{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T06:00:48Z","timestamp":1782280848921,"version":"3.54.5"},"posted":{"date-parts":[[2025,10,20]]},"group-title":"Immunology","reference-count":51,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,10,20]],"date-time":"2025-10-20T00:00:00Z","timestamp":1760918400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,10,20]]},"abstract":"<jats:title>SUMMARY<\/jats:title>\n                <jats:p>\n                  The first exposure to a pathogen or an antigen profoundly impacts immune responses upon subsequent encounter with related pathogens. This immune imprinting explains that infection or vaccination with currently circulating SARS-CoV-2 variants primarily recalls cross-reactive memory B cells and antibodies induced by prior Wu spike (S) glycoprotein exposure rather than priming\n                  <jats:italic>de novo<\/jats:italic>\n                  responses. The magnitude and persistence of immune imprinting in mRNA vaccinated populations and the prospect to overcome it are not understood. To understand the impact of immune imprinting, we investigated memory B cell and plasma antibody responses after administration of multiple doses of XBB.1.5 and JN.1\/KP.2 updated COVID-19 vaccine boosters. We found that administration of the JN.1\/KP.2 booster elicited broadly neutralizing antibody responses against recently circulating SARS-CoV-2 variants that were accounted for by recall of Wu S-induced immunity. We detected an increased fraction of serum antibodies and particularly memory B cells recognizing XBB.1.5 S and KP.2 S, but not Wu S, relative to individuals who received a single XBB.1.5 booster a year prior. These findings suggest that repeated exposures to antigenically divergent S trimers contribute to progressively overcoming immune imprinting and support vaccine updates and innovation to provide continued protection against COVID-19.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>In brief<\/jats:title>\n                  <jats:p>Immune imprinting due to repeated SARS-CoV-2 Wuhan-Hu-1 spike exposures is widely observed in humans. Tortorici et al. show that the humoral immune response is dominated by recall of pre-existing Wu S-induced serum antibodies and memory B cells after administration of multiple XBB.1.5 and JN.1\/KP.2 COVID-19 vaccine boosters. However, the detection of an appreciable fraction of serum antibodies and particularly memory B cells binding the updated vaccine antigens, but not Wu, suggests a path towards overcoming immune imprinting<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Highlights<\/jats:title>\n                  <jats:list list-type=\"bullet\">\n                    <jats:list-item>\n                      <jats:p>XBB.1.5, JN.1 and KP.2 S COVID-19 vaccine boosters elicit neutralizing antibodies against current variants.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Serum neutralizing activity against circulating variants elicited after multiple doses of updated COVID-19 vaccine boosters derive from recall of Wu S-elicited antibodies.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Non-neutralizing antibodies specific for the updated spike antigens were detected after multiple, updated COVID-19 boosters.<\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list>\n                <\/jats:sec>","DOI":"10.1101\/2025.10.16.682893","type":"posted-content","created":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T03:05:18Z","timestamp":1761015918000},"source":"Crossref","is-referenced-by-count":0,"title":["Repeated COVID-19 vaccine boosters elicit variant-specific memory B cells in humans"],"prefix":"10.64898","author":[{"given":"M. Alejandra","family":"Tortorici","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaitlin R.","family":"Sprouse","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amin","family":"Addetia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jack T.","family":"Brown","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alex","family":"Harteloo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Elias-Warren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helen Y.","family":"Chu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Veesler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025102309300589000_2025.10.16.682893v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2022.01.011"},{"key":"2025102309300589000_2025.10.16.682893v1.2","doi-asserted-by":"crossref","unstructured":"McCallum, M. , Walls, A.C. , Sprouse, K.R. , Bowen, J.E. , Rosen, L.E. , Dang, H.V. , De Marco, A. , Franko, N. , Tilles, S.W. , Logue, J. , et al. (2021). Molecular basis of immune evasion by the Delta and Kappa SARS-CoV-2 variants. Science, eabl 8506.","DOI":"10.1101\/2021.08.11.455956"},{"key":"2025102309300589000_2025.10.16.682893v1.3","doi-asserted-by":"crossref","unstructured":"McCallum, M. , Czudnochowski, N. , Rosen, L.E. , Zepeda, S.K. , Bowen, J.E. , Walls, A.C. , Hauser, K. , Joshi, A. , Stewart, C. , Dillen, J.R. , et al. (2022). Structural basis of SARS-CoV-2 Omicron immune evasion and receptor engagement. Science, eabn 8652.","DOI":"10.1101\/2021.12.28.474380"},{"key":"2025102309300589000_2025.10.16.682893v1.4","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-04386-2"},{"key":"2025102309300589000_2025.10.16.682893v1.5","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-04385-3"},{"key":"2025102309300589000_2025.10.16.682893v1.6","doi-asserted-by":"publisher","DOI":"10.1038\/d41586-021-03826-3"},{"key":"2025102309300589000_2025.10.16.682893v1.7","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-08315-x"},{"key":"2025102309300589000_2025.10.16.682893v1.8","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1011868"},{"key":"2025102309300589000_2025.10.16.682893v1.9","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03530-2"},{"key":"2025102309300589000_2025.10.16.682893v1.10","doi-asserted-by":"publisher","DOI":"10.1038\/S41586-020-03041-6"},{"key":"2025102309300589000_2025.10.16.682893v1.11","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-021-01377-8"},{"key":"2025102309300589000_2025.10.16.682893v1.12","doi-asserted-by":"publisher","DOI":"10.1126\/science.abj0299"},{"key":"2025102309300589000_2025.10.16.682893v1.13","doi-asserted-by":"publisher","DOI":"10.1016\/J.CELL.2020.09.037"},{"key":"2025102309300589000_2025.10.16.682893v1.14","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.adf1421"},{"key":"2025102309300589000_2025.10.16.682893v1.15","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abi9915"},{"key":"2025102309300589000_2025.10.16.682893v1.16","doi-asserted-by":"publisher","DOI":"10.1126\/science.abg9175"},{"key":"2025102309300589000_2025.10.16.682893v1.17","doi-asserted-by":"publisher","DOI":"10.1038\/d41586-021-03832-5"},{"key":"2025102309300589000_2025.10.16.682893v1.18","first-page":"572","article-title":"On the doctrine of original antigenic sin","volume":"104","year":"1960","journal-title":"Proc Am Philos Soc"},{"key":"2025102309300589000_2025.10.16.682893v1.19","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMOA2114583"},{"key":"2025102309300589000_2025.10.16.682893v1.20","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abn8057"},{"key":"2025102309300589000_2025.10.16.682893v1.21","doi-asserted-by":"publisher","DOI":"10.2807\/1560-7917.ES.2022.27.2.2101197"},{"key":"2025102309300589000_2025.10.16.682893v1.22","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2024.02.016"},{"key":"2025102309300589000_2025.10.16.682893v1.23","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1317793111"},{"key":"2025102309300589000_2025.10.16.682893v1.24","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1213737110"},{"key":"2025102309300589000_2025.10.16.682893v1.25","doi-asserted-by":"crossref","first-page":"101668","DOI":"10.1016\/j.xcrm.2024.101668","article-title":"Hybrid immunity to SARS-CoV-2 arises from serological recall of IgG antibodies distinctly imprinted by infection or vaccination","volume":"5","year":"2024","journal-title":"Cell Rep. Med"},{"key":"2025102309300589000_2025.10.16.682893v1.26","doi-asserted-by":"publisher","DOI":"10.1126\/science.aag1322"},{"key":"2025102309300589000_2025.10.16.682893v1.27","doi-asserted-by":"publisher","DOI":"10.1126\/science.1205669"},{"key":"2025102309300589000_2025.10.16.682893v1.28","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20101352"},{"key":"2025102309300589000_2025.10.16.682893v1.29","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-06487-6"},{"key":"2025102309300589000_2025.10.16.682893v1.30","doi-asserted-by":"crossref","unstructured":"Park, Y.-J. , Pinto, D. , Walls, A.C. , Liu, Z. , De Marco, A. , Benigni, F. , Zatta, F. , Silacci-Fregni, C. , Bassi, J. , Sprouse, K.R. , et al. (2022). Imprinted antibody responses against SARS-CoV-2 Omicron sublineages. Science, eadc 9127.","DOI":"10.1126\/science.adc9127"},{"key":"2025102309300589000_2025.10.16.682893v1.31","first-page":"521","article-title":"Imprinted SARS-CoV-2 humoral immunity induces convergent Omicron RBD evolution","volume":"614","year":"2023","journal-title":"Nature"},{"key":"2025102309300589000_2025.10.16.682893v1.32","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2024.02.017"},{"key":"2025102309300589000_2025.10.16.682893v1.33","doi-asserted-by":"crossref","first-page":"101258","DOI":"10.1016\/j.xcrm.2023.101258","article-title":"Deep immunological imprinting due to the ancestral spike in the current bivalent COVID-19 vaccine","volume":"4","year":"2023","journal-title":"Cell Rep Med"},{"key":"2025102309300589000_2025.10.16.682893v1.34","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-07539-1"},{"key":"2025102309300589000_2025.10.16.682893v1.35","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-06025-4"},{"key":"2025102309300589000_2025.10.16.682893v1.36","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.abq3511"},{"key":"2025102309300589000_2025.10.16.682893v1.37","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.abq2427"},{"key":"2025102309300589000_2025.10.16.682893v1.38","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.adk5845"},{"key":"2025102309300589000_2025.10.16.682893v1.39","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-06753-7"},{"key":"2025102309300589000_2025.10.16.682893v1.40","doi-asserted-by":"crossref","first-page":"2412623","DOI":"10.1080\/22221751.2024.2412623","article-title":"Prolonged Omicron-specific B cell maturation alleviates immune imprinting induced by SARS-CoV-2 inactivated vaccine","volume":"13","year":"2024","journal-title":"Emerg. Microbes Infect"},{"key":"2025102309300589000_2025.10.16.682893v1.41","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-05609-w"},{"key":"2025102309300589000_2025.10.16.682893v1.42","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-05715-3"},{"key":"2025102309300589000_2025.10.16.682893v1.43","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.adp9927"},{"key":"2025102309300589000_2025.10.16.682893v1.44","doi-asserted-by":"crossref","first-page":"100690","DOI":"10.1016\/j.mcpro.2023.100690","article-title":"Into the dark serum proteome: Personalized features of IgG1 and IgA1 repertoires in severe COVID-19 patients","volume":"23","year":"2024","journal-title":"Mol. Cell. Proteomics"},{"key":"2025102309300589000_2025.10.16.682893v1.45","doi-asserted-by":"crossref","unstructured":"Addetia, A. , Sch\u00e4fer, A. , Sprouse, K. , Valdez, A. , Taylor, A. , Navarro, M.-J. , Brown, J.T. , Leaf, E.M. , Miranda, M.C. , Walls, A.C. , et al. (2025). Phylogeny-driven design of broadly protective sarbecovirus receptor-binding domain nanoparticle vaccines. Immunology.","DOI":"10.1101\/2025.05.11.652904"},{"key":"2025102309300589000_2025.10.16.682893v1.46","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(23)00373-0"},{"key":"2025102309300589000_2025.10.16.682893v1.47","doi-asserted-by":"crossref","unstructured":"Kurhade, C. , Zou, J. , Xia, H. , Liu, M. , Chang, H.C. , Ren, P. , Xie, X. , and Shi, P.-Y . (2022). Low neutralization of SARS-CoV-2 Omicron BA.2.75.2, BQ.1.1 and XBB.1 by parental mRNA vaccine or a BA.5 bivalent booster. Nat. Med., 1\u20134.","DOI":"10.1101\/2022.10.31.514580"},{"key":"2025102309300589000_2025.10.16.682893v1.48","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMc2402779"},{"key":"2025102309300589000_2025.10.16.682893v1.49","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-025-59344-7"},{"key":"2025102309300589000_2025.10.16.682893v1.50","doi-asserted-by":"publisher","DOI":"10.1126\/science.abd0826"},{"key":"2025102309300589000_2025.10.16.682893v1.51","doi-asserted-by":"publisher","DOI":"10.1016\/J.CHOM.2020.06.021"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2025.10.16.682893","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T05:08:35Z","timestamp":1782277715000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2025.10.16.682893"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,20]]},"references-count":51,"URL":"https:\/\/doi.org\/10.1101\/2025.10.16.682893","relation":{"is-preprint-of":[{"id-type":"doi","id":"10.1016\/j.celrep.2026.117052","asserted-by":"subject"}]},"subject":[],"published":{"date-parts":[[2025,10,20]]},"subtype":"preprint"}}