IGHV3-53 antibody abundance drives divergent SARS-CoV-2 immune imprinting

Niu, X.; Jian, F.; Li, Y.; Li, K.; Lei, S.; Song, W.; Kong, R.; Cai, X.; An, R.; Wang, Y.; Huang, Y.; Yu, L.; Wang, W.; Sun, H.; Yu, Y.; Wang, J.; Zhang, B.; Zhu, T.; Huang, J.; Shao, F.; Luo, S.; Tan, X.; Cao, Y.

doi:10.64898/2025.12.18.694353

bioRxiv · 10.64898/2025.12.18.694353

IGHV3-53 antibody abundance drives divergent SARS-CoV-2 immune imprinting

Niu, X.·Jian, F.·Li, Y.·Li, K.·Lei, S.·Song, W.·Kong, R.·Cai, X.·An, R.·Wang, Y.·Huang, Y.·Yu, L.·Wang, W.·Sun, H.·Yu, Y.·Wang, J.·Zhang, B.·Zhu, T.·Huang, J.·Shao, F.·Luo, S.·Tan, X.·Cao, Y.

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Abstract

The mechanisms driving divergent SARS-CoV-2 immune imprinting in populations with distinct SARS-CoV-2 exposure histories remain unclear. However, conventional wild-type mouse models fail to recapitulate severe imprinting, even after potent ancestral-strain mRNA immunization, hindering imprinting-related mechanistic investigation and vaccine evaluation. Here, we surprisingly found that V(D)J-humanized mice could faithfully recapitulate human severe imprinting phenotypes. Comprehensive antibody repertoire analysis and deep mutational scanning-based epitope mapping of 583 monoclonal antibodies from these models revealed that the pre-existing IGHV3-53/66 antibody abundance determine imprinting severity through antibody-mediated masking of Omicron-specific epitopes. Both passive IGHV3-53/66 antibody transfer and IGHV3-53 knock-in were sufficient to induce severe imprinting in wild-type mice. Together, these findings demonstrate that the V(D)J germline repertoire--even a single germline-encoded antibody response--can profoundly shape humoral imprinting severity. Accordingly, we established an IGHV3-53 knock-in mouse model that accurately recapitulates the human antibody landscape, providing a valuable tool for guiding future COVID-19 vaccine updates.

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Niu, X., Jian, F., Li, Y., Li, K., Lei, S., Song, W., Kong, R., Cai, X., An, R., Wang, Y., Huang, Y., Yu, L., Wang, W., Sun, H., Yu, Y., Wang, J., Zhang, B., Zhu, T., Huang, J., Shao, F., Luo, S., Tan, X., Cao, Y.. 2025-12-19. IGHV3-53 antibody abundance drives divergent SARS-CoV-2 immune imprinting. https://doi.org/10.64898/2025.12.18.694353

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