B cell imprinting in children impairs antibodies to the haemagglutinin stalk

Immune imprinting<sup>1</sup> or original antigenic sin<sup>2</sup> is a phenomenon whereby the immune system preferentially recalls its initial response to a related, often evolving pathogen after subsequent exposure. Despite its important implications for vaccine development, the causes of imprinting remain unclear. Here, to understand the basis and impact of imprinting by influenza A viruses, we characterized the B cell responses of young children after consecutive first infections with divergent H1N1 and H3N2 strains of influenza. Children had a primary but otherwise similar B cell response to that of adults. Adult B cells commonly cross-reacted with past strains using more stereotyped and mutated immunoglobulin genes, indicating substantial homosubtypic imprinting. In children, after consecutive heterosubtypic primary infections, up to 6% of memory B cells are H1/H3 cross-reactive and bind to the highly conserved central stalk epitope-a lead target for broadly protective vaccine candidates. Over 90% of these B cells had a higher affinity for the imprinting H3N2 strain, resulting in reduced breadth and neutralization potency against H1N1 strains. Mechanistically, the imprinting H3 strains and affected H1 strains shared a residue change in the stalk epitope (D46N) that was central to the nearly universal shift in reactivity, despite differing by only a single atomic group. In conclusion, imprinting by influenza viruses can cause a deleterious shift of nearly the entire memory recall response against key, conserved epitopes.

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Journal
Nature
Published
2026-03-11
DOI
https://doi.org/10.1038/s41586-026-10248-6
Primary Topic
Immunodeficiency and Autoimmune Disorders
Type
article
Field-Weighted Citation Impact
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article

B cell imprinting in children impairs antibodies to the haemagglutinin stalk

Johannes R. Loeffler, Asunción Mejías, Patrick C. Wilson, Aubree Gordon et al.
Nature
Immunodeficiency and Autoimmune Disorders
article

B cell imprinting in children impairs antibodies to the haemagglutinin stalk

Johannes R. Loeffler, Asunción Mejías, Patrick C. Wilson, Aubree Gordon, Gyunghe Jo, Jordan Chervin, Tossapol Pholcharee, Atsuhiro Yasuhara, Jiachen Huang, Lora Campredon, Joshua J.C. McGrath, Nicholas C. Wu, Hassanein H. Abozeid, Julianna Han, Siriruk Changrob, Octavio Ramilo, Olivia M. Swanson, Guillermina Kuan, Qi Wen Teo, Gabriele Neumann, Florian Krammer, Yoshihiro Kawaoka, M. H. Huang, J. Z. Sun, Chloe Troxell, Sean A. Nelson, Nai‐Ying Zheng, Alesandra J. Rodriguez, Li Li, Huibin Lv, Ángel Balmaseda, Paul G. Thomas, E. Kaitlynn Allen, Yanbin Fu, Monica L. Fernández-Quintero, Robert Hoezl, Andrew B. Ward
article en

Abstract

Immune imprinting<sup>1</sup> or original antigenic sin<sup>2</sup> is a phenomenon whereby the immune system preferentially recalls its initial response to a related, often evolving pathogen after subsequent exposure. Despite its important implications for vaccine development, the causes of imprinting remain unclear. Here, to understand the basis and impact of imprinting by influenza A viruses, we characterized the B cell responses of young children after consecutive first infections with divergent H1N1 and H3N2 strains of influenza. Children had a primary but otherwise similar B cell response to that of adults. Adult B cells commonly cross-reacted with past strains using more stereotyped and mutated immunoglobulin genes, indicating substantial homosubtypic imprinting. In children, after consecutive heterosubtypic primary infections, up to 6% of memory B cells are H1/H3 cross-reactive and bind to the highly conserved central stalk epitope-a lead target for broadly protective vaccine candidates. Over 90% of these B cells had a higher affinity for the imprinting H3N2 strain, resulting in reduced breadth and neutralization potency against H1N1 strains. Mechanistically, the imprinting H3 strains and affected H1 strains shared a residue change in the stalk epitope (D46N) that was central to the nearly universal shift in reactivity, despite differing by only a single atomic group. In conclusion, imprinting by influenza viruses can cause a deleterious shift of nearly the entire memory recall response against key, conserved epitopes.

Nature
Scripps Research Institute (US), St. Jude Children's Research Hospital (US), Nationwide Children's Hospital (US), University of Wisconsin–Madison (US), Cairo University (EG), University of Illinois Urbana-Champaign (US), Cornell University (US), University of Michigan (US), Ministerio de Salud (NI), Sustainable Sciences Institute (US), Weill Cornell Medicine (US), The University of Tokyo (JP), Medical University of Vienna (AT), Icahn School of Medicine at Mount Sinai (US)
Good health and well-being
Openalex Percentile: Top 24%
Immunodeficiency and Autoimmune Disorders
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