Dissecting the Clonal Composition and Determinants of Neutralization Potency Enhancement of Serum Dimeric and Monomeric IgA to Human Norovirus

Dissecting the Clonal Composition and Determinants of Neutralization Potency Enhancement of Serum Dimeric and Monomeric IgA to Human Norovirus | 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 Dissecting the Clonal Composition and Determinants of Neutralization Potency Enhancement of Serum Dimeric and Monomeric IgA to Human Norovirus George Georgiou, Juyeon Park, Gyunghee Jo, Yaoska Reyes, Whitney Pickens, and 24 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8066364/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Protection against human norovirus infection, which is the major cause of acute gastroenteritis, is strongly correlated with humoral immunity, particularly with IgA binding titers in serum and mucosal surfaces. Serum IgA is mostly monomeric (mIgA), with 10-20% present as dimeric (dIgA). Using serum antibody proteomics, we determined the clonal composition of the serum IgG, mIgA, and dIgA repertoires specific to GII.4 virus-like particles (VLPs) following oral vaccination with an adenoviral vectored norovirus vaccine candidate, which phenocopies the route of administration and the higher IgA to IgG serum titers associated with natural infection. We detected a low level of clonal overlap between circulating IgG and IgA at steady state, which, however, increased up to 65% following vaccination. Importantly, > 80% of serum mIgA specific to VLP was also found as dIgA, yet the mIgA:dIgA abundance ratio for different clonotypes varied by up to 250-fold (0.4190). We observed a similar congruence of the influenza hemagglutinin-binding dIgA and mIgA repertoires in serum following intramuscular flu vaccination. For antibodies targeting the apex, but not the lateral cleft, of the protruding (P) domain on human norovirus VLPs, IgA dimerization conferred markedly improved ligand blockade titers, resulting in higher potency towards the neutralization of live virus in the human intestinal enteroid system. Cryo-EM structures of prototypical apical and lateral cleft binding antibodies, coupled with cryo-ET imaging of VLP cross-linking mediated by dIgA, revealed that epitope accessibility, antibody binding orientation, and proximity to the attachment ligand binding site required for virus entry into host cells all influence the epitope-dependent differential potency of dIgA. Our findings elucidate key features of the molecular nature of the IgA serological response and the structural basis for the high neutralization potency of dIgA in an epitope-specific manner. Biological sciences/Immunology/Adaptive immunity/Humoral immunity/Antibodies Biological sciences/Immunology/Infectious diseases/Viral infection Full Text Additional Declarations Yes there is potential Competing Interest. L.C.L. and R.S.B. hold patents on norovirus vaccine design (US Patent application no. 18/292,199, “Methods and compositions for norovirus chimeric therapeutics”) and ongoing collaborations with Vaxart, Takeda Vaccines, HilleVax, Merck, GIVAX, Maine Biotech, and BioNTech that are unrelated and do not pose conflicts of interest with this report. L.C.L. and R.S.B. receive royalties from Maine Biotech, which do not pose a conflict of interest with this work. R.S.B. is a member of the advisory committee for Vaxart and Invivyd. B.A.F. and S.N.T. are employees of Vaxart, Inc and received stock options. G.G. receives royalties or compensation from Amgen, Asher Bio, and Grifols, none of which pose a conflict of interest with this work. G.G. owns stock in Vaxart. A.B.W. is a co-inventor of the licensed prefusion coronavirus spike stabilization technology and has received royalty payments for the licensure, which do not pose a conflict of interest with this work. A.B.W. and J.H. consult for Third Rock Ventures and Merida Biosciences on topics unrelated to this work. The laboratory of A.B.W. received unrelated sponsored research agreements from Third Rock Ventures during the conduct of the study. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention, USA. J.P., G.J., Y.R., W.P., D.S.K., A.B., V.P.C., C.L., D.K., D.P., V.L., P.D.B., M.L.M., E.S., R.Z.B., J.M., M.R.Z., J.V., T.M.R., J.L., J.J.L., and Z.K. have no competing interests. Supplementary Files 102925SupplementaryMovie.mov Supplementary video 110825MSSupplementalFigureTableJPv17.pdf Supplementary Figures and Tables Cite Share Download PDF Status: Posted 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. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-8066364","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":545330658,"identity":"8c49b17a-ad35-4a8f-8bb8-7afc9079c186","order_by":0,"name":"George 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L.C.L. and R.S.B. receive royalties from Maine Biotech, which do not pose a conflict of interest with this work. R.S.B. is a member of the advisory committee for Vaxart and Invivyd. B.A.F. and S.N.T. are employees of Vaxart, Inc and received stock options. G.G. receives royalties or compensation from Amgen, Asher Bio, and Grifols, none of which pose a conflict of interest with this work. G.G. owns stock in Vaxart. A.B.W. is a co-inventor of the licensed prefusion coronavirus spike stabilization technology and has received royalty payments for the licensure, which do not pose a conflict of interest with this work. A.B.W. and J.H. consult for Third Rock Ventures and Merida Biosciences on topics unrelated to this work. The laboratory of A.B.W. received unrelated sponsored research agreements from Third Rock Ventures during the conduct of the study. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention, USA. J.P., G.J., Y.R., W.P., D.S.K., A.B., V.P.C., C.L., D.K., D.P., V.L., P.D.B., M.L.M., E.S., R.Z.B., J.M., M.R.Z., J.V., T.M.R., J.L., J.J.L., and Z.K. have no competing interests.","formattedTitle":"Dissecting the Clonal Composition and Determinants of Neutralization Potency Enhancement of Serum Dimeric and Monomeric IgA to Human Norovirus","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-8066364/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8066364/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Protection against human norovirus infection, which is the major cause of acute gastroenteritis, is strongly correlated with humoral immunity, particularly with IgA binding titers in serum and mucosal surfaces. Serum IgA is mostly monomeric (mIgA), with 10-20% present as dimeric (dIgA). Using serum antibody proteomics, we determined the clonal composition of the serum IgG, mIgA, and dIgA repertoires specific to GII.4 virus-like particles (VLPs) following oral vaccination with an adenoviral vectored norovirus vaccine candidate, which phenocopies the route of administration and the higher IgA to IgG serum titers associated with natural infection. We detected a low level of clonal overlap between circulating IgG and IgA at steady state, which, however, increased up to 65% following vaccination. Importantly, \u003e 80% of serum mIgA specific to VLP was also found as dIgA, yet the mIgA:dIgA abundance ratio for different clonotypes varied by up to 250-fold (0.4190). We observed a similar congruence of the influenza hemagglutinin-binding dIgA and mIgA repertoires in serum following intramuscular flu vaccination. For antibodies targeting the apex, but not the lateral cleft, of the protruding (P) domain on human norovirus VLPs, IgA dimerization conferred markedly improved ligand blockade titers, resulting in higher potency towards the neutralization of live virus in the human intestinal enteroid system. Cryo-EM structures of prototypical apical and lateral cleft binding antibodies, coupled with cryo-ET imaging of VLP cross-linking mediated by dIgA, revealed that epitope accessibility, antibody binding orientation, and proximity to the attachment ligand binding site required for virus entry into host cells all influence the epitope-dependent differential potency of dIgA. Our findings elucidate key features of the molecular nature of the IgA serological response and the structural basis for the high neutralization potency of dIgA in an epitope-specific manner.","manuscriptTitle":"Dissecting the Clonal Composition and Determinants of Neutralization Potency Enhancement of Serum Dimeric and Monomeric IgA to Human Norovirus","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-02 11:53:05","doi":"10.21203/rs.3.rs-8066364/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"5c1ccfe8-5bb9-4d10-ad43-e4e507ece013","owner":[],"postedDate":"December 2nd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":58022069,"name":"Biological sciences/Immunology/Adaptive immunity/Humoral immunity/Antibodies"},{"id":58022070,"name":"Biological sciences/Immunology/Infectious diseases/Viral infection"}],"tags":[],"updatedAt":"2025-12-02T11:53:05+00:00","versionOfRecord":[],"versionCreatedAt":"2025-12-02 11:53:05","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8066364","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8066364","identity":"rs-8066364","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}