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Proc Natl Acad Sci U S A
. 2026 Aug 11;123(32):e2535385123.
doi: 10.1073/pnas.2535385123. Epub 2026 Aug 5.
A structural and mechanistic atlas of NTD antibody neutralization and immune escape across SARS-CoV-2 prototype and its (sub-)variants
Jianjie Zhou # 1 , Wenyu Li # 1 2 , Xiaoyun Wang # 1 3 , Junqing Sun 1 , Shuxin Guo 4 5 , Xiaoyu Rong 1 , Zhou Tong 1 , Lianpan Dai 1 , William Jun Liu 6 , Jianxun Qi 1 3 , George Fu Gao 1 4 6 , Qihui Wang 1 3
Affiliations
The N-terminal domain (NTD) of the SARS-CoV-2 spike (S) is a critical antibody target, yet its epitope organization, neutralization mechanisms, and immune evasion strategies remain incompletely resolved. Here, we classify NTD antibodies into nine spatially distinct classes (designated as NTD-1 to NTD-9), including a cryptic epitope defined here (NTD-8). Mechanistic studies reveal that NTD-5 and NTD-9 antibodies neutralize by inducing S1 shedding, thereby extending this mechanism to selected NTD-directed antibodies. Format profiling shows that while most NTD antibodies require bivalency, selected antibodies from NTD-3, NTD-5, and NTD-9 retain neutralizing activity in Fab form. Profiling 41 antibodies across prototype, Delta, and 17 Omicron subvariants defines an epitope-resolved escape landscape and enables dissection of three convergent evasion strategies: contact residue disruption, glycan shielding, and conformational remodeling. Notably, the KP.3.1.1 subvariant uses a dual escape mechanism in which ∆S31 introduces N30 glycosylation and substantially remodels the S27-R34 region, undermining recognition by both NTD-5 and NTD-9 antibodies. These findings provide a structural and mechanistic framework for rational vaccine and antibody design resilient to antigenic drift.
Keywords: N-terminal domain; NTD antibody epitope classification; SARS-CoV-2; immune escape; neutralization mechanism.
. 2026 Aug 11;123(32):e2535385123.
doi: 10.1073/pnas.2535385123. Epub 2026 Aug 5.
A structural and mechanistic atlas of NTD antibody neutralization and immune escape across SARS-CoV-2 prototype and its (sub-)variants
Jianjie Zhou # 1 , Wenyu Li # 1 2 , Xiaoyun Wang # 1 3 , Junqing Sun 1 , Shuxin Guo 4 5 , Xiaoyu Rong 1 , Zhou Tong 1 , Lianpan Dai 1 , William Jun Liu 6 , Jianxun Qi 1 3 , George Fu Gao 1 4 6 , Qihui Wang 1 3
Affiliations
- PMID: 42555640
- DOI: 10.1073/pnas.2535385123
The N-terminal domain (NTD) of the SARS-CoV-2 spike (S) is a critical antibody target, yet its epitope organization, neutralization mechanisms, and immune evasion strategies remain incompletely resolved. Here, we classify NTD antibodies into nine spatially distinct classes (designated as NTD-1 to NTD-9), including a cryptic epitope defined here (NTD-8). Mechanistic studies reveal that NTD-5 and NTD-9 antibodies neutralize by inducing S1 shedding, thereby extending this mechanism to selected NTD-directed antibodies. Format profiling shows that while most NTD antibodies require bivalency, selected antibodies from NTD-3, NTD-5, and NTD-9 retain neutralizing activity in Fab form. Profiling 41 antibodies across prototype, Delta, and 17 Omicron subvariants defines an epitope-resolved escape landscape and enables dissection of three convergent evasion strategies: contact residue disruption, glycan shielding, and conformational remodeling. Notably, the KP.3.1.1 subvariant uses a dual escape mechanism in which ∆S31 introduces N30 glycosylation and substantially remodels the S27-R34 region, undermining recognition by both NTD-5 and NTD-9 antibodies. These findings provide a structural and mechanistic framework for rational vaccine and antibody design resilient to antigenic drift.
Keywords: N-terminal domain; NTD antibody epitope classification; SARS-CoV-2; immune escape; neutralization mechanism.