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Cell Host Microbe
. 2026 Apr 27:S1931-3128(26)00160-5.
doi: 10.1016/j.chom.2026.04.004. Online ahead of print.
Childhood immunological imprinting of cross-subtype antibodies targeting the hemagglutinin head domain of influenza viruses
Shuk Hang Li 1 , Bo Wang 2 , Gyunghee Jo 2 , Artem Mikelov 3 , Reilly K Atkinson 1 , Valerie Le Sage 4 , Colleen Furey 1 , Jordan T Ort 1 , Naiqing Ye 1 , Sydney Gang 1 , Ruhi Shah 1 , Jefferson J S Santos 1 , Katharina Röltgen 3 , Shilpa A Joshi 3 , Ji-Yeun Lee 3 , Taylor A Pursell 3 , Elizabeth M Drapeau 1 , Julianna Han 2 , Amy P Callear 5 , Ronald G Collman 6 , Arnold S Monto 5 , Emily T Martin 5 , Seema S Lakdawala 7 , Andrew B Ward 2 , Ian A Wilson 8 , Scott D Boyd 9 , Scott E Hensley 10
Affiliations
Influenza virus cross-subtype antibodies targeting epitopes in the hemagglutinin (HA) head are rare because these epitopes are variable between influenza virus subtypes. We found that a large proportion of monoclonal antibodies (mAbs) isolated from individuals immunized with the 2021-22 seasonal influenza vaccine bound to an epitope on the HA head of both the H1N1 vaccine strain and H3N2 strains from the mid-1990s. The unmutated common ancestors of many of these mAbs reacted to both the 1990s H3s and the 2021-22 H1 vaccine strain. These cross-subtype antibodies were also found in polyclonal sera, but only among individuals born in the 1990s. Ferrets sequentially exposed to a 1990s H3N2 virus and contemporary influenza vaccine also produced H1/H3 cross-reactive antibodies. Recently, H1N1 viruses have acquired a substitution that abrogates the binding of these antibodies. Together, our study demonstrates how prior influenza virus exposures can influence the specificity of antibodies elicited by entirely different influenza virus subtypes.
Keywords: X-ray crystallography; cross-reactive antibodies; immune imprinting; influenza; negative-stain EM; vaccination.
. 2026 Apr 27:S1931-3128(26)00160-5.
doi: 10.1016/j.chom.2026.04.004. Online ahead of print.
Childhood immunological imprinting of cross-subtype antibodies targeting the hemagglutinin head domain of influenza viruses
Shuk Hang Li 1 , Bo Wang 2 , Gyunghee Jo 2 , Artem Mikelov 3 , Reilly K Atkinson 1 , Valerie Le Sage 4 , Colleen Furey 1 , Jordan T Ort 1 , Naiqing Ye 1 , Sydney Gang 1 , Ruhi Shah 1 , Jefferson J S Santos 1 , Katharina Röltgen 3 , Shilpa A Joshi 3 , Ji-Yeun Lee 3 , Taylor A Pursell 3 , Elizabeth M Drapeau 1 , Julianna Han 2 , Amy P Callear 5 , Ronald G Collman 6 , Arnold S Monto 5 , Emily T Martin 5 , Seema S Lakdawala 7 , Andrew B Ward 2 , Ian A Wilson 8 , Scott D Boyd 9 , Scott E Hensley 10
Affiliations
- PMID: 42049037
- DOI: 10.1016/j.chom.2026.04.004
Influenza virus cross-subtype antibodies targeting epitopes in the hemagglutinin (HA) head are rare because these epitopes are variable between influenza virus subtypes. We found that a large proportion of monoclonal antibodies (mAbs) isolated from individuals immunized with the 2021-22 seasonal influenza vaccine bound to an epitope on the HA head of both the H1N1 vaccine strain and H3N2 strains from the mid-1990s. The unmutated common ancestors of many of these mAbs reacted to both the 1990s H3s and the 2021-22 H1 vaccine strain. These cross-subtype antibodies were also found in polyclonal sera, but only among individuals born in the 1990s. Ferrets sequentially exposed to a 1990s H3N2 virus and contemporary influenza vaccine also produced H1/H3 cross-reactive antibodies. Recently, H1N1 viruses have acquired a substitution that abrogates the binding of these antibodies. Together, our study demonstrates how prior influenza virus exposures can influence the specificity of antibodies elicited by entirely different influenza virus subtypes.
Keywords: X-ray crystallography; cross-reactive antibodies; immune imprinting; influenza; negative-stain EM; vaccination.