Enhancing RBD exposure and S1 shedding by an extremely conserved SARS-CoV-2 NTD epitope
Qianhui Zhu, Pan Liu, Shuo Liu, Can Yue & Xiangxi Wang
Abstract
Multiple waves of outbreaks of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have resulted in unprecedented public health and socioeconomic crises. After 4 years of primary as well as breakthrough infections and under the increased immune pressure exerted by vaccination, SARS-CoV-2 has evolved into multiple variants that displayed either enhanced transmissibility or immune escape properties. The currently dominant variant, BA.2.86 sublineages, with over 35 mutations in Spike (S), showed higher immune evasion and formed a distinct BA.2.86 sub-lineage branch via phylogenetic analysis of the primary sequences of S. To mitigate the spread of epidemic and impact on public health, a large number of monoclonal antibodies have been developed and deployed rapidly. The class I anti-RBD NAbs like DXP-604 and LY-CoV016, which bind RBD “up” conformation, can block ACE2 binding and have strong neutralizing activity. However, RBD is also a domain with a very high mutation frequency, rendering most clinically authorized anti-RBD NAbs ineffective against new BA.2.86 sublineages harboring such mutations.3 Among the four classes of anti-NTD NAbs (α, β, γ, δ), the first three classes antibodies have been evaded due to antigenic changes. Here, we found that two δ-class antibodies, XG2v046 and XGv280, which recognize the conserved epitope of NTD and can enhance RBD exposure and S1 shedding by promoting RBD to assume “up” conformation as a neutralizing mechanism, have broad-spectrum neutralizing effects on SARS-CoV-2 variants. Importantly, the new regulatory mechanism of the anti-NTD NAbs enables those anti-“up” RBD NAbs that were nearly ineffective against new variants to regain effectiveness and broaden their spectrum of activity. As such, the host immune system has developed an antiviral mechanism against ongoing antigenic variation via a secondary-protective barrier formed by a subset of conserved anti-NTD antibodies represented by XG2v046 and XGv280 in synergy with partial anti-RBD antibodies.
附件下载：
Enhancing RBD exposure and S1 shedding by an extremely conserved SARS-CoV-2 NTD epitope, Signal Transduct Tar, 28 Aug 2024
Signal Transduction and Targeted Therapy, 28 August, 2024, DOI：https://doi.org/10.1038/s41392-024-01940-y
Enhancing RBD exposure and S1 shedding by an extremely conserved SARS-CoV-2 NTD epitope
Qianhui Zhu, Pan Liu, Shuo Liu, Can Yue & Xiangxi Wang
Abstract
Multiple waves of outbreaks of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have resulted in unprecedented public health and socioeconomic crises. After 4 years of primary as well as breakthrough infections and under the increased immune pressure exerted by vaccination, SARS-CoV-2 has evolved into multiple variants that displayed either enhanced transmissibility or immune escape properties. The currently dominant variant, BA.2.86 sublineages, with over 35 mutations in Spike (S), showed higher immune evasion and formed a distinct BA.2.86 sub-lineage branch via phylogenetic analysis of the primary sequences of S. To mitigate the spread of epidemic and impact on public health, a large number of monoclonal antibodies have been developed and deployed rapidly. The class I anti-RBD NAbs like DXP-604 and LY-CoV016, which bind RBD “up” conformation, can block ACE2 binding and have strong neutralizing activity. However, RBD is also a domain with a very high mutation frequency, rendering most clinically authorized anti-RBD NAbs ineffective against new BA.2.86 sublineages harboring such mutations.3 Among the four classes of anti-NTD NAbs (α, β, γ, δ), the first three classes antibodies have been evaded due to antigenic changes. Here, we found that two δ-class antibodies, XG2v046 and XGv280, which recognize the conserved epitope of NTD and can enhance RBD exposure and S1 shedding by promoting RBD to assume “up” conformation as a neutralizing mechanism, have broad-spectrum neutralizing effects on SARS-CoV-2 variants. Importantly, the new regulatory mechanism of the anti-NTD NAbs enables those anti-“up” RBD NAbs that were nearly ineffective against new variants to regain effectiveness and broaden their spectrum of activity. As such, the host immune system has developed an antiviral mechanism against ongoing antigenic variation via a secondary-protective barrier formed by a subset of conserved anti-NTD antibodies represented by XG2v046 and XGv280 in synergy with partial anti-RBD antibodies.
文章链接：https://www.nature.com/articles/s41392-024-01940-y