Increased receptor binding and spike glycosylation, remodeled immune escape of surging SARS-CoV-2 subvariant BA.3.2.2/RE.2.2/Cicada

• 成果类型: Article
• 署名作者: Li, Linjie; Nguyen, Linh; Qu, Hao; Wu, Qile; Gao, Pengyue; Li, Dedong; Li, Xinyu; Liu, Xueyuan; Jiang, Qiuyao; Liu, Kefang; Wong, Catherine C. L.; Gao, George Fu
• 署名单位: Chinese Academy of Sciences; Institute of Microbiology, CAS; Chinese Academy of Sciences; University of Chinese Academy of Sciences, CAS; Chinese Academy of Sciences; University of Science & Technology of China, CAS; Liaoning University; Shandong University; Shandong First Medical University & Shandong Academy of Medical Sciences; Beijing Life Science Academy; Chinese Academy of Medical Sciences - Peking Union Medical College; Peking Union Medical College Hospital; Tsinghua University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2614163123
• 发表日期: 2026-09-15
• 页码: e2614163123
• 关键词: sars-cov-2; BA.3.2.2; receptor-binding; immune escape; glycosylation; BA.2.86; virus

摘要

SARS-CoV-2 continues to evolve. The subvariant BA.3.2 (Cicada), a derivative of the Omicron BA.3 subtype first detected in late 2024, harbors multiple spike protein mutations, ORF7 and ORF8 deletions, and has recently evolved sublineages (BA.3.2.1 and BA.3.2.2), rendering it a critical target for epidemiological surveillance. The BA.3.2.2 sublineage, represented by RE.2.2, shows a marked upward trend in late 2025. Using surface plasmon resonance, we found that RE.2.2's spike (S) protein receptor-binding domain (RBD) exhibits relatively high affinity for human receptor angiotensin-converting enzyme 2, with structural analysis identifying the R493Q reverse mutation as the key determinant. Pseudovirus infection and antibody neutralization assays demonstrated that RE.2.2 exhibited a distinct neutralization profile compared to contemporaneous dominant subvariants. Notably, several antibodies that previously lacked neutralizing activity (e.g., S2K146 and L4.65) to other subvariants regained neutralizing potency against RE.2.2, which was associated with key mutations including G446D. Profiling of RE.2.2 RBD binding to ACE2 orthologs across species showed no significant difference in species tropism from the representative Omicron BA.1. Importantly, RE.2.2 exhibits the newly emerged N-linked glycosylation at spike protein N529 (absent in all other subvariants), a modification potentially associated with immune evasion or spike protein conformational dynamics. In addition, we corroborated the O-follow-N glycosylation observation as previously reported, where O-linked glycans preferentially localize near N-glycosylation sites, implying coordinated glycan organization as an extra layer of spike regulation. These findings illuminate the evolutionary characteristics, functional changes, and the constrained virus immune escape of BA.3.2.2 (RE.2.2), providing critical insights into antibody development and variant surveillance.