228: Two non-competing H3N2 stem antibodies reveal evolving antigenicity

Gopal AB et al., Nat Commun - Structural and functional characterization of two group 2 H3 HA stem antibodies, 2F02 and AG2-G02, shows distinct non-overlapping epitopes, protection in mice, and antigenic changes driven by HA2 position 32 that limit AG2-G02 binding. Key terms: influenza H3N2, hemagglutinin stem, broadly neutralizing antibodies, antigenic evolution, vaccine design.

Study Highlights:
Cryo-EM structures show 2F02 targets the central stem epitope while AG2-G02 targets the lower stem epitope and the two can bind concurrently to an HA trimer. Both antibodies neutralize diverse H3 strains in vitro and provide prophylactic protection in mice, with Fc-mediated effector functions contributing to in vivo efficacy. AG2-G02 binding is lost to recent human H3N2 HAs carrying R32 at HA2, whereas T32 or I32 permit binding. Human plasma binding profiles mirror the historical shift from T32 to I32 to R32, indicating altered population antigenicity of the lower stem over time.

Conclusion:
Natural evolution at HA2 position 32 has changed the antigenicity of the H3N2 HA lower stem, impacting binding of certain group 2 stem antibodies and informing vaccine design strategies

Music:
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First author:
Gopal AB

Journal:
Nat Commun

DOI:
10.1038/s41467-025-65595-1

Reference:
Gopal AB, Lv H, Ouyang WO, Teo QW, Luo Y, Tang YS, Luo M, Mok CKP, Wu NC. Characterization of two non-competing antibodies to influenza H3N2 hemagglutinin stem reveals its evolving antigenicity. Nat Commun. 2025;16:10557. https://doi.org/10.1038/s41467-025-65595-1

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

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QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-12-14.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited sections discussing: identification and epitopes of AG2-G02 and 2F02; structural/functional characterization; concurrent binding to an HA trimer; antigenic evolution at HA2 position 32; Fc-mediated protection in vivo; serological/population memory implications; vaccine-design implications.
- transcript topics: Identification and non-overlapping epitopes of AG2-G02 (lower stem) and 2F02 (central stem); Cryo-EM structural analysis and concurrent binding to an HA trimer; Antigenic evolution at HA2 position 32 (T32, I32, R32) and its effect on binding; In vivo Fc-mediated protection and importance of Fc effector functions; Serological analysis across pre-2003 adults, post-2011 adults, and post-2011 infants; Implications for universal influenza vaccine design targeting multiple stem epitopes

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 7
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- AG2-G02 targets the lower stem epitope; 2F02 targets the central stem epitope; epitopes are distinct and non-overlapping
- AG2-G02 and 2F02 can bind concurrently to the same HA trimer (non-competitive binding with six Fabs on a single trimer)