🕷️ Crawler Inspector

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Raw Queries and Responses

1. Shard Calculation

Query:

Response:

Calculated Shard: 23 (from laksa098)

2. Crawled Status Check

Query:

curl -X POST \
  'http://laksa023.int.ahrefs:8124/' \
  -H 'Content-Type: text/plain' \
  -H 'X-ClickHouse-Database: crawler3' \
  -H 'Authorization: Basic YXBpOg==' \
  -d 'SELECT getAhrefsURLFromUnparsed(src_unparsed) AS found_url, ifNull(toUnixTimestamp(download_stamp), 0) AS crawl_time, ifNull(toUnixTimestamp(props_url_first_seen), 0) AS first_indexed_time, download_http_code AS http_code, src_unparsed AS src_unparsed, src_root_hash AS src_root_hash, history_drop_reason AS history_drop_reason, meta_title AS meta_title, meta_descriptions AS meta_descriptions, attrs_boilerpipe_text AS attrs_boilerpipe_text, attrs_markdown AS attrs_markdown, attrs_readable_markdown AS attrs_readable_markdown, meta_canonical AS meta_canonical FROM crawler3.page_info_local FINAL PREWHERE (src_root_hash, src_unparsed) IN ((getAhrefsRootHashFromUnparsed(getAhrefsUnparsedNoserviceFromURL(\'https://www.science.org/doi/10.1126/scitranslmed.adq1086\')), getAhrefsUnparsedNoserviceFromURL(\'https://www.science.org/doi/10.1126/scitranslmed.adq1086\'))) FORMAT JSONEachRow'

Response:

{"found_url":"https:\/\/www.science.org\/doi\/10.1126\/scitranslmed.adq1086","crawl_time":1769178847,"first_indexed_time":1738180307,"http_code":200,"src_unparsed":"org,science!www,\/doi\/10.1126\/scitranslmed.adq1086 s443","src_root_hash":"18350995765413815023","history_drop_reason":null,"meta_title":"Prior vaccination prevents overactivation of innate immune responses during COVID-19 breakthrough infection | Science Translational Medicine","meta_descriptions":["At this stage in the COVID-19 pandemic, most infections are “breakthrough” infections that occur in individuals with prior severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exposure. To ..."],"attrs_boilerpipe_text":"Editor’s summary\nSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines were instrumental in curbing the COVID-19 pandemic, with the benefit of vaccination primarily attributed to the adaptive immune response. Although it is well established that antibodies and T cells against SARS-CoV-2 prevent severe disease, the role of the innate immune system should not be disregarded. Here, Chan\net al.\ndemonstrated precisely why. The authors compared individuals infected with SARS-CoV-2 during the Delta wave with or without prior vaccination. They found that prior vaccination tamped down excessive inflammatory responses often associated with more severe disease, particularly in monocytes and natural killer cells. The authors further validated these findings in a separate cohort during a different wave of infection. These data suggest that vaccination may influence the innate immune response, and consequently disease severity, during a SARS-CoV-2 breakthrough infection. —Courtney Malo\nAbstract\nAt this stage in the COVID-19 pandemic, most infections are “breakthrough” infections that occur in individuals with prior severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exposure. To refine long-term vaccine strategies against emerging variants, we examined both innate and adaptive immunity in breakthrough infections. We performed single-cell transcriptomic, proteomic, and functional profiling of primary and breakthrough infections to compare immune responses from unvaccinated and vaccinated individuals during the SARS-CoV-2 Delta wave. Breakthrough infections were characterized by a less activated transcriptomic profile in monocytes and natural killer cells, with induction of pathways limiting monocyte migratory potential and natural killer cell proliferation. Furthermore, we observed a female-specific increase in transcriptomic and proteomic activation of multiple innate immune cell subsets during breakthrough infections. These insights suggest that prior SARS-CoV-2 vaccination prevents overactivation of innate immune responses during breakthrough infections with discernible sex-specific patterns and underscore the potential of harnessing vaccines in mitigating pathologic immune responses resulting from overactivation.\nAccess the full article\nView all access options to continue reading this article.\nSupplementary Materials\nThe PDF file includes:\nMaterials and methods\nFigs. S1 to S13\nTables S1 to S5\nReferences (\n67\n–\n84\n)\nDownload\n7.59 MB\nOther Supplementary Material for this manuscript includes the following:\nMDAR Reproducibility Checklist\nDownload\n459.58 KB\nREFERENCES AND NOTES\n1\nZ. Al-Aly, B. Bowe, Y. Xie, Long COVID after breakthrough SARS-CoV-2 infection.\nNat. Med.\n28\n, 1461–1467 (2022).\n2\nQ. Fan, J. Shi, Y. Yang, G. Tang, M. Jiang, J. Li, J. Tang, L. Li, X. Wen, L. Zhang, X. Deng, Y. Wang, Y. Lan, L. Li, P. Peng, Y. Tong, H. Lu, L. Yan, Y. Liu, S. Cai, Y. Li, X. Mo, M. Li, X. Deng, Z. Hu, H. Yu, F. Hu, J. Liu, X. Tang, F. Li, Clinical characteristics and immune profile alterations in vaccinated individuals with breakthrough Delta SARS-CoV-2 infections.\nNat. Commun.\n13\n, 3979 (2022).\n3\nA.-R. Y. Collier, C. M. Brown, K. Mcmahan, J. Yu, J. Liu, C. Jacob-Dolan, A. Chandrashekar,D. Tierney, J. L. Ansel, M. Rowe, D. Sellers, K. Ahmad, R. Aguayo, T. Anioke, S. Gardner,M. Siamatu, L. Bermudez Rivera, M. R. Hacker, L. C. Madoff, D. H. Barouch, Immune responses in fully vaccinated individuals following breakthrough infection with the SARS-CoV-2 Delta variant in Provincetown, Massachusetts. medRxiv 21265113 [Preprint] (2021).\nhttps:\/\/doi.org\/10.1101\/2021.10.18.21265113\n.\n4\nM. Koutsakos, W. S. Lee, A. Reynaldi, H.-X. Tan, G. Gare, P. Kinsella, K. C. Liew, G. Taiaroa, D. A. Williamson, H. E. Kent, E. Stadler, D. Cromer, D. S. Khoury, A. K. Wheatley, J. A. Juno, M. P. Davenport, S. J. Kent, The magnitude and timing of recalled immunity after breakthrough infection is shaped by SARS-CoV-2 variants.\nImmunity\n55\n, 1316–1326.e4 (2022).\n5\nJ. Pušnik, W. O. Monzon-Posadas, J. Zorn, K. Peters, M. Baum, H. Proksch, C. B. Schlüter, G. Alter, T. Menting, H. Streeck, SARS-CoV-2 humoral and cellular immunity following different combinations of vaccination and breakthrough infection.\nNat. Commun.\n14\n, 572 (2023).\n6\nM. M. Painter, T. S. Johnston, K. A. Lundgreen, J. J. S. Santos, J. S. Qin, R. R. Goel, S. A. Apostolidis, D. Mathew, B. Fulmer, J. C. Williams, M. L. McKeague, A. Pattekar, A. Goode, S. Nasta, A. E. Baxter, J. R. Giles, A. N. Skelly, L. E. Felley, M. McLaughlin, J. Weaver, P. M. BioBank, O. Kuthuru, J. Dougherty, S. Adamski, S. Long, M. Kee, C. Clendenin, R. da Silva Antunes, A. Grifoni, D. Weiskopf, A. Sette, A. C. Huang, D. J. Rader, S. E. Hensley, P. Bates, A. R. Greenplate, E. J. 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Pastor, D. Swaim, R. Dewar, T. Rehman, H. C. Highbarger, P. Lallemand, S. Laverdure, J. Adelsberger, A. Rupert, W. Li, J. Krack, G. Teferi, J. Kuruppu, J. R. Strich, R. Davey, R. Childs, D. Chertow, J. A. Kovacs, C. Barnett, P. Torabi-Parizi, A. F. Suffredini, COVID-ARC Study Group, Vaccination ameliorates cellular inflammatory responses in SARS-CoV-2 breakthrough infections.\nJ. Infect. Dis.\n228\n, 46–58 (2023).\n19\nP. S. Arunachalam, M. K. D. Scott, T. Hagan, C. Li, Y. Feng, F. Wimmers, L. Grigoryan, M. Trisal, V. V. Edara, L. Lai, S. E. Chang, A. Feng, S. Dhingra, M. Shah, A. S. Lee, S. Chinthrajah, S. B. Sindher, V. Mallajosyula, F. Gao, N. Sigal, S. Kowli, S. Gupta, K. Pellegrini, G. Tharp, S. Maysel-Auslender, S. Hamilton, H. Aoued, K. Hrusovsky, M. Roskey, S. E. Bosinger, H. T. Maecker, S. D. Boyd, M. M. Davis, P. J. Utz, M. S. Suthar, P. Khatri, K. C. Nadeau, B. Pulendran, Systems vaccinology of the BNT162b2 mRNA vaccine in humans.\nNature\n596\n, 410–416 (2021).\n20\nM. 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Fredriksson, Homogenous 96-Plex PEA immunoassay exhibiting high sensitivity, specificity, and excellent scalability.\nPLOS ONE\n9\n, e95192 (2014).","attrs_markdown":"[Skip to main content](https:\/\/www.science.org\/doi\/10.1126\/scitranslmed.adq1086#main-content-focus)\n\n- [news](https:\/\/www.science.org\/news)\n- [careers](https:\/\/www.science.org\/careers)\n- [commentary](https:\/\/www.science.org\/commentary)\n- [Journals](https:\/\/www.science.org\/journals)\n\n[![](https:\/\/www.science.org\/pb-assets\/images\/styleguide\/logo-dark-1672180581427.svg) ![Science](https:\/\/www.science.org\/pb-assets\/images\/styleguide\/logo-1672180580750.svg)](https:\/\/www.science.org\/)\n\n- [Log in](https:\/\/www.science.org\/action\/ssostart?redirectUri=%2Fdoi%2F10.1126%2Fscitranslmed.adq1086)\n- [Become A Member](https:\/\/promo.aaas.org\/science\/join\/?CTC=SMHPJN)\n\n[![journal-menu-img](https:\/\/www.science.org\/cms\/asset\/a51ce242-9dc7-42a4-86ca-98ef032dd13c\/science.2026.391.issue-6783.cover.gif)science](https:\/\/www.science.org\/journal\/science \"Science\")\n\n[![journal-menu-img](https:\/\/www.science.org\/cms\/asset\/e566ebbd-d9d9-4cac-988c-d12905e2d83f\/sciadv.2026.12.issue-4.cover.gif)science advances](https:\/\/www.science.org\/journal\/sciadv \"Science\")\n\n[![journal-menu-img](https:\/\/www.science.org\/cms\/asset\/cba30519-96c0-495c-9947-985829095f0c\/sciimmunol.2026.11.issue-115.cover.gif)science immunology](https:\/\/www.science.org\/journal\/sciimmunol \"Science\")\n\n[![journal-menu-img](https:\/\/www.science.org\/cms\/asset\/1333ca1b-6bc8-4d65-ab59-8dbf5853a774\/scirobotics.2026.11.issue-110.cover.gif)science robotics](https:\/\/www.science.org\/journal\/scirobotics \"Science\")\n\n[![journal-menu-img](https:\/\/www.science.org\/cms\/asset\/2610723a-6c19-4439-8c13-f3aaa9a746a3\/signaling.2026.19.issue-921.cover.gif)science signaling](https:\/\/www.science.org\/journal\/signaling \"Science\")\n\n[![journal-menu-img](https:\/\/www.science.org\/cms\/asset\/ddf0f849-fce1-4ea1-93b3-8a24d56a9777\/stm.2026.18.issue-833.cover.gif)science translational medicine](https:\/\/www.science.org\/journal\/stm \"Science\")\n\n[![journal-menu-img](https:\/\/www.science.org\/pb-assets\/images\/styleguide\/spj-cover-1695403298717.png)science partner journals](https:\/\/spj.science.org\/ \"Science Partner Journals\")\n\nSearching:\n\nAnywhere\n\n[Anywhere](https:\/\/www.science.org\/doi\/10.1126\/scitranslmed.adq1086#quick-search-form-9ea9b667-c3ce-40d1-870b-f7e001bbac01-0)[Science](https:\/\/www.science.org\/doi\/10.1126\/scitranslmed.adq1086#quick-search-form-9ea9b667-c3ce-40d1-870b-f7e001bbac01-1)[Science Advances](https:\/\/www.science.org\/doi\/10.1126\/scitranslmed.adq1086#quick-search-form-9ea9b667-c3ce-40d1-870b-f7e001bbac01-2)[Science Immunology](https:\/\/www.science.org\/doi\/10.1126\/scitranslmed.adq1086#quick-search-form-9ea9b667-c3ce-40d1-870b-f7e001bbac01-3)[Science Robotics](https:\/\/www.science.org\/doi\/10.1126\/scitranslmed.adq1086#quick-search-form-9ea9b667-c3ce-40d1-870b-f7e001bbac01-4)[Science Signaling](https:\/\/www.science.org\/doi\/10.1126\/scitranslmed.adq1086#quick-search-form-9ea9b667-c3ce-40d1-870b-f7e001bbac01-5)[Science Translational Medicine](https:\/\/www.science.org\/doi\/10.1126\/scitranslmed.adq1086#quick-search-form-9ea9b667-c3ce-40d1-870b-f7e001bbac01-6)\n\n[Advanced Search](https:\/\/www.science.org\/search\/advanced)\n\nSearch\n\n###### Trending Terms:\n- [cancer](https:\/\/www.science.org\/action\/doSearch?AllField=cancer)\n- [climate](https:\/\/www.science.org\/action\/doSearch?AllField=climate)\n- [artificial intelligence](https:\/\/www.science.org\/action\/doSearch?AllField=artificial%20intelligence)\n- [postdoc](https:\/\/www.science.org\/action\/doSearch?AllField=postdoc)\n- [aging](https:\/\/www.science.org\/action\/doSearch?AllField=aging)\n\n- [Log In](https:\/\/www.science.org\/action\/ssostart?redirectUri=\/doi\/10.1126\/scitranslmed.adq1086)\n\n- [Become A Member](https:\/\/promo.aaas.org\/science\/join\/?CTC=SMLDJN)\n- [Donate](https:\/\/www.science.org\/news\/donate?intcmp=sitemenu-donate&utm_id=recB0g01G48yiGSBD)\n\n[science.org](https:\/\/www.science.org\/)\n\n- [news](https:\/\/www.science.org\/news)\n- [careers](https:\/\/www.science.org\/careers)\n- [commentary](https:\/\/www.science.org\/commentary)\n- [Journals](https:\/\/www.science.org\/journals)\n- [science](https:\/\/www.science.org\/journal\/science)\n- [science advances](https:\/\/www.science.org\/journal\/sciadv)\n- [science immunology](https:\/\/www.science.org\/journal\/sciimmunol)\n- [science robotics](https:\/\/www.science.org\/journal\/scirobotics)\n- [science signaling](https:\/\/www.science.org\/journal\/signaling)\n- [science translational medicine](https:\/\/www.science.org\/journal\/stm)\n  - 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[Submit manuscript](https:\/\/cts.sciencemag.org\/)\n\n[GET OUR E-ALERTS](https:\/\/www.science.org\/action\/showPreferences?menuTab=Alerts)\n\nMain content starts here\n\n[Home](https:\/\/www.science.org\/)[Science Translational Medicine](https:\/\/www.science.org\/journal\/stm)[Vol. 17, No. 783](https:\/\/www.science.org\/toc\/stm\/17\/783)Prior vaccination prevents overactivation of innate immune responses during COVID-19 breakthrough infection\n\n[Back To Vol. 17, No. 783](https:\/\/www.science.org\/toc\/stm\/17\/783)\n\nNo access\n\nResearch Article\n\nCORONAVIRUS\n\nShare on\n# Prior vaccination prevents overactivation of innate immune responses during COVID-19 breakthrough infection\n[Leslie Chan](https:\/\/www.science.org\/doi\/10.1126\/scitranslmed.adq1086#con1) <https:\/\/orcid.org\/0000-0002-5064-140X>, [Kassandra Pinedo](https:\/\/www.science.org\/doi\/10.1126\/scitranslmed.adq1086#con2) <https:\/\/orcid.org\/0009-0008-5356-6813>, \\[...\\] , [Mikayla A. Stabile](https:\/\/www.science.org\/doi\/10.1126\/scitranslmed.adq1086#con3), [Rebecca E. Hamlin](https:\/\/www.science.org\/doi\/10.1126\/scitranslmed.adq1086#con4) <https:\/\/orcid.org\/0000-0001-7336-6028>, \\[...\\] , [Shaun M. Pienkos](https:\/\/www.science.org\/doi\/10.1126\/scitranslmed.adq1086#con5) <https:\/\/orcid.org\/0009-0001-8409-4803>, [Kalani Ratnasiri](https:\/\/www.science.org\/doi\/10.1126\/scitranslmed.adq1086#con6) <https:\/\/orcid.org\/0000-0001-5953-0004>, [Stanford COVID-19 Biobank](https:\/\/www.science.org\/doi\/10.1126\/scitranslmed.adq1086#con7), [Samuel Yang](https:\/\/www.science.org\/doi\/10.1126\/scitranslmed.adq1086#con8) <https:\/\/orcid.org\/0000-0003-1123-9036>, [Andra L. Blomkalns](https:\/\/www.science.org\/doi\/10.1126\/scitranslmed.adq1086#con9) <https:\/\/orcid.org\/0000-0001-5760-6351>, \\[...\\] , [Kari C. Nadeau](https:\/\/www.science.org\/doi\/10.1126\/scitranslmed.adq1086#con10) <https:\/\/orcid.org\/0000-0002-2146-2955>, [Bali Pulendran](https:\/\/www.science.org\/doi\/10.1126\/scitranslmed.adq1086#con11) <https:\/\/orcid.org\/0000-0001-6517-4333>, [Ruth O’Hara](https:\/\/www.science.org\/doi\/10.1126\/scitranslmed.adq1086#con12) <https:\/\/orcid.org\/0000-0001-6583-4995>, [Angela J. Rogers](https:\/\/www.science.org\/doi\/10.1126\/scitranslmed.adq1086#con13) <https:\/\/orcid.org\/0000-0001-6969-6200>, [Susan P. Holmes](https:\/\/www.science.org\/doi\/10.1126\/scitranslmed.adq1086#con14) <https:\/\/orcid.org\/0000-0002-2208-8168>, and [Catherine A. Blish](https:\/\/www.science.org\/doi\/10.1126\/scitranslmed.adq1086#con15) <https:\/\/orcid.org\/0000-0001-6946-7627>\\+12 authors \\+10 authors \\+5 authors  fewer[Authors Info & Affiliations](https:\/\/www.science.org\/doi\/10.1126\/scitranslmed.adq1086#tab-contributors)\n\nScience Translational Medicine\n\n29 Jan 2025\n\nVol 17, Issue 783\n\n[DOI: 10.1126\/scitranslmed.adq1086](https:\/\/doi.org\/10.1126\/scitranslmed.adq1086)\n\n[PREVIOUS ARTICLE Undocking of an extensive ciliary network induces proteostasis and cell fate switching resulting in severe primary ciliary dyskinesiaPrevious](https:\/\/www.science.org\/doi\/10.1126\/scitranslmed.adp5173 \"Undocking of an extensive ciliary network induces proteostasis and cell fate switching resulting in severe primary ciliary dyskinesia\")\n\n[NEXT ARTICLE Correcting a pathogenic mitochondrial DNA mutation by base editing in miceNext](https:\/\/www.science.org\/doi\/10.1126\/scitranslmed.adr0792 \"Correcting a pathogenic mitochondrial DNA mutation by base editing in mice\")\n\n[Notifications](https:\/\/www.science.org\/action\/addCitationAlert?doi=10.1126%2Fscitranslmed.adq1086)[Bookmark](https:\/\/www.science.org\/personalize\/addFavoritePublication?doi=10.1126%2Fscitranslmed.adq1086)\n\n[CHECK ACCESS](https:\/\/www.science.org\/doi\/10.1126\/scitranslmed.adq1086#core-collateral-purchase-access)\n\nContents\n\n- [Editor’s summary](https:\/\/www.science.org\/doi\/10.1126\/scitranslmed.adq1086#editor-abstract)\n- [Abstract](https:\/\/www.science.org\/doi\/10.1126\/scitranslmed.adq1086#abstract)\n- [Supplementary Materials](https:\/\/www.science.org\/doi\/10.1126\/scitranslmed.adq1086#supplementary-materials)\n- [REFERENCES AND NOTES](https:\/\/www.science.org\/doi\/10.1126\/scitranslmed.adq1086#bibliography)\n\n- [Information & Authors](https:\/\/www.science.org\/doi\/10.1126\/scitranslmed.adq1086#core-collateral-info)\n- [Metrics & Citations](https:\/\/www.science.org\/doi\/10.1126\/scitranslmed.adq1086#core-collateral-metrics)\n- [Check Access](https:\/\/www.science.org\/doi\/10.1126\/scitranslmed.adq1086#core-collateral-purchase-access)\n- [References](https:\/\/www.science.org\/doi\/10.1126\/scitranslmed.adq1086#core-collateral-references)\n- [Figures](https:\/\/www.science.org\/doi\/10.1126\/scitranslmed.adq1086#core-collateral-figures)\n- [Tables](https:\/\/www.science.org\/doi\/10.1126\/scitranslmed.adq1086#core-collateral-tables)\n- [Media](https:\/\/www.science.org\/doi\/10.1126\/scitranslmed.adq1086#core-collateral-media)\n- [Share](https:\/\/www.science.org\/doi\/10.1126\/scitranslmed.adq1086#core-collateral-share)\n\n## Editor’s summary\nSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines were instrumental in curbing the COVID-19 pandemic, with the benefit of vaccination primarily attributed to the adaptive immune response. Although it is well established that antibodies and T cells against SARS-CoV-2 prevent severe disease, the role of the innate immune system should not be disregarded. Here, Chan *et al.* demonstrated precisely why. The authors compared individuals infected with SARS-CoV-2 during the Delta wave with or without prior vaccination. They found that prior vaccination tamped down excessive inflammatory responses often associated with more severe disease, particularly in monocytes and natural killer cells. The authors further validated these findings in a separate cohort during a different wave of infection. These data suggest that vaccination may influence the innate immune response, and consequently disease severity, during a SARS-CoV-2 breakthrough infection. —Courtney Malo\n\n## Abstract\nAt this stage in the COVID-19 pandemic, most infections are “breakthrough” infections that occur in individuals with prior severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exposure. To refine long-term vaccine strategies against emerging variants, we examined both innate and adaptive immunity in breakthrough infections. We performed single-cell transcriptomic, proteomic, and functional profiling of primary and breakthrough infections to compare immune responses from unvaccinated and vaccinated individuals during the SARS-CoV-2 Delta wave. Breakthrough infections were characterized by a less activated transcriptomic profile in monocytes and natural killer cells, with induction of pathways limiting monocyte migratory potential and natural killer cell proliferation. Furthermore, we observed a female-specific increase in transcriptomic and proteomic activation of multiple innate immune cell subsets during breakthrough infections. These insights suggest that prior SARS-CoV-2 vaccination prevents overactivation of innate immune responses during breakthrough infections with discernible sex-specific patterns and underscore the potential of harnessing vaccines in mitigating pathologic immune responses resulting from overactivation.\n\n## Access the full article\nView all access options to continue reading this article.\n\n[CHECK ACCESS](https:\/\/www.science.org\/doi\/10.1126\/scitranslmed.adq1086#core-collateral-purchase-access)\n\nALREADY A SUBSCRIBER OR AAAS MEMBER? Sign in as an [individual](https:\/\/www.science.org\/action\/showLogin?redirectUri=%2Fdoi%2F10.1126%2Fscitranslmed.adq1086) or via your [institution](https:\/\/www.science.org\/action\/ssostart?redirectUri=%2Fdoi%2F10.1126%2Fscitranslmed.adq1086)\n\n## Supplementary Materials\n### The PDF file includes:\nMaterials and methods\n\nFigs. S1 to S13\n\nTables S1 to S5\n\nReferences ([*67*](https:\/\/www.science.org\/doi\/10.1126\/scitranslmed.adq1086#R67)–[*84*](https:\/\/www.science.org\/doi\/10.1126\/scitranslmed.adq1086#R84))\n\n- [Download](https:\/\/www.science.org\/doi\/suppl\/10.1126\/scitranslmed.adq1086\/suppl_file\/scitranslmed.adq1086_sm.pdf)\n- 7\\.59 MB\n\n### Other Supplementary Material for this manuscript includes the following:\nData files S1 to S4\n\n- [Download](https:\/\/www.science.org\/doi\/suppl\/10.1126\/scitranslmed.adq1086\/suppl_file\/scitranslmed.adq1086_data_files_s1_to_s4.zip)\n- 1\\.59 MB\n\nMDAR Reproducibility Checklist\n\n- [Download](https:\/\/www.science.org\/doi\/suppl\/10.1126\/scitranslmed.adq1086\/suppl_file\/scitranslmed.adq1086_mdar_reproducibility_checklist.pdf)\n- 459\\.58 KB\n\n## REFERENCES AND NOTES\n1\n\nZ. Al-Aly, B. Bowe, Y. Xie, Long COVID after breakthrough SARS-CoV-2 infection. *Nat. 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No claim to original U.S. Government Works.\n\n<https:\/\/www.sciencemag.org\/about\/science-licenses-journal-article-reuse>\n\nThis is an article distributed under the terms of the [Science Journals Default License](https:\/\/www.science.org\/content\/page\/science-licenses-journal-article-reuse).\n\n#### Permissions\nRequest permissions for this article.\n\n[Request Permissions](https:\/\/s100.copyright.com\/AppDispatchServlet?publisherName=AAAS&publication=scitransmed&title=Prior+vaccination+prevents+overactivation+of+innate+immune+responses+during+COVID-19+breakthrough+infection&publicationDate=2025-01-29&author=Leslie+Chan%2C+Kassandra+Pinedo%2C+Mikayla+A.+Stabile%2C+Rebecca+E.+Hamlin%2C+et+al.&contentID=10.1126%2Fscitranslmed.adq1086&volumeNum=17&issueNum=783&numPages=17&orderBeanReset=true&section=A)\n#### Article versions\n#### Submission history\n**Received**: 3 May 2024\n\n**Resubmitted**: 10 September 2024\n\n**Accepted**: 16 December 2024\n\n#### Acknowledgments\nWe are grateful to all participants in this cohort. We appreciate M. Davis and his laboratory for allowing us to use the Helios mass cytometer. Special thanks to A. Rustagi for assistance with the Parse Biosciences scRNA-seq library preparation and preprocessing pipeline. We thank N. Neff and A. Seng at the Chan Zuckerberg Biohub for assistance with sequencing. We thank T. T. Nguyen at Stanford University’s Human Immune Monitoring Core for performing the Olink plasma proteomic assay. We are grateful to I. de los Rios Kobara for the gift of SARS-CoV-2 Delta pseudovirus and assistance with the pseudovirus neutralization assay protocol. We thank P. Kim, J. Bloom, and D. Xu for the gift of HeLa-ACE2-TMPRSS2 cells. Figure illustrations were created using [BioRender.com](http:\/\/biorender.com\/).\n\n**Funding:** This work was supported by NIH-funded institutional training grants 5T32AI007290-37 (to L.C.), F31AI179125 (to L.C.), T32AI007502 (to R.E.H.), and 5T32HL129970 (to S.M.P.); the Bill and Melinda Gates Foundation OPP113682 (to C.A.B.); NIH\/NIAID K23 HL124663 (to A.J.R.); Burroughs Wellcome Investigators in the Pathogenesis of Infectious Disease 1016687 (to C.A.B.); a gift from the Quattrone family (to C.A.B.); NIH\/NIAID U19AI057229–17W1 COVID SUPP \\#2 (to C.A.B.); the Chan Zuckerberg Biohub Investigator Program (to C.A.B.); and the Mercatus Center (to C.A.B.).\n\n**Author contributions:** L.C. and C.A.B. conceived the project and designed experiments. S.Y., A.L.B., K.C.N., R.O., A.J.R., and C.A.B. conceived the clinical cohort of infected COVID-19 participants and obtained clinical samples. Stanford COVID-19 Biobank enrolled, consented, and processed clinical samples. K.P. coordinated transfer of COVID-19 clinical samples and provided clinical input. B.P. and K.C.N. conceived the clinical cohort of healthy COVID-19–vaccinated participants and obtained clinical samples. L.C., R.E.H., M.A.S., and K.P. produced the mass cytometry reagents. L.C., K.P., and M.A.S. acquired mass cytometry data. L.C. acquired single-cell transcriptomic data. L.C. performed bioinformatic and statistical analyses with supervision from S.P.H. and C.A.B. R.E.H., S.M.P., K.R., and S.P.H. provided intellectual input. L.C. and C.A.B. wrote the manuscript, which was reviewed by all authors.\n\n**Competing interests:** C.A.B. is a scientific advisory board member of ImmuneBridge, DeepCell Inc., and Qihan Bio on topics unrelated to this manuscript. B.P. served on the external immunology board of GSK and on the scientific advisory boards of Sanofi, Medicago, Boehringer Ingelheim, Pharmajet, Icosavax, and Ed-Jen. K.C.N. consults for Excellergy, Red Tree Ventures, Before Brands, Alladapt, Cour Pharma, Latitude, Regeneron, and IgGenix; is a cofounder of Before Brands, Alladpt, Latitude, and IgGenix; and is a national scientific committee member at Immune Tolerance Network (ITN) and NIH clinical research centers. All other authors declare that they have no competing interests.\n\n**Data and materials availability:** All data associated with this study are present in the paper or the Supplementary Materials. Mass cytometry FCS files with deidentified metadata supporting this publication are available at Flow Repository (<http:\/\/flowrepository.org>) under repository ID: FR-FCM-Z77Q. Data from scRNA-seq are deposited in the Gene Expression Omnibus (GEO) database under accession no. GSE261862. Olink data are available in data file S1. Data from the ChAdOx1-nCOV-199 vaccination validation cohort are deposited in GEO under accession no. GSE228842. A Zenodo repository for all original code used for analysis and visualization is available at DOI: [10\\.5281\/zenodo.13972674](https:\/\/doi.org\/10.5281\/zenodo.13972674).\n\n**Stanford COVID-19 Biobank:** In addition to the authors (C.A.B., A.L.B., K.C.N., R.O., A.J.R., and S.Y.), the following Stanford COVID-19 Biobank members contributed to enrollment, acquisition of participant consent, and processing of clinical samples:\n\nThanmayi Ranganath2, Nancy Q. Zhao1,2, Aaron J. Wilk1,2,10, Rosemary Vergara2, Julia L. McKechnie1,2, Lauren de la Parte2, Kathleen Whittle Dantzler2, Maureen Ty2, Nimish Kathale2, Giovanny J. Martínez-Colón2, Arjun Rustagi2, Geoff Ivison1,2, Ruoxi Pi2, Madeline J. Lee1,2, Rachel E. Brewer12,13, Taylor Hollis2, Andrea Baird2, Michele Ugur14, Michal C. Tal13, Drina Bogusch2, Georgie Nahass2, Kazim Haider2, Kim Quyen Thi Tran2, Laura Simpson2, Hena N. Din2,15, Jonasel Roque2, Rosen Mann2, Iris Chang2,15, Evan Do2,15, Andrea Fernandes2,15, Shu-Chen Lyu15, Wenming Zhang2,15, Monali Manohar2,15, James W. Krempski15, Anita Visweswaran2, Elizabeth J. Zudock3, Kathryn Jee16, Komal Kumar17, Jennifer A. Newberry3, James V. Quinn3, Donald Schreiber3, Euan A. Ashley2\n\nAffiliations 1 to 11 are listed on the first page of the paper.\n\n12Department of Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA.\n\n13Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.\n\n14Stanford Health Care, Stanford University, Stanford, CA 94305, USA.\n\n15Sean N. Parker Center for Allergy and Asthma Research, Palo Alto, CA 94304, USA.\n\n16Department of Dermatology, Stanford University School of Medicine, Stanford, CA 94305, USA.\n\n17Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA.\n\n### Authors\n#### Affiliations\nLeslie Chan <https:\/\/orcid.org\/0000-0002-5064-140X>\n\nStanford Immunology Program, Stanford University School of Medicine, Stanford, CA 94305, USA.\n\nDepartment of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.\n\nRoles: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Resources, Software, Validation, Visualization, Writing - original draft, and Writing - review & editing.\n\n[View all articles by this author](https:\/\/www.science.org\/authored-by\/Chan\/Leslie)\n\nKassandra Pinedo <https:\/\/orcid.org\/0009-0008-5356-6813>\n\nDepartment of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.\n\nRoles: Conceptualization, Investigation, Methodology, Resources, and Validation.\n\n[View all articles by this author](https:\/\/www.science.org\/authored-by\/Pinedo\/Kassandra)\n\nMikayla A. Stabile\n\nDepartment of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.\n\nRole: Investigation.\n\n[View all articles by this author](https:\/\/www.science.org\/authored-by\/Stabile\/Mikayla+A)\n\nRebecca E. Hamlin <https:\/\/orcid.org\/0000-0001-7336-6028>\n\nDepartment of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.\n\nRoles: Investigation, Resources, and Writing - review & editing.\n\n[View all articles by this author](https:\/\/www.science.org\/authored-by\/Hamlin\/Rebecca+E)\n\nShaun M. Pienkos <https:\/\/orcid.org\/0009-0001-8409-4803>\n\nDepartment of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.\n\nRoles: Conceptualization, Methodology, and Software.\n\n[View all articles by this author](https:\/\/www.science.org\/authored-by\/Pienkos\/Shaun+M)\n\nKalani Ratnasiri <https:\/\/orcid.org\/0000-0001-5953-0004>\n\nStanford Immunology Program, Stanford University School of Medicine, Stanford, CA 94305, USA.\n\nDepartment of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.\n\nRole: Software.\n\n[View all articles by this author](https:\/\/www.science.org\/authored-by\/Ratnasiri\/Kalani)\n\nStanford COVID-19 Biobank[†](https:\/\/www.science.org\/doi\/10.1126\/scitranslmed.adq1086#afn1)\n\nRole: Resources.\n\n[View all articles by this author](https:\/\/www.science.org\/authored-by\/group\/Stanford+COVID-19+Biobank)\n\nSamuel Yang <https:\/\/orcid.org\/0000-0003-1123-9036>\n\nDepartment of Emergency Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.\n\nRoles: Resources, Supervision, Validation, and Writing - review & editing.\n\n[View all articles by this author](https:\/\/www.science.org\/authored-by\/Yang\/Samuel)\n\nAndra L. Blomkalns <https:\/\/orcid.org\/0000-0001-5760-6351>\n\nDepartment of Emergency Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.\n\nRoles: Conceptualization, Investigation, Project administration, Resources, and Writing - review & editing.\n\n[View all articles by this author](https:\/\/www.science.org\/authored-by\/Blomkalns\/Andra+L)\n\nKari C. Nadeau <https:\/\/orcid.org\/0000-0002-2146-2955>\n\nDepartment of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.\n\nDepartment of Environmental Health, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA.\n\nRoles: Data curation, Funding acquisition, Investigation, Project administration, Resources, and Writing - review & editing.\n\n[View all articles by this author](https:\/\/www.science.org\/authored-by\/Nadeau\/Kari+C)\n\nBali Pulendran <https:\/\/orcid.org\/0000-0001-6517-4333>\n\nInstitute for Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, CA 94305, USA.\n\nDepartment of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.\n\nDepartment of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA.\n\nRoles: Resources and Writing - review & editing.\n\n[View all articles by this author](https:\/\/www.science.org\/authored-by\/Pulendran\/Bali)\n\nRuth O’Hara <https:\/\/orcid.org\/0000-0001-6583-4995>\n\nDepartment of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA.\n\nRoles: Conceptualization, Investigation, Supervision, and Writing - review & editing.\n\n[View all articles by this author](https:\/\/www.science.org\/authored-by\/O%E2%80%99Hara\/Ruth)\n\nAngela J. Rogers <https:\/\/orcid.org\/0000-0001-6969-6200>\n\nDepartment of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.\n\nRoles: Resources and Writing - review & editing.\n\n[View all articles by this author](https:\/\/www.science.org\/authored-by\/Rogers\/Angela+J)\n\nSusan P. Holmes <https:\/\/orcid.org\/0000-0002-2208-8168>\n\nDepartment of Statistics, Stanford University, Stanford, CA 94305, USA.\n\nRoles: Formal analysis, Software, Supervision, Validation, and Writing - review & editing.\n\n[View all articles by this author](https:\/\/www.science.org\/authored-by\/Holmes\/Susan+P)\n\nCatherine A. Blish[\\*](https:\/\/www.science.org\/doi\/10.1126\/scitranslmed.adq1086#cor1) <https:\/\/orcid.org\/0000-0001-6946-7627> [cblish@stanford.edu](mailto:cblish@stanford.edu)\n\nDepartment of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.\n\nStanford Medical Scientist Training Program, Stanford University School of Medicine, Stanford, CA 94305, USA.\n\nChan Zuckerberg Biohub, San Francisco, CA 94158, USA.\n\nRoles: Conceptualization, Funding acquisition, Methodology, Project administration, Resources, Supervision, Validation, Writing - original draft, and Writing - review & editing.\n\n[View all articles by this author](https:\/\/www.science.org\/authored-by\/Blish\/Catherine+A)\n\n#### Funding Information\n[National Institutes of Health](http:\/\/dx.doi.org\/10.13039\/100000002): 5T32AI007290-37\n\n[National Institutes of Health](http:\/\/dx.doi.org\/10.13039\/100000002): T32AI007502\n\n[National Institutes of Health](http:\/\/dx.doi.org\/10.13039\/100000002): 5T32HL129970\n\n[National Institutes of Health](http:\/\/dx.doi.org\/10.13039\/100000002): K23 HL124663\n\n[Bill and Melinda Gates Foundation](http:\/\/dx.doi.org\/10.13039\/100000865): OPP113682\n\n[Mercatus Center](http:\/\/dx.doi.org\/10.13039\/100022674)\n\nQuattrone Family\n\nChan Zuckerberg Biohub Investigator program\n\nCOVID SUPP \\#2: U19AI057229 - 17W1\n\nBurroughs Wellcome Investigators in the Pathogenesis of Infectious Disease: 1016687\n\nU19AI057229 – 17W1 COVID SUPP \\#2: 17W1 COVID SUPP\n\nRuth L. Kirschstein National Research Service Award Individual Predoctoral Fellowship: F31AI179125\n\n#### Notes\n†\n\nThe full list of authors and their affilitiations is listed at the end of the Acknowledgements.\n\n\\*\n\nCorresponding author. Email: [cblish@stanford.edu](mailto:cblish@stanford.edu)\n\n## Metrics & Citations\n### Metrics\n#### Article Usage\n**Note:** The article usage is presented with a three- to four-day delay and will update daily once available. Due to this delay, usage data will not appear immediately following publication.\n\nCitation information is sourced from [Crossref Cited-by](https:\/\/www.crossref.org\/services\/cited-by\/ \"Follow link\") service.\n\n- 12 citation in Crossref\n- [11 citation in Web of Science](http:\/\/gateway.webofknowledge.com\/gateway\/Gateway.cgi?GWVersion=2&DestApp=WOS_CPL&UsrCustomerID=5e3815c904498985e796fc91436abd9a&SrcAuth=atyponcel&SrcApp=literatum&DestLinkType=CitingArticles&KeyUT=WOS:001408181600004)\n#### Altmetrics\n\n### Citations\n#### Cite as\n- Leslie Chan *et al.*\n\n,\n\nPrior vaccination prevents overactivation of innate immune responses during COVID-19 breakthrough infection.*Sci. Transl. Med.***17**,eadq1086(2025).DOI:[10\\.1126\/scitranslmed.adq1086](https:\/\/doi.org\/10.1126\/scitranslmed.adq1086)\n\n#### Export citation\nSelect the format you want to export the citation of this publication.\n\n#### Cited by\n1. - Mona Agrawal,\n   - Armando S. Flores-Torres,\n   - John S. Franks,\n   - Sarah Y. Lang,\n   - Thomas P. Fabrizio,\n   - Kristin E. McNair,\n   - Laura V. Boywid,\n   - Ashley J. Blair,\n   - Chloe N. Hundman,\n   - Nicholas D. Hysmith,\n   - Michael A. Whitt,\n   - Rachael Keating,\n   - Paul G. Thomas,\n   - Richard J. Webby,\n   - Amanda M. Green,\n   - Heather S. Smallwood,\n   Early mucosal IFN-α, IP-10, and IL-1RA and synchronized mucosal and systemic immune responses mediate COVID-19 disease progression, mBio, (2025).<https:\/\/doi.org\/10.1128\/mbio.01491-25>\n   [Crossref](https:\/\/doi.org\/10.1128\/mbio.01491-25)\n2. - Bing Zhang,\n   - Xinyi Cui,\n   - Zihan Wang,\n   - Zhengyang Gao,\n   - Fanxiang Meng,\n   - Kun Liu,\n   - Yuting Qian,\n   Review and Prospect of Post-COVID-19 Syndrome: New Challenges Faced by Public Health Nursing in the Future, Journal of Disease and Public Health, **1**, 2, (31-41), (2025).<https:\/\/doi.org\/10.71052\/jdph\/SHDW4714>\n   [Crossref](https:\/\/doi.org\/10.71052\/jdph\/SHDW4714)\n3. - Meng Yao,\n   - Jian Zhou,\n   - Jialun Mei,\n   - Chuan Gao,\n   - Peng Ding,\n   - Gan Li,\n   - Changqing Zhang,\n   - Zhiwei Li,\n   - Junjie Gao,\n   Trained Immunity in Health and Disease, MedComm, **6**, 11, (2025).<https:\/\/doi.org\/10.1002\/mco2.70461>\n   [Crossref](https:\/\/doi.org\/10.1002\/mco2.70461)\n4. - Amy C. Sherman,\n   - Glenda E. Gray,\n   - Bin Cao,\n   - Kelvin K. W. To,\n   - Nadine Rouphael,\n   - Ana Maria Henao-Restrepo,\n   - Anthony C. Gordon,\n   - Lindsey R. Baden,\n   Acute SARS-CoV-2 infection, Nature Reviews Disease Primers, **11**, 1, (2025).<https:\/\/doi.org\/10.1038\/s41572-025-00662-x>\n   [Crossref](https:\/\/doi.org\/10.1038\/s41572-025-00662-x)\n5. - Frank Twum Aboagye,\n   - Lawrence Annison,\n   - Ebenezer Krampah Aidoo,\n   - Maame Ekua Acquah,\n   - Yvonne Aryeetey Ashong,\n   - Betty Bandoh Oppong,\n   - Lawrencia Osae-Nyarko,\n   - Isaac Owusu-Frimpong,\n   - Henry Kwadwo Hackman,\n   - Sharon Annison,\n   - Queenstar Dedei Quarshie,\n   - Abena Konadu Owusu-Senyah Enninful,\n   - Naa Adjeley Kuma,\n   - Bill Clinton Egyam,\n   - Mike Y. Osei-Atweneboana,\n   Cycle threshold values and SARS-CoV-2 variant associations with breakthrough infections: a retrospective study in Accra, Ghana, BMC Infectious Diseases, **25**, 1, (2025).<https:\/\/doi.org\/10.1186\/s12879-025-11732-6>\n   [Crossref](https:\/\/doi.org\/10.1186\/s12879-025-11732-6)\n6. - Jie Ning,\n   - Yue Xu,\n   - Yayi Ren,\n   - Zelin Zhang,\n   - Ying Chen,\n   - Xianhuang Zeng,\n   - Jianquan Zhang,\n   - Chao Wu,\n   Immunodominant T cell responses to SARS-CoV-2 nucleocapsid protein in Omicron breakthrough infection post-inactivated vaccination, Virulence, **16**, 1, (2025).<https:\/\/doi.org\/10.1080\/21505594.2025.2566241>\n   [Crossref](https:\/\/doi.org\/10.1080\/21505594.2025.2566241)\n7. - Jessica A. Breznik,\n   - Matthew S. Miller,\n   - Dawn M.E. Bowdish,\n   Rationalizing recommendations for influenza and COVID-19 vaccines, Vaccine, **65**, (127775), (2025).<https:\/\/doi.org\/10.1016\/j.vaccine.2025.127775>\n   [Crossref](https:\/\/doi.org\/10.1016\/j.vaccine.2025.127775)\n8. - C. Jessica E. Metcalf,\n   - Andrea L. Graham,\n   - Andrew J. Yates,\n   - Derek A. T. Cummings,\n   Convergence and divergence of individual immune responses over the life course, Science, **389**, 6760, (604-609), (2025).[\/doi\/10.1126\/science.ady9543](https:\/\/www.science.org\/doi\/10.1126\/science.ady9543 \"Abstract\")\n   [Abstract](https:\/\/www.science.org\/doi\/10.1126\/science.ady9543)\n9. - Sissy Therese Sonnleitner,\n   - Samira Walder,\n   - Eva Hinterbichler,\n   - Ludwig Knabl,\n   - Roswitha Poernbacher,\n   - Gernot Walder,\n   Decoding the transcriptome from bulk RNA of infection-naïve versus imprinted patients with SARS-CoV-2 Omicron B.1.1.529, Microbiology Spectrum, **13**, 8, (2025).<https:\/\/doi.org\/10.1128\/spectrum.02914-24>\n   [Crossref](https:\/\/doi.org\/10.1128\/spectrum.02914-24)\n10. - Simon Woelfel,\n    - Joel Dütschler,\n    - Daniel Junker,\n    - Marius König,\n    - Georg Leinenkugel,\n    - Claudia Krieger,\n    - Samuel Truniger,\n    - Annett Franke,\n    - Seraina Koller,\n    - Katline Metzger-Peter,\n    - Nicola Frei,\n    - Werner C. Albrich,\n    - Matthias Friedrich,\n    - Jan Hendrik Niess,\n    - Nicole Schneiderhan-Marra,\n    - Alex Dulovic,\n    - Wolfgang Korte,\n    - Justus J. Bürgi,\n    - Stephan Brand,\n    XBB.1.5 COVID-19 mRNA Vaccines Induce Inadequate Mucosal Immunity in Patients with Inflammatory Bowel Disease, Vaccines, **13**, 7, (759), (2025).<https:\/\/doi.org\/10.3390\/vaccines13070759>\n    [Crossref](https:\/\/doi.org\/10.3390\/vaccines13070759)\n11. 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Meta Title	Prior vaccination prevents overactivation of innate immune responses during COVID-19 breakthrough infection \| Science Translational Medicine
Meta Description	At this stage in the COVID-19 pandemic, most infections are “breakthrough” infections that occur in individuals with prior severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exposure. To ...
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Boilerpipe Text	Editor’s summary Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines were instrumental in curbing the COVID-19 pandemic, with the benefit of vaccination primarily attributed to the adaptive immune response. Although it is well established that antibodies and T cells against SARS-CoV-2 prevent severe disease, the role of the innate immune system should not be disregarded. Here, Chan et al. demonstrated precisely why. The authors compared individuals infected with SARS-CoV-2 during the Delta wave with or without prior vaccination. They found that prior vaccination tamped down excessive inflammatory responses often associated with more severe disease, particularly in monocytes and natural killer cells. The authors further validated these findings in a separate cohort during a different wave of infection. These data suggest that vaccination may influence the innate immune response, and consequently disease severity, during a SARS-CoV-2 breakthrough infection. —Courtney Malo Abstract At this stage in the COVID-19 pandemic, most infections are “breakthrough” infections that occur in individuals with prior severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exposure. To refine long-term vaccine strategies against emerging variants, we examined both innate and adaptive immunity in breakthrough infections. We performed single-cell transcriptomic, proteomic, and functional profiling of primary and breakthrough infections to compare immune responses from unvaccinated and vaccinated individuals during the SARS-CoV-2 Delta wave. Breakthrough infections were characterized by a less activated transcriptomic profile in monocytes and natural killer cells, with induction of pathways limiting monocyte migratory potential and natural killer cell proliferation. Furthermore, we observed a female-specific increase in transcriptomic and proteomic activation of multiple innate immune cell subsets during breakthrough infections. These insights suggest that prior SARS-CoV-2 vaccination prevents overactivation of innate immune responses during breakthrough infections with discernible sex-specific patterns and underscore the potential of harnessing vaccines in mitigating pathologic immune responses resulting from overactivation. Access the full article View all access options to continue reading this article. Supplementary Materials The PDF file includes: Materials and methods Figs. S1 to S13 Tables S1 to S5 References ( 67 – 84 ) Download 7.59 MB Other Supplementary Material for this manuscript includes the following: MDAR Reproducibility Checklist Download 459.58 KB REFERENCES AND NOTES 1 Z. Al-Aly, B. Bowe, Y. Xie, Long COVID after breakthrough SARS-CoV-2 infection. Nat. Med. 28 , 1461–1467 (2022). 2 Q. Fan, J. Shi, Y. Yang, G. Tang, M. Jiang, J. 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[Submit manuscript](https://cts.sciencemag.org/) [GET OUR E-ALERTS](https://www.science.org/action/showPreferences?menuTab=Alerts) Main content starts here [Home](https://www.science.org/)[Science Translational Medicine](https://www.science.org/journal/stm)[Vol. 17, No. 783](https://www.science.org/toc/stm/17/783)Prior vaccination prevents overactivation of innate immune responses during COVID-19 breakthrough infection [Back To Vol. 17, No. 783](https://www.science.org/toc/stm/17/783) No access Research Article CORONAVIRUS Share on # Prior vaccination prevents overactivation of innate immune responses during COVID-19 breakthrough infection [Leslie Chan](https://www.science.org/doi/10.1126/scitranslmed.adq1086#con1) <https://orcid.org/0000-0002-5064-140X>, [Kassandra Pinedo](https://www.science.org/doi/10.1126/scitranslmed.adq1086#con2) <https://orcid.org/0009-0008-5356-6813>, \[...\] , [Mikayla A. Stabile](https://www.science.org/doi/10.1126/scitranslmed.adq1086#con3), [Rebecca E. Hamlin](https://www.science.org/doi/10.1126/scitranslmed.adq1086#con4) <https://orcid.org/0000-0001-7336-6028>, \[...\] , [Shaun M. Pienkos](https://www.science.org/doi/10.1126/scitranslmed.adq1086#con5) <https://orcid.org/0009-0001-8409-4803>, [Kalani Ratnasiri](https://www.science.org/doi/10.1126/scitranslmed.adq1086#con6) <https://orcid.org/0000-0001-5953-0004>, [Stanford COVID-19 Biobank](https://www.science.org/doi/10.1126/scitranslmed.adq1086#con7), [Samuel Yang](https://www.science.org/doi/10.1126/scitranslmed.adq1086#con8) <https://orcid.org/0000-0003-1123-9036>, [Andra L. Blomkalns](https://www.science.org/doi/10.1126/scitranslmed.adq1086#con9) <https://orcid.org/0000-0001-5760-6351>, \[...\] , [Kari C. Nadeau](https://www.science.org/doi/10.1126/scitranslmed.adq1086#con10) <https://orcid.org/0000-0002-2146-2955>, [Bali Pulendran](https://www.science.org/doi/10.1126/scitranslmed.adq1086#con11) <https://orcid.org/0000-0001-6517-4333>, [Ruth O’Hara](https://www.science.org/doi/10.1126/scitranslmed.adq1086#con12) <https://orcid.org/0000-0001-6583-4995>, [Angela J. Rogers](https://www.science.org/doi/10.1126/scitranslmed.adq1086#con13) <https://orcid.org/0000-0001-6969-6200>, [Susan P. Holmes](https://www.science.org/doi/10.1126/scitranslmed.adq1086#con14) <https://orcid.org/0000-0002-2208-8168>, and [Catherine A. Blish](https://www.science.org/doi/10.1126/scitranslmed.adq1086#con15) <https://orcid.org/0000-0001-6946-7627>\+12 authors \+10 authors \+5 authors fewer[Authors Info & Affiliations](https://www.science.org/doi/10.1126/scitranslmed.adq1086#tab-contributors) Science Translational Medicine 29 Jan 2025 Vol 17, Issue 783 [DOI: 10.1126/scitranslmed.adq1086](https://doi.org/10.1126/scitranslmed.adq1086) [PREVIOUS ARTICLE Undocking of an extensive ciliary network induces proteostasis and cell fate switching resulting in severe primary ciliary dyskinesiaPrevious](https://www.science.org/doi/10.1126/scitranslmed.adp5173 "Undocking of an extensive ciliary network induces proteostasis and cell fate switching resulting in severe primary ciliary dyskinesia") [NEXT ARTICLE Correcting a pathogenic mitochondrial DNA mutation by base editing in miceNext](https://www.science.org/doi/10.1126/scitranslmed.adr0792 "Correcting a pathogenic mitochondrial DNA mutation by base editing in mice") [Notifications](https://www.science.org/action/addCitationAlert?doi=10.1126%2Fscitranslmed.adq1086)[Bookmark](https://www.science.org/personalize/addFavoritePublication?doi=10.1126%2Fscitranslmed.adq1086) [CHECK ACCESS](https://www.science.org/doi/10.1126/scitranslmed.adq1086#core-collateral-purchase-access) Contents - [Editor’s summary](https://www.science.org/doi/10.1126/scitranslmed.adq1086#editor-abstract) - [Abstract](https://www.science.org/doi/10.1126/scitranslmed.adq1086#abstract) - [Supplementary Materials](https://www.science.org/doi/10.1126/scitranslmed.adq1086#supplementary-materials) - [REFERENCES AND NOTES](https://www.science.org/doi/10.1126/scitranslmed.adq1086#bibliography) - [Information & Authors](https://www.science.org/doi/10.1126/scitranslmed.adq1086#core-collateral-info) - [Metrics & Citations](https://www.science.org/doi/10.1126/scitranslmed.adq1086#core-collateral-metrics) - [Check Access](https://www.science.org/doi/10.1126/scitranslmed.adq1086#core-collateral-purchase-access) - [References](https://www.science.org/doi/10.1126/scitranslmed.adq1086#core-collateral-references) - [Figures](https://www.science.org/doi/10.1126/scitranslmed.adq1086#core-collateral-figures) - [Tables](https://www.science.org/doi/10.1126/scitranslmed.adq1086#core-collateral-tables) - [Media](https://www.science.org/doi/10.1126/scitranslmed.adq1086#core-collateral-media) - [Share](https://www.science.org/doi/10.1126/scitranslmed.adq1086#core-collateral-share) ## Editor’s summary Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines were instrumental in curbing the COVID-19 pandemic, with the benefit of vaccination primarily attributed to the adaptive immune response. Although it is well established that antibodies and T cells against SARS-CoV-2 prevent severe disease, the role of the innate immune system should not be disregarded. Here, Chan et al. demonstrated precisely why. The authors compared individuals infected with SARS-CoV-2 during the Delta wave with or without prior vaccination. They found that prior vaccination tamped down excessive inflammatory responses often associated with more severe disease, particularly in monocytes and natural killer cells. The authors further validated these findings in a separate cohort during a different wave of infection. These data suggest that vaccination may influence the innate immune response, and consequently disease severity, during a SARS-CoV-2 breakthrough infection. —Courtney Malo ## Abstract At this stage in the COVID-19 pandemic, most infections are “breakthrough” infections that occur in individuals with prior severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exposure. To refine long-term vaccine strategies against emerging variants, we examined both innate and adaptive immunity in breakthrough infections. We performed single-cell transcriptomic, proteomic, and functional profiling of primary and breakthrough infections to compare immune responses from unvaccinated and vaccinated individuals during the SARS-CoV-2 Delta wave. Breakthrough infections were characterized by a less activated transcriptomic profile in monocytes and natural killer cells, with induction of pathways limiting monocyte migratory potential and natural killer cell proliferation. Furthermore, we observed a female-specific increase in transcriptomic and proteomic activation of multiple innate immune cell subsets during breakthrough infections. These insights suggest that prior SARS-CoV-2 vaccination prevents overactivation of innate immune responses during breakthrough infections with discernible sex-specific patterns and underscore the potential of harnessing vaccines in mitigating pathologic immune responses resulting from overactivation. ## Access the full article View all access options to continue reading this article. [CHECK ACCESS](https://www.science.org/doi/10.1126/scitranslmed.adq1086#core-collateral-purchase-access) ALREADY A SUBSCRIBER OR AAAS MEMBER? Sign in as an [individual](https://www.science.org/action/showLogin?redirectUri=%2Fdoi%2F10.1126%2Fscitranslmed.adq1086) or via your [institution](https://www.science.org/action/ssostart?redirectUri=%2Fdoi%2F10.1126%2Fscitranslmed.adq1086) ## Supplementary Materials ### The PDF file includes: Materials and methods Figs. S1 to S13 Tables S1 to S5 References ([67](https://www.science.org/doi/10.1126/scitranslmed.adq1086#R67)–[84](https://www.science.org/doi/10.1126/scitranslmed.adq1086#R84)) - [Download](https://www.science.org/doi/suppl/10.1126/scitranslmed.adq1086/suppl_file/scitranslmed.adq1086_sm.pdf) - 7\.59 MB ### Other Supplementary Material for this manuscript includes the following: Data files S1 to S4 - [Download](https://www.science.org/doi/suppl/10.1126/scitranslmed.adq1086/suppl_file/scitranslmed.adq1086_data_files_s1_to_s4.zip) - 1\.59 MB MDAR Reproducibility Checklist - [Download](https://www.science.org/doi/suppl/10.1126/scitranslmed.adq1086/suppl_file/scitranslmed.adq1086_mdar_reproducibility_checklist.pdf) - 459\.58 KB ## REFERENCES AND NOTES 1 Z. Al-Aly, B. Bowe, Y. Xie, Long COVID after breakthrough SARS-CoV-2 infection. Nat. Med. 28, 1461–1467 (2022). 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[Request Permissions](https://s100.copyright.com/AppDispatchServlet?publisherName=AAAS&publication=scitransmed&title=Prior+vaccination+prevents+overactivation+of+innate+immune+responses+during+COVID-19+breakthrough+infection&publicationDate=2025-01-29&author=Leslie+Chan%2C+Kassandra+Pinedo%2C+Mikayla+A.+Stabile%2C+Rebecca+E.+Hamlin%2C+et+al.&contentID=10.1126%2Fscitranslmed.adq1086&volumeNum=17&issueNum=783&numPages=17&orderBeanReset=true&section=A) #### Article versions #### Submission history Received: 3 May 2024 Resubmitted: 10 September 2024 Accepted: 16 December 2024 #### Acknowledgments We are grateful to all participants in this cohort. We appreciate M. Davis and his laboratory for allowing us to use the Helios mass cytometer. Special thanks to A. Rustagi for assistance with the Parse Biosciences scRNA-seq library preparation and preprocessing pipeline. We thank N. Neff and A. Seng at the Chan Zuckerberg Biohub for assistance with sequencing. We thank T. T. Nguyen at Stanford University’s Human Immune Monitoring Core for performing the Olink plasma proteomic assay. We are grateful to I. de los Rios Kobara for the gift of SARS-CoV-2 Delta pseudovirus and assistance with the pseudovirus neutralization assay protocol. We thank P. Kim, J. Bloom, and D. Xu for the gift of HeLa-ACE2-TMPRSS2 cells. Figure illustrations were created using [BioRender.com](http://biorender.com/). Funding: This work was supported by NIH-funded institutional training grants 5T32AI007290-37 (to L.C.), F31AI179125 (to L.C.), T32AI007502 (to R.E.H.), and 5T32HL129970 (to S.M.P.); the Bill and Melinda Gates Foundation OPP113682 (to C.A.B.); NIH/NIAID K23 HL124663 (to A.J.R.); Burroughs Wellcome Investigators in the Pathogenesis of Infectious Disease 1016687 (to C.A.B.); a gift from the Quattrone family (to C.A.B.); NIH/NIAID U19AI057229–17W1 COVID SUPP \#2 (to C.A.B.); the Chan Zuckerberg Biohub Investigator Program (to C.A.B.); and the Mercatus Center (to C.A.B.). Author contributions: L.C. and C.A.B. conceived the project and designed experiments. S.Y., A.L.B., K.C.N., R.O., A.J.R., and C.A.B. conceived the clinical cohort of infected COVID-19 participants and obtained clinical samples. Stanford COVID-19 Biobank enrolled, consented, and processed clinical samples. K.P. coordinated transfer of COVID-19 clinical samples and provided clinical input. B.P. and K.C.N. conceived the clinical cohort of healthy COVID-19–vaccinated participants and obtained clinical samples. L.C., R.E.H., M.A.S., and K.P. produced the mass cytometry reagents. L.C., K.P., and M.A.S. acquired mass cytometry data. L.C. acquired single-cell transcriptomic data. L.C. performed bioinformatic and statistical analyses with supervision from S.P.H. and C.A.B. R.E.H., S.M.P., K.R., and S.P.H. provided intellectual input. L.C. and C.A.B. wrote the manuscript, which was reviewed by all authors. Competing interests: C.A.B. is a scientific advisory board member of ImmuneBridge, DeepCell Inc., and Qihan Bio on topics unrelated to this manuscript. B.P. served on the external immunology board of GSK and on the scientific advisory boards of Sanofi, Medicago, Boehringer Ingelheim, Pharmajet, Icosavax, and Ed-Jen. K.C.N. consults for Excellergy, Red Tree Ventures, Before Brands, Alladapt, Cour Pharma, Latitude, Regeneron, and IgGenix; is a cofounder of Before Brands, Alladpt, Latitude, and IgGenix; and is a national scientific committee member at Immune Tolerance Network (ITN) and NIH clinical research centers. All other authors declare that they have no competing interests. Data and materials availability: All data associated with this study are present in the paper or the Supplementary Materials. Mass cytometry FCS files with deidentified metadata supporting this publication are available at Flow Repository (<http://flowrepository.org>) under repository ID: FR-FCM-Z77Q. Data from scRNA-seq are deposited in the Gene Expression Omnibus (GEO) database under accession no. GSE261862. Olink data are available in data file S1. Data from the ChAdOx1-nCOV-199 vaccination validation cohort are deposited in GEO under accession no. GSE228842. A Zenodo repository for all original code used for analysis and visualization is available at DOI: [10\.5281/zenodo.13972674](https://doi.org/10.5281/zenodo.13972674). Stanford COVID-19 Biobank: In addition to the authors (C.A.B., A.L.B., K.C.N., R.O., A.J.R., and S.Y.), the following Stanford COVID-19 Biobank members contributed to enrollment, acquisition of participant consent, and processing of clinical samples: Thanmayi Ranganath2, Nancy Q. Zhao1,2, Aaron J. Wilk1,2,10, Rosemary Vergara2, Julia L. McKechnie1,2, Lauren de la Parte2, Kathleen Whittle Dantzler2, Maureen Ty2, Nimish Kathale2, Giovanny J. Martínez-Colón2, Arjun Rustagi2, Geoff Ivison1,2, Ruoxi Pi2, Madeline J. Lee1,2, Rachel E. Brewer12,13, Taylor Hollis2, Andrea Baird2, Michele Ugur14, Michal C. Tal13, Drina Bogusch2, Georgie Nahass2, Kazim Haider2, Kim Quyen Thi Tran2, Laura Simpson2, Hena N. Din2,15, Jonasel Roque2, Rosen Mann2, Iris Chang2,15, Evan Do2,15, Andrea Fernandes2,15, Shu-Chen Lyu15, Wenming Zhang2,15, Monali Manohar2,15, James W. Krempski15, Anita Visweswaran2, Elizabeth J. Zudock3, Kathryn Jee16, Komal Kumar17, Jennifer A. Newberry3, James V. Quinn3, Donald Schreiber3, Euan A. Ashley2 Affiliations 1 to 11 are listed on the first page of the paper. 12Department of Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA. 13Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA. 14Stanford Health Care, Stanford University, Stanford, CA 94305, USA. 15Sean N. Parker Center for Allergy and Asthma Research, Palo Alto, CA 94304, USA. 16Department of Dermatology, Stanford University School of Medicine, Stanford, CA 94305, USA. 17Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA. ### Authors #### Affiliations Leslie Chan <https://orcid.org/0000-0002-5064-140X> Stanford Immunology Program, Stanford University School of Medicine, Stanford, CA 94305, USA. Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA. Roles: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Resources, Software, Validation, Visualization, Writing - original draft, and Writing - review & editing. [View all articles by this author](https://www.science.org/authored-by/Chan/Leslie) Kassandra Pinedo <https://orcid.org/0009-0008-5356-6813> Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA. Roles: Conceptualization, Investigation, Methodology, Resources, and Validation. [View all articles by this author](https://www.science.org/authored-by/Pinedo/Kassandra) Mikayla A. Stabile Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA. Role: Investigation. [View all articles by this author](https://www.science.org/authored-by/Stabile/Mikayla+A) Rebecca E. Hamlin <https://orcid.org/0000-0001-7336-6028> Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA. Roles: Investigation, Resources, and Writing - review & editing. [View all articles by this author](https://www.science.org/authored-by/Hamlin/Rebecca+E) Shaun M. Pienkos <https://orcid.org/0009-0001-8409-4803> Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA. Roles: Conceptualization, Methodology, and Software. [View all articles by this author](https://www.science.org/authored-by/Pienkos/Shaun+M) Kalani Ratnasiri <https://orcid.org/0000-0001-5953-0004> Stanford Immunology Program, Stanford University School of Medicine, Stanford, CA 94305, USA. Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA. Role: Software. [View all articles by this author](https://www.science.org/authored-by/Ratnasiri/Kalani) Stanford COVID-19 Biobank[†](https://www.science.org/doi/10.1126/scitranslmed.adq1086#afn1) Role: Resources. [View all articles by this author](https://www.science.org/authored-by/group/Stanford+COVID-19+Biobank) Samuel Yang <https://orcid.org/0000-0003-1123-9036> Department of Emergency Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA. Roles: Resources, Supervision, Validation, and Writing - review & editing. [View all articles by this author](https://www.science.org/authored-by/Yang/Samuel) Andra L. Blomkalns <https://orcid.org/0000-0001-5760-6351> Department of Emergency Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA. Roles: Conceptualization, Investigation, Project administration, Resources, and Writing - review & editing. [View all articles by this author](https://www.science.org/authored-by/Blomkalns/Andra+L) Kari C. Nadeau <https://orcid.org/0000-0002-2146-2955> Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA. Department of Environmental Health, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA. Roles: Data curation, Funding acquisition, Investigation, Project administration, Resources, and Writing - review & editing. [View all articles by this author](https://www.science.org/authored-by/Nadeau/Kari+C) Bali Pulendran <https://orcid.org/0000-0001-6517-4333> Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, CA 94305, USA. Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA. Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA. Roles: Resources and Writing - review & editing. [View all articles by this author](https://www.science.org/authored-by/Pulendran/Bali) Ruth O’Hara <https://orcid.org/0000-0001-6583-4995> Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA. Roles: Conceptualization, Investigation, Supervision, and Writing - review & editing. [View all articles by this author](https://www.science.org/authored-by/O%E2%80%99Hara/Ruth) Angela J. Rogers <https://orcid.org/0000-0001-6969-6200> Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA. Roles: Resources and Writing - review & editing. [View all articles by this author](https://www.science.org/authored-by/Rogers/Angela+J) Susan P. Holmes <https://orcid.org/0000-0002-2208-8168> Department of Statistics, Stanford University, Stanford, CA 94305, USA. Roles: Formal analysis, Software, Supervision, Validation, and Writing - review & editing. [View all articles by this author](https://www.science.org/authored-by/Holmes/Susan+P) Catherine A. Blish[\](https://www.science.org/doi/10.1126/scitranslmed.adq1086#cor1) <https://orcid.org/0000-0001-6946-7627> [cblish@stanford.edu](mailto:cblish@stanford.edu) Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA. Stanford Medical Scientist Training Program, Stanford University School of Medicine, Stanford, CA 94305, USA. Chan Zuckerberg Biohub, San Francisco, CA 94158, USA. Roles: Conceptualization, Funding acquisition, Methodology, Project administration, Resources, Supervision, Validation, Writing - original draft, and Writing - review & editing. [View all articles by this author](https://www.science.org/authored-by/Blish/Catherine+A) #### Funding Information [National Institutes of Health](http://dx.doi.org/10.13039/100000002): 5T32AI007290-37 [National Institutes of Health](http://dx.doi.org/10.13039/100000002): T32AI007502 [National Institutes of Health](http://dx.doi.org/10.13039/100000002): 5T32HL129970 [National Institutes of Health](http://dx.doi.org/10.13039/100000002): K23 HL124663 [Bill and Melinda Gates Foundation](http://dx.doi.org/10.13039/100000865): OPP113682 [Mercatus Center](http://dx.doi.org/10.13039/100022674) Quattrone Family Chan Zuckerberg Biohub Investigator program COVID SUPP \#2: U19AI057229 - 17W1 Burroughs Wellcome Investigators in the Pathogenesis of Infectious Disease: 1016687 U19AI057229 – 17W1 COVID SUPP \#2: 17W1 COVID SUPP Ruth L. Kirschstein National Research Service Award Individual Predoctoral Fellowship: F31AI179125 #### Notes † The full list of authors and their affilitiations is listed at the end of the Acknowledgements. \ Corresponding author. Email: [cblish@stanford.edu](mailto:cblish@stanford.edu) ## Metrics & Citations ### Metrics #### Article Usage Note: The article usage is presented with a three- to four-day delay and will update daily once available. Due to this delay, usage data will not appear immediately following publication. 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Yates, - Derek A. T. Cummings, Convergence and divergence of individual immune responses over the life course, Science, 389, 6760, (604-609), (2025).[/doi/10.1126/science.ady9543](https://www.science.org/doi/10.1126/science.ady9543 "Abstract") [Abstract](https://www.science.org/doi/10.1126/science.ady9543) 9. - Sissy Therese Sonnleitner, - Samira Walder, - Eva Hinterbichler, - Ludwig Knabl, - Roswitha Poernbacher, - Gernot Walder, Decoding the transcriptome from bulk RNA of infection-naïve versus imprinted patients with SARS-CoV-2 Omicron B.1.1.529, Microbiology Spectrum, 13, 8, (2025).<https://doi.org/10.1128/spectrum.02914-24> [Crossref](https://doi.org/10.1128/spectrum.02914-24) 10. - Simon Woelfel, - Joel Dütschler, - Daniel Junker, - Marius König, - Georg Leinenkugel, - Claudia Krieger, - Samuel Truniger, - Annett Franke, - Seraina Koller, - Katline Metzger-Peter, - Nicola Frei, - Werner C. 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