tetano
Editor, Senior Moderator
J Med Virol
. 2026 Jan;98(1):e70790.
doi: 10.1002/jmv.70790.
Structural Adaptability of IgA and IgM Supports Broad SARS-CoV-2 Variant Neutralization
Yalcin Pisil[SUP] 1 [/SUP], Hisatoshi Shida[SUP] 1 [/SUP], Sandra Morales Ruiz[SUP] 1 [/SUP], Kyunghak Cho[SUP] 1 [/SUP], Metehan Gungor[SUP] 2 [/SUP], Zafer Yazici[SUP] 3 [/SUP], Tomoyuki Miura[SUP] 1 [/SUP]
Affiliations
Neutralizing emerging SARS-CoV-2 variants requires antibodies effective not only against epitope mutations but also under variable antigenic presentations. We assessed the neutralization capacity of the same anti-RBD monoclonal antibody (8A5) expressed as IgG, IgA, or IgM against 18 variants, identifying three neutralization classes: variants susceptible to all isotypes, variants resistant to IgG but sensitive to IgA/IgM, and variants resistant to all isotypes. Mutation analysis revealed that S371L-S373P-S375F disrupted IgG binding while partially preserving IgA/IgM activity, whereas L371F induced conformational changes abolishing all antibody interactions. Notably, some variants lacking these mutations still escaped IgG, suggesting geometric factors contribute to differential efficacy. To explore this, we performed negative-stain electron microscopy, which showed heterogeneous spike distributions across virion surfaces. ELISA assays with decreasing spike concentrations revealed that IgG binding declined sharply under low antigen density, while IgA and IgM maintained strong binding, reflecting their extended architecture and multivalency. These findings indicate that spatial adaptability, in addition to affinity, contributes to effective neutralization. IgA and IgM can engage antigens under sparse or conformationally altered conditions, suggesting potential advantages over IgG against certain variants. These insights may support the rational design of IgA- and IgM-based antibody therapeutics, highlighting their potential role in combating SARS-CoV-2 variants and other emerging viral pathogens.
Keywords: IgA; IgG; IgM; SARS‐CoV‐2; mAb; neutralization.
. 2026 Jan;98(1):e70790.
doi: 10.1002/jmv.70790.
Structural Adaptability of IgA and IgM Supports Broad SARS-CoV-2 Variant Neutralization
Yalcin Pisil[SUP] 1 [/SUP], Hisatoshi Shida[SUP] 1 [/SUP], Sandra Morales Ruiz[SUP] 1 [/SUP], Kyunghak Cho[SUP] 1 [/SUP], Metehan Gungor[SUP] 2 [/SUP], Zafer Yazici[SUP] 3 [/SUP], Tomoyuki Miura[SUP] 1 [/SUP]
Affiliations
- PMID: 41537598
- PMCID: PMC12805870
- DOI: 10.1002/jmv.70790
Neutralizing emerging SARS-CoV-2 variants requires antibodies effective not only against epitope mutations but also under variable antigenic presentations. We assessed the neutralization capacity of the same anti-RBD monoclonal antibody (8A5) expressed as IgG, IgA, or IgM against 18 variants, identifying three neutralization classes: variants susceptible to all isotypes, variants resistant to IgG but sensitive to IgA/IgM, and variants resistant to all isotypes. Mutation analysis revealed that S371L-S373P-S375F disrupted IgG binding while partially preserving IgA/IgM activity, whereas L371F induced conformational changes abolishing all antibody interactions. Notably, some variants lacking these mutations still escaped IgG, suggesting geometric factors contribute to differential efficacy. To explore this, we performed negative-stain electron microscopy, which showed heterogeneous spike distributions across virion surfaces. ELISA assays with decreasing spike concentrations revealed that IgG binding declined sharply under low antigen density, while IgA and IgM maintained strong binding, reflecting their extended architecture and multivalency. These findings indicate that spatial adaptability, in addition to affinity, contributes to effective neutralization. IgA and IgM can engage antigens under sparse or conformationally altered conditions, suggesting potential advantages over IgG against certain variants. These insights may support the rational design of IgA- and IgM-based antibody therapeutics, highlighting their potential role in combating SARS-CoV-2 variants and other emerging viral pathogens.
Keywords: IgA; IgG; IgM; SARS‐CoV‐2; mAb; neutralization.