tetano
Editor, Senior Moderator
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[SUP] #[/SUP][SUP] 1 [/SUP], Wenyu Li[SUP] #[/SUP][SUP] 1 2 [/SUP], Xiaoyun Wang[SUP] #[/SUP][SUP] 1 3 [/SUP], Junqing Sun[SUP] 1 [/SUP], Shuxin Guo[SUP] 4 5 [/SUP], Xiaoyu Rong[SUP] 1 [/SUP], Zhou Tong[SUP] 1 [/SUP], Lianpan Dai[SUP] 1 [/SUP], William Jun Liu[SUP] 6 [/SUP], Jianxun Qi[SUP] 1 3 [/SUP], George Fu Gao[SUP] 1 4 6 [/SUP], Qihui Wang[SUP] 1 3 [/SUP]
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[SUP] #[/SUP][SUP] 1 [/SUP], Wenyu Li[SUP] #[/SUP][SUP] 1 2 [/SUP], Xiaoyun Wang[SUP] #[/SUP][SUP] 1 3 [/SUP], Junqing Sun[SUP] 1 [/SUP], Shuxin Guo[SUP] 4 5 [/SUP], Xiaoyu Rong[SUP] 1 [/SUP], Zhou Tong[SUP] 1 [/SUP], Lianpan Dai[SUP] 1 [/SUP], William Jun Liu[SUP] 6 [/SUP], Jianxun Qi[SUP] 1 3 [/SUP], George Fu Gao[SUP] 1 4 6 [/SUP], Qihui Wang[SUP] 1 3 [/SUP]
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.