{
  "abstract": "The recurrent emergence of the F456L substitution in SARS-CoV-2 Omicron sublineages has been associated with immune evasion, yet its impact on vaccine-induced immune responses remains poorly understood. Using a trimeric RBD-HR subunit vaccine platform, we investigated how residue 456 influences the functional immunogenicity of the receptor-binding domain (RBD). We found that the F456L substitution markedly reduced neutralizing antibody responses against multiple SARS-CoV-2 variants, despite maintaining comparable levels of total antigen-specific IgG, indicating a selective impairment of functional immunogenicity rather than overall antigenicity. Single-cell RNA sequencing and B-cell receptor (BCR) repertoire analyses further revealed that the F456L mutation weakened germinal center responses, reduced clonal expansion, and impaired repertoire remodeling of antigen-specific B cells. Structural modeling, biolayer interferometry, and calcium flux assays demonstrated that aromatic residues at position 456 promote effective germline BCR recognition and activation. Importantly, replacing the non-aromatic leucine residue with aromatic amino acids, including tyrosine or tryptophan, restored the neutralizing antibody-eliciting capacity of the antigen. Together, these findings identify aromaticity at residue 456 as a critical determinant of RBD functional immunogenicity and demonstrate how a single amino acid substitution can reshape B-cell responses and antibody quality. This work provides important insights for rational vaccine antigen design and advances our understanding of how site-specific mutations regulate antiviral immunity.",
  "abstract_shown": true,
  "affiliations": [
    "Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, People's Republic of China.",
    "Division of Gastrointestinal Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, China. toddy@scu.edu.cn.",
    "Department of Infection Control, West China Hospital, Sichuan University, Chengdu, China. toddy@scu.edu.cn.",
    "National Kunming High-level Biosafety Primate Research Center, Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Yunnan, China. lushuaiyao-km@163.com.",
    "Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, People's Republic of China. hecaihc@163.com.",
    "Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, People's Republic of China. lugw@scu.edu.cn.",
    "Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, People's Republic of China. xiaweiwei@scu.edu.cn."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 30,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Dandan Peng"
    },
    {
      "affs": [
        0
      ],
      "name": "Zimin Chen",
      "orcid": "0000-0002-2862-9674"
    },
    {
      "affs": [
        0
      ],
      "name": "Minyang Fu"
    },
    {
      "affs": [
        0
      ],
      "name": "Weiqi Hong",
      "orcid": "0000-0003-1668-2301"
    },
    {
      "affs": [
        0
      ],
      "name": "Mengzhe Dai",
      "orcid": "0009-0006-5734-2812"
    },
    {
      "affs": [
        0
      ],
      "name": "Hao Zeng"
    },
    {
      "affs": [
        0
      ],
      "name": "Sheng Lin"
    },
    {
      "affs": [
        0
      ],
      "name": "Hong Lei"
    },
    {
      "affs": [
        0
      ],
      "name": "Jingyun Yang",
      "orcid": "0000-0003-1908-1480"
    },
    {
      "affs": [
        0
      ],
      "name": "Jie Shi"
    },
    {
      "affs": [
        0
      ],
      "name": "Xiya Huang"
    },
    {
      "affs": [
        0
      ],
      "name": "Chunjun Ye"
    },
    {
      "affs": [
        0
      ],
      "name": "Furong Qin"
    },
    {
      "affs": [
        0
      ],
      "name": "Yu Zhang"
    },
    {
      "affs": [
        0
      ],
      "name": "Ying Hao"
    },
    {
      "affs": [
        0
      ],
      "name": "Binhan Wang"
    },
    {
      "affs": [
        0
      ],
      "name": "Wenyan Ren",
      "orcid": "0000-0001-6333-8496"
    },
    {
      "affs": [
        0
      ],
      "name": "Li Chen"
    },
    {
      "affs": [
        0
      ],
      "name": "Jian Liu"
    },
    {
      "affs": [
        0
      ],
      "name": "Aqu Alu",
      "orcid": "0000-0002-9981-0120"
    },
    {
      "affs": [
        0
      ],
      "name": "Yishan Lu"
    },
    {
      "affs": [
        0
      ],
      "name": "Xinyi Du"
    },
    {
      "affs": [
        0
      ],
      "name": "Jiong Li",
      "orcid": "0000-0002-3742-630X"
    },
    {
      "affs": [
        0
      ],
      "name": "Huashan Shi",
      "orcid": "0000-0002-9958-9892"
    },
    {
      "affs": [
        0
      ],
      "name": "Yuquan Wei"
    },
    {
      "affs": [
        1,
        2
      ],
      "name": "Yi Chen",
      "orcid": "0000-0002-5180-3490"
    },
    {
      "affs": [
        3
      ],
      "name": "Shuaiyao Lu",
      "orcid": "0000-0003-1675-9735"
    },
    {
      "affs": [
        4
      ],
      "name": "Cai He"
    },
    {
      "affs": [
        5
      ],
      "name": "Guangwen Lu",
      "orcid": "0000-0001-7568-592X"
    },
    {
      "affs": [
        6
      ],
      "name": "Xiawei Wei",
      "orcid": "0000-0002-6513-6422"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/49pef38b6nb0t.bib",
  "cited_by": 0,
  "doi": "10.1038/s41392-026-02939-3",
  "fulltext_url": "https://europepmc.org/articles/PMC13720146",
  "id": "49pef38b6nb0t",
  "issns": [
    "2095-9907",
    "2059-3635"
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  "landing_url": "https://europepmc.org/article/MED/42957648",
  "language": "eng",
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
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  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
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  "native_subjects": [
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      "heading",
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      "2725|SARS-CoV-2 and COVID-19 Research"
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  "pdf_url": "https://europepmc.org/articles/PMC13720146?pdf=render",
  "pmcid": "PMC13720146",
  "pmid": "42957648",
  "published": "2026-10-28",
  "publisher": "Nature Publishing Group",
  "ris": "https://research.draconitic.com/paper/49pef38b6nb0t.ris",
  "sources": [
    {
      "first_seen": "2026-10-31T12:21:21Z",
      "native_id": "MED:42957648",
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      "url": "https://europepmc.org/article/MED/42957648"
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    {
      "first_seen": "2026-11-02T12:23:59Z",
      "native_id": "PMC13720146",
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  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2725|SARS-CoV-2 and COVID-19 Research",
      "subfield": "infectious-disease"
    }
  ],
  "title": "Aromaticity at spike position 456 affects functional immunogenicity of SARS-CoV-2 Omicron variant receptor-binding domain.",
  "title_text": "Aromaticity at spike position 456 affects functional immunogenicity of SARS-CoV-2 Omicron variant receptor-binding domain.",
  "type": "peer-reviewed",
  "updated_at": "2026-11-03T12:21:05Z",
  "url": "https://research.draconitic.com/paper/49pef38b6nb0t",
  "venue": "Signal transduction and targeted therapy",
  "versions": []
}