enhance antibody breadth and potency, suggesting the potential of vaccine strategies to promote the maturation of these widely prevalent public antibodies.
Takeo Kuwata, K. Okazaki, Hiroshi Morioka et al.· Immunity, Inflammation and D...· 0 citations
Two human-derived monoclonal antibodies are characterized that recognize conserved epitopes on the SARS-CoV-2 RBD and retain activity across antigenically distinct variants, and conserved, mutationally constrained epitopes may serve as targets for vaccines designed to elicit antibody responses resilient to ongoing SARS-CoV-2 evolution and future sarbecovirus emergence.
M. Abernathy, William B. Foreman, Jasmyn A. Lopez et al.· bioRxiv· 0 citations
Despite widespread COVID‐19 vaccination, emerging SARS‐CoV‐2 variants continue to evade neutralizing responses. To determine how exposure history influences neutralizing breadth against SARS‐CoV‐2, plasma collected from 46 participants in the Clinical, Virological and Immunological COVID‐19 study cohort (CVIC) was analyzed. Participants were categorized into six groups reflecting distinct SARS‐CoV‐2 exposure profiles: individuals infected with either Wuhan‐Hu‐1 or Delta variants, infection‐naïve individuals who received two or four doses of mRNA vaccine (including a bivalent BA.4/5 booster), previously infected individuals subsequently vaccinated, and individuals with four vaccine doses plus breakthrough Omicron infection. Neutralizing breadth was assessed using a pseudoparticle panel representing major variants of interest/concern (Alpha, Beta, Gamma, Delta, Lambda, and Kappa) and a panel of representative Omicron subvariants (BA.1, BA.2, BA.5, BA.2.75, BA.2.86, BQ.1, XBB.1.5, EG.5, HV.1, and JN.1). Primary exposure through infection elicited potent homologous but variable heterologous neutralization, whereas vaccination alone induced lower yet more consistent responses across variants. Additional antigenic exposures, through either repeated vaccination or breakthrough infection, markedly enhanced cross‐variant neutralization, with the greatest potency and breadth of neutralizing responses observed in individuals with the highest number of SARS‐CoV‐2 exposures. Nonetheless, neutralizing activity against more recently emerged Omicron subvariants, including EG.5, HV.1, and JN.1, remained low. Taken together, these findings demonstrate that both the nature and number of antigenic exposures can shape the potency and breadth of SARS‐CoV‐2 neutralizing responses. While cumulative exposures improve cross‐variant immunity, ongoing viral evolution continues to erode neutralization capacity, emphasizing the need for continued variant monitoring and periodic vaccine reformulation to maintain population‐level protection.
Greta Vizgirda, Alexander P. Underwood, Ulrik Fahnøe et al.· Journal of Medical Virology· 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
Mechanistic studies reveal that NTD-5 and NTD-9 antibodies neutralize by inducing S1 shedding, thereby extending this mechanism to selected NTD-directed antibodies and providing a structural and mechanistic framework for rational vaccine and antibody design resilient to antigenic drift.
Jian-Jie Zhou, Wen-Yu Li, Xiaoyu Wang et al.· Proceedings of the National...· 0 citations
Population immune pressure from vaccination and prior infection continues to drive the evolution of SARS-CoV-2. Systematic characterization of RBD mutations under complex immune backgrounds is essential for understanding viral adaptation and evolutionary trajectories. Here, we applied a deep mutational scanning (DMS) to comprehensively map the neutralization escape landscape of the Omicron variant JN.1 and its descendant lineage XEC, under immune pressure from individuals who experienced Omicron breakthrough infections following three doses of inactivated vaccines. A neutralization escape map for the single amino acid substitutions in the RBD of JN.1 or XEC was generated, and the escape efficiency of each mutation was determined. The results show that RBD escape mutations are hierarchically organized: low-intensity signals are widespread, whereas high-intensity escape is confined to a few key sites. These escape mutations are not confined solely to the receptor-binding motif (RBM) but are broadly distributed across the entire RBD. Many escape sites could accommodate multiple amino acid substitutions. Integration of DMS data with genomic surveillance of circulating variants from 2024 to 2025 revealed significant overlap between experimentally identified escape sites and mutations observed in natural isolates. This overlap increased substantially in 2025, with site concordance rising from 27.17% and 26.81% to 45.09% and 47.10% for JN.1 and XEC, respectively. The natural prevalence of these escape mutations is further shaped by factors such as receptor-binding affinity, protein stability, and epistatic interactions. Overall, our findings suggest that SARS-CoV-2 antigenic evolution follows the pattern of multiple pathways within a constrained space, providing new insights into the adaptive mechanisms of Omicron-derived variants under hybrid immune pressure.
Chengwei Shao, Jian-Guang Fu, Fei Deng et al.· Microorganisms· 0 citations
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