Potent type-specific de novo antibodies complement broadly reactive imprinted antibodies in immune responses to SARS-CoV-2 variants

For rapidly mutating viruses such as influenza viruses and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), immune memory recalled by antigenically drifted variants primarily comprises antibodies that cross-react to the priming strain rather than de novo elicited responses, a phenomenon termed original antigenic sin or immune imprinting. The composition and functionality of de novo responses elicited by variant exposures remain unclear. Here we isolated and characterized hundreds of recall and de novo neutralizing monoclonal antibodies after sequential exposures to SARS-CoV-2 variants in ancestral-imprinted humans. De novo variant type-specific antibodies used different V(D)J genes that were closer to germline sequence, potently neutralized future variants and targeted distinct receptor binding domain epitopes compared to ancestral cross-reactive (recall) antibodies. Nevertheless, neutralizing responses to the updated 2024-2025 booster were predominantly ancestral cross-reactive. These results reveal the distinct contributions of recall and de novo antibodies to a balanced immune response and underscore the benefit of updated booster vaccines, which augment both subsets.

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Publication Details

Journal
Nature Immunology
Published
2026-08-14
DOI
https://doi.org/10.1038/s41590-026-02613-4
Citations
1
Primary Topic
Immunodeficiency and Autoimmune Disorders
Type
article
Field-Weighted Citation Impact
3.54

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article

Potent type-specific de novo antibodies complement broadly reactive imprinted antibodies in immune responses to SARS-CoV-2 variants

Farida Laboune, Tongqing Zhou, Sarah D. Smith, Mark M. Painter et al.
1 citations
Nature Immunology
Immunodeficiency and Autoimmune Disorders
3.54
article

Potent type-specific de novo antibodies complement broadly reactive imprinted antibodies in immune responses to SARS-CoV-2 variants

Farida Laboune, Tongqing Zhou, Sarah D. Smith, Mark M. Painter, Naomi R. Douek, Bob C. Lin, Scott E. Hensley, Daniel C. Douek, Chaim A. Schramm, Timothy S. Johnston, Theodore C. Pierson, Lingshu Wang, Amy Henry, E. John Wherry, Leonid Serebryannyy, Shuk Hang Li, Shuishu Wang, Bernadeta Dadonaite, Nicole A. Doria‐Rose, I‐Ting Teng, Jesse D. Bloom, Reilly K. Atkinson, Rachel Kazmierski, Haijuan Du, Robin Schlesinger, Divya Swaminathan, Lucas Kampman
article en
1 citations

Abstract

For rapidly mutating viruses such as influenza viruses and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), immune memory recalled by antigenically drifted variants primarily comprises antibodies that cross-react to the priming strain rather than de novo elicited responses, a phenomenon termed original antigenic sin or immune imprinting. The composition and functionality of de novo responses elicited by variant exposures remain unclear. Here we isolated and characterized hundreds of recall and de novo neutralizing monoclonal antibodies after sequential exposures to SARS-CoV-2 variants in ancestral-imprinted humans. De novo variant type-specific antibodies used different V(D)J genes that were closer to germline sequence, potently neutralized future variants and targeted distinct receptor binding domain epitopes compared to ancestral cross-reactive (recall) antibodies. Nevertheless, neutralizing responses to the updated 2024-2025 booster were predominantly ancestral cross-reactive. These results reveal the distinct contributions of recall and de novo antibodies to a balanced immune response and underscore the benefit of updated booster vaccines, which augment both subsets.

Nature Immunology
National Institutes of Health (US), Howard Hughes Medical Institute (US), Fred Hutch Cancer Center (US), Translational Therapeutics (United States) (US), National Institute of Allergy and Infectious Diseases (US), University of Pennsylvania (US)
Division of Intramural Research, National Institute of Allergy and Infectious Diseases, Parker Institute for Cancer Immunotherapy, National Institute of Allergy and Infectious Diseases
Good health and well-being
Openalex Percentile: Top 5%
Immunodeficiency and Autoimmune Disorders
3.54
DOIOpen Access PDFOpenAlex
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