A single residue change only differing by an atomic group can drive imprinting to influenza

A single residue change only differing by an atomic group can drive imprinting to influenza | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Biological Sciences - Article A single residue change only differing by an atomic group can drive imprinting to influenza Patrick Wilson, Jiayi Sun, Gyunghee Jo, Chloe Troxell, Yanbin Fu, and 30 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6914018/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 11 Mar, 2026 Read the published version in Nature → Version 1 posted You are reading this latest preprint version Abstract First described as original antigenic sin (OAS), which is deleterious, or now immune imprinting, which also accounts for beneficial effects, it is clear that immune responses to viruses tend to be biased by previous exposure to similar strains. Various non-exclusive models for the basis of imprinting include that it results from unique features of childhood immunity; it is driven by pre-existing serum antibodies via epitope masking; or it occurs as a byproduct of residual memory following viral antigenic evolution. To understand the basis and impact of imprinting from influenza, we characterized the B cell responses of young children upon consecutive first infections with divergent H1N1 and H3N2 influenza viruses. Here, we show that beyond being a primary response, there are no major phenotypic differences in the B cell response of children compared to that of adults. The distinct immunoglobulin variable (IgV) gene repertoire of influenza virus hemagglutinin (HA)-reactive B cells in children, along with increased cross-reactivity to past strains in adults, suggests significant homosubtypic imprinting in adults. As most B cells induced after consecutive infections with antigenically distant H1N1 and H3N2 are strain-specific, heterosubtypic imprinting is rare. However, these successive infections resulted in up to 6% of H1/H3 cross-reactive B cells, targeting the highly conserved central stalk epitope. These B cells express antibodies that are dominantly affected by imprinting with reduced affinity, neutralization potency, and breadth of activity. Mechanistically, H3 to H1 imprinting was caused by a single amino acid change (D46N), differing by just a carboxyl versus an amide atomic group on the central stalk epitope, resulting in a detrimental shift in the specificity of most H1/H3 cross-neutralizing B cells from seven children. We conclude that imprinting by influenza is most evident at the individual epitope level, where minor molecular differences can have a significant impact and need to be accounted for in epitope-targeting vaccine designs. Biological sciences/Immunology/Adaptive immunity/Humoral immunity/Immunological memory Biological sciences/Immunology/Adaptive immunity/Humoral immunity/Antibodies Biological sciences/Immunology/Infectious diseases/Influenza virus Full Text Additional Declarations Yes there is potential Competing Interest. J.Han, J.Huang, and A.B.W. are consultants for Third Rock Ventures. The laboratory of A.B.W. received unrelated sponsored research agreements from Third Rock Ventures during the conduct of the study. Supplementary Files PDBvalidationreportscombined.pdf PDB validation reports (6 combined) Cite Share Download PDF Status: Published Journal Publication published 11 Mar, 2026 Read the published version in Nature → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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The laboratory of A.B.W. received unrelated sponsored research agreements from Third Rock Ventures during the conduct of the study.","formattedTitle":"A single residue change only differing by an atomic group can drive imprinting to influenza","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-6914018/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6914018/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"First described as original antigenic sin (OAS), which is deleterious, or now immune imprinting, which also accounts for beneficial effects, it is clear that immune responses to viruses tend to be biased by previous exposure to similar strains. Various non-exclusive models for the basis of imprinting include that it results from unique features of childhood immunity; it is driven by pre-existing serum antibodies via epitope masking; or it occurs as a byproduct of residual memory following viral antigenic evolution. To understand the basis and impact of imprinting from influenza, we characterized the B cell responses of young children upon consecutive first infections with divergent H1N1 and H3N2 influenza viruses. Here, we show that beyond being a primary response, there are no major phenotypic differences in the B cell response of children compared to that of adults. The distinct immunoglobulin variable (IgV) gene repertoire of influenza virus hemagglutinin (HA)-reactive B cells in children, along with increased cross-reactivity to past strains in adults, suggests significant homosubtypic imprinting in adults. As most B cells induced after consecutive infections with antigenically distant H1N1 and H3N2 are strain-specific, heterosubtypic imprinting is rare. However, these successive infections resulted in up to 6% of H1/H3 cross-reactive B cells, targeting the highly conserved central stalk epitope. These B cells express antibodies that are dominantly affected by imprinting with reduced affinity, neutralization potency, and breadth of activity. Mechanistically, H3 to H1 imprinting was caused by a single amino acid change (D46N), differing by just a carboxyl versus an amide atomic group on the central stalk epitope, resulting in a detrimental shift in the specificity of most H1/H3 cross-neutralizing B cells from seven children. We conclude that imprinting by influenza is most evident at the individual epitope level, where minor molecular differences can have a significant impact and need to be accounted for in epitope-targeting vaccine designs.","manuscriptTitle":"A single residue change only differing by an atomic group can drive imprinting to influenza","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-07 13:04:20","doi":"10.21203/rs.3.rs-6914018/v1","editorialEvents":[],"status":"published","journal":{"display":false,"email":"[email protected]","identity":"nature","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"nature","sideBox":"Learn more about [Nature](http://www.nature.com/nature/)","snPcode":"","submissionUrl":"","title":"Nature","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"caedd81b-2544-4733-b0c6-60ab393a94ee","owner":[],"postedDate":"July 7th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":51057176,"name":"Biological sciences/Immunology/Adaptive immunity/Humoral immunity/Immunological memory"},{"id":51057177,"name":"Biological sciences/Immunology/Adaptive immunity/Humoral immunity/Antibodies"},{"id":51057178,"name":"Biological sciences/Immunology/Infectious diseases/Influenza virus"}],"tags":[],"updatedAt":"2026-03-12T10:45:19+00:00","versionOfRecord":{"articleIdentity":"rs-6914018","link":"https://doi.org/10.1038/s41586-026-10248-6","journal":{"identity":"nature","isVorOnly":false,"title":"Nature"},"publishedOn":"2026-03-11 04:00:00","publishedOnDateReadable":"March 11th, 2026"},"versionCreatedAt":"2025-07-07 13:04:20","video":"","vorDoi":"10.1038/s41586-026-10248-6","vorDoiUrl":"https://doi.org/10.1038/s41586-026-10248-6","workflowStages":[]},"version":"v1","identity":"rs-6914018","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6914018","identity":"rs-6914018","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}