Hybrid heterologous immunity shapes robust antiviral responses in children and minimizes age-related immunological differences

Hybrid heterologous immunity shapes robust antiviral responses in children and minimizes age-related immunological differences | 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 Article Hybrid heterologous immunity shapes robust antiviral responses in children and minimizes age-related immunological differences Roland Elling, Miriam Eisner, Vivien Karl, Fiona Seger, Anna Willems, and 18 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9365291/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract Background: Understanding how children mount effective antiviral immune responses is critical for preparedness against current and future emerging pathogens. Acute respiratory viral infections provide a tractable human model to dissect age-specific immunity, yet the integration of humoral, cellular, and mucosal responses in children remains incompletely defined. Insights into cross-reactive and durable immune mechanisms are essential to inform vaccination strategies and pandemic readiness. Methods: 182 participants (96 children, 86 adults) from 41 families with newly confirmed SARS-CoV-2 infection were enrolled in the prospective OMI-Kids study (DRKS00029155). Repeated PCR testing, symptom monitoring, saliva sampling, and blood collection 6–8 weeks post household infection enabled detailed immune profiling. Humoral and cellular responses, including neutralization against Hu-1, BA.2, and EG.5.1, as well as HLA-restricted CD8+ T cell responses, were analyzed across distinct immunity profiles. Cytokine autoantibodies were quantified using a multiplex bead-based IgG assay. Findings: Serum and salivary IgG and IgA levels correlated strongly, supporting saliva as a reliable, non-invasive proxy for immune monitoring in children. Antibodies elicited by Hu-1–based infection or vaccination showed partial cross-reactivity to BA.2 but failed to neutralize EG.5.1. Despite limited antibody breadth, T cell-mediated immunity was conserved across variants, with no major age-dependent differences in the magnitude, HLA breadth or functionality of virus-specific T cell responses. Conclusion: These findings highlight fundamental features of antiviral immunity in children, characterized by constrained antibody breadth but robust and conserved cellular responses in the context of SARS-CoV-2 evolution. Cross-reactive T cell immunity may represent a key mechanism of protection against severe disease despite ongoing viral evolution. This work establishes a framework for leveraging acute viral infections as a human model to inform immune protection, surveillance strategies, and vaccine design for future emerging pathogens. Biological sciences/Immunology/Adaptive immunity/Cellular immunity Biological sciences/Immunology/Adaptive immunity/Humoral immunity/Antibodies Health sciences/Medical research/Paediatric research Biological sciences/Microbiology/Virology/Viral host response Biological sciences/Immunology/Infectious diseases/Viral infection Full Text Additional Declarations There is NO Competing Interest. Supplementary Files SupplementalPDF25Mar2026.docx Supplementary Information Cite Share Download PDF Status: Under Review 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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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9365291","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":623630877,"identity":"cd4a0265-69f0-4aeb-948a-9bdebed9cbc4","order_by":0,"name":"Roland 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Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-9365291/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9365291/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eUnderstanding how children mount effective antiviral immune responses is critical for preparedness against current and future emerging pathogens. Acute respiratory viral infections provide a tractable human model to dissect age-specific immunity, yet the integration of humoral, cellular, and mucosal responses in children remains incompletely defined. Insights into cross-reactive and durable immune mechanisms are essential to inform vaccination strategies and pandemic readiness.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003e182 participants (96 children, 86 adults) from 41 families with newly confirmed SARS-CoV-2 infection were enrolled in the prospective OMI-Kids study (DRKS00029155). Repeated PCR testing, symptom monitoring, saliva sampling, and blood collection 6–8 weeks post household infection enabled detailed immune profiling. Humoral and cellular responses, including neutralization against Hu-1, BA.2, and EG.5.1, as well as HLA-restricted CD8+ T cell responses, were analyzed across distinct immunity profiles. Cytokine autoantibodies were quantified using a multiplex bead-based IgG assay.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFindings: \u003c/strong\u003eSerum and salivary IgG and IgA levels correlated strongly, supporting saliva as a reliable, non-invasive proxy for immune monitoring in children. Antibodies elicited by Hu-1–based infection or vaccination showed partial cross-reactivity to BA.2 but failed to neutralize EG.5.1. Despite limited antibody breadth, T cell-mediated immunity was conserved across variants, with no major age-dependent differences in the magnitude, HLA breadth or functionality of virus-specific T cell responses.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion: \u003c/strong\u003eThese findings highlight fundamental features of antiviral immunity in children, characterized by constrained antibody breadth but robust and conserved cellular responses in the context of SARS-CoV-2 evolution. Cross-reactive T cell immunity may represent a key mechanism of protection against severe disease despite ongoing viral evolution. This work establishes a framework for leveraging acute viral infections as a human model to inform immune protection, surveillance strategies, and vaccine design for future emerging pathogens.\u003c/p\u003e","manuscriptTitle":"Hybrid heterologous immunity shapes robust antiviral responses in children and minimizes age-related immunological differences","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-16 10:58:52","doi":"10.21203/rs.3.rs-9365291/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-communications","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"NCOMMS","sideBox":"Learn more about [Nature Communications](http://www.nature.com/ncomms/)","snPcode":"","submissionUrl":"https://mts-ncomms.nature.com/","title":"Nature Communications","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Communications","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"ce9965d2-699b-448a-8234-783ff8a8a109","owner":[],"postedDate":"April 16th, 2026","published":true,"recentEditorialEvents":[{"type":"editorInvitedReview","content":"This content is not available.","date":"2026-05-08T20:38:14+00:00","index":1,"fulltext":"This content is not available."},{"type":"editorInvitedReview","content":"This content is not available.","date":"2026-05-07T07:21:25+00:00","index":2,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2026-04-30T14:43:29+00:00","index":3,"fulltext":"This content is not available."}],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":66371035,"name":"Biological sciences/Immunology/Adaptive immunity/Cellular immunity"},{"id":66371036,"name":"Biological sciences/Immunology/Adaptive immunity/Humoral immunity/Antibodies"},{"id":66371037,"name":"Health sciences/Medical research/Paediatric research"},{"id":66371038,"name":"Biological sciences/Microbiology/Virology/Viral host response"},{"id":66371039,"name":"Biological sciences/Immunology/Infectious diseases/Viral infection"}],"tags":[],"updatedAt":"2026-04-16T10:58:52+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-16 10:58:52","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9365291","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9365291","identity":"rs-9365291","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}