tetano
Editor, Senior Moderator
Nature
. 2026 Mar 11.
doi: 10.1038/s41586-026-10248-6. Online ahead of print.
B cell imprinting in children impairs antibodies to the haemagglutinin stalk
Jiayi Sun[SUP] #[/SUP][SUP] 1 [/SUP], Gyunghee Jo[SUP] #[/SUP][SUP] 2 [/SUP], Chloe A Troxell[SUP] 1 [/SUP], Yanbin Fu[SUP] 1 [/SUP], Robert Hoezl[SUP] 3 4 [/SUP], Huibin Lv[SUP] 5 6 [/SUP], Hassanein H Abozeid[SUP] 7 8 [/SUP], Qi Wen Teo[SUP] 5 6 [/SUP], Tossapol Pholcharee[SUP] 5 [/SUP], Joshua J C McGrath[SUP] 1 [/SUP], Siriruk Changrob[SUP] 1 [/SUP], Sean A Nelson[SUP] 1 [/SUP], Atsuhiro Yasuhara[SUP] 1 [/SUP], Min Huang[SUP] 1 [/SUP], Nai-Ying Zheng[SUP] 1 [/SUP], Jordan C Chervin[SUP] 1 [/SUP], Lei Li[SUP] 1 [/SUP], Monica L Fernández-Quintero[SUP] 2 [/SUP], Johannes R Loeffler[SUP] 2 [/SUP], Alesandra J Rodriguez[SUP] 2 [/SUP], Jiachen Huang[SUP] 2 [/SUP], Olivia M Swanson[SUP] 2 [/SUP], Angel Balmaseda[SUP] 9 10 [/SUP], Guillermina Kuan[SUP] 9 11 [/SUP], Lora Campredon[SUP] 12 [/SUP], E Kaitlynn Allen[SUP] 13 [/SUP], Gabriele Neumann[SUP] 7 [/SUP], Nicholas C Wu[SUP] 5 6 [/SUP], Yoshihiro Kawaoka[SUP] 7 14 15 [/SUP], Florian Krammer[SUP] 3 4 16 17 [/SUP], Asuncion Mejias[SUP] 18 19 [/SUP], Octavio Ramilo[SUP] 18 19 [/SUP], Paul G Thomas[SUP] 13 [/SUP], Aubree Gordon[SUP] 12 [/SUP], Andrew B Ward[SUP] 2 [/SUP], Julianna Han[SUP] 2 [/SUP], Patrick C Wilson[SUP] 20 [/SUP]
Affiliations
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.
. 2026 Mar 11.
doi: 10.1038/s41586-026-10248-6. Online ahead of print.
B cell imprinting in children impairs antibodies to the haemagglutinin stalk
Jiayi Sun[SUP] #[/SUP][SUP] 1 [/SUP], Gyunghee Jo[SUP] #[/SUP][SUP] 2 [/SUP], Chloe A Troxell[SUP] 1 [/SUP], Yanbin Fu[SUP] 1 [/SUP], Robert Hoezl[SUP] 3 4 [/SUP], Huibin Lv[SUP] 5 6 [/SUP], Hassanein H Abozeid[SUP] 7 8 [/SUP], Qi Wen Teo[SUP] 5 6 [/SUP], Tossapol Pholcharee[SUP] 5 [/SUP], Joshua J C McGrath[SUP] 1 [/SUP], Siriruk Changrob[SUP] 1 [/SUP], Sean A Nelson[SUP] 1 [/SUP], Atsuhiro Yasuhara[SUP] 1 [/SUP], Min Huang[SUP] 1 [/SUP], Nai-Ying Zheng[SUP] 1 [/SUP], Jordan C Chervin[SUP] 1 [/SUP], Lei Li[SUP] 1 [/SUP], Monica L Fernández-Quintero[SUP] 2 [/SUP], Johannes R Loeffler[SUP] 2 [/SUP], Alesandra J Rodriguez[SUP] 2 [/SUP], Jiachen Huang[SUP] 2 [/SUP], Olivia M Swanson[SUP] 2 [/SUP], Angel Balmaseda[SUP] 9 10 [/SUP], Guillermina Kuan[SUP] 9 11 [/SUP], Lora Campredon[SUP] 12 [/SUP], E Kaitlynn Allen[SUP] 13 [/SUP], Gabriele Neumann[SUP] 7 [/SUP], Nicholas C Wu[SUP] 5 6 [/SUP], Yoshihiro Kawaoka[SUP] 7 14 15 [/SUP], Florian Krammer[SUP] 3 4 16 17 [/SUP], Asuncion Mejias[SUP] 18 19 [/SUP], Octavio Ramilo[SUP] 18 19 [/SUP], Paul G Thomas[SUP] 13 [/SUP], Aubree Gordon[SUP] 12 [/SUP], Andrew B Ward[SUP] 2 [/SUP], Julianna Han[SUP] 2 [/SUP], Patrick C Wilson[SUP] 20 [/SUP]
Affiliations
- PMID: 41813896
- DOI: 10.1038/s41586-026-10248-6
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.