Gut microbiota: a new factor modulating the immunizing potential of viral and cancer vaccines

Gut microbiota: a new factor modulating the immunizing potential of viral and cancer vaccines | 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 Gut microbiota: a new factor modulating the immunizing potential of viral and cancer vaccines Laurence Zitvogel, Agathe Carrier, Paolo Manghi, Carolina Alves Costa Silva, and 44 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4294379/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract Vaccines represent a major public health intervention against infectious diseases and potentially cancer. Surrogate markers of vaccine efficacy usually rely on neutralizing antibody titers afflicted by high interindividual variabilities. Automated multiplexed T cell assays currently allow to test the clinical relevance of T lymphocyte responses during vaccine rollout. We examined cellular and/or humoral immune responses in five independent cohorts of health care workers, young healthy individuals and patients with cancer (melanoma or lung cancer) receiving various immunizing formulations (non-replicating, viral/tumoral, mRNA/peptides/cellular/viral particles). Here we show that about 20% of vaccinees to non-replicating formulations fail to mount protective antibody and Th1/Tc1 responses while 9% receiving a live vaccine were hyperresponders. Vaccine outliers could at least in part be attributed to gut dysbiosis at baseline, evaluated by shotgun metagenomics-based machine learning or the TOPOSCORE. These findings highlight the requirement of diagnostic tools to identify intestinal dysbiosis, as well as microbiota-centered interventions to optimize the efficiency of mass vaccinations. Biological sciences/Cancer Biological sciences/Immunology/Vaccines Biological sciences/Immunology/Adaptive immunity Biological sciences/Microbiology/Virology Biological sciences/Microbiology/Bacteria/Metagenomics Full Text Additional Declarations Yes there is potential Competing Interest. LZ is a cofounder of everImmune, a biotech company devoted to the use of commensal microbes for the treatment of cancers. LD is a SAB member of everImmune. LZ has received a research support from BIOMERIEUX for the implementation of the VIDAS in monitoring Th1/Tc1 immune responses to the vaccine. ES is inventor of the patent filed by LZ regarding ‘The Polarity and Specificity Of Sars-Cov2 -Specific T Lymphocyte Responses As A Biomarker Of Disease Susceptibility’. SF is a consultant for: Bristol Myers Squibb, Varian, ViewRay, Elekta, Regeneron, Eisai, Astra Zeneca, MedImmune, Merck US, EMD Serono/Merck, Boehringer Ingelheim, Genentech/ROCHE, EMBioSys, Telix. SF received grant/research support from: Bristol Myers Squibb, Varian, Regeneron, Merck, Celldex, Arcus. FB is a bioMérieux employee. EG is PI of Investigator Initiated Trial sponsored by Arcus Biosciences. KFB received consultancy fees (all paid to the institute) from MSD, Pierre Fabre, Merck and Framingham. GK is a scientific co-founder of EverImmune, Osasuna Therapeutics, Samsara Therapeutics and Therafast Bio. GK is in the scientific advisory boards of Hevolution, Institut Servier and Longevity Vision Funds. GK is the inventor of patents covering therapeutic targeting of aging, cancer, cystic fibrosis and metabolic disorders. GK’s brother, Romano Kroemer, was an employee of Sanofi and now consults for Boehringer-Ingelheim. SK has received honoraria from Cymab, Plectonic, TCR2 Inc, Novartis, BMS, Miltenyi and GSK. SK is inventor of several patents in the field of immuno-oncology. SK received license fees from TCR2 Inc and Carina Biotech. AG received research support from Tabby Therapeutics and Plectonic for work unrelated to the manuscript. SK received research support from Tabby Therapeutics, TCR2 Inc., Plectonic GmBH, Catalym GmBH and Arcus Bioscience for work unrelated to the manuscript. J.A.W. reports compensation for speaker’s bureau and honoria from PeerView and serves as a consultant and/or advisory board member for Gustave Roussy Cancer Center, OSE Immunotherapeutics, Bayer Therapeutics, James Cancer Center OSU, and Daiichi Sankyo. The remaining authors declare no competing interests. Supplementary Files Supplementaltable4OCT52025.pdf Supplemental Table 4 Supplementaltable5a.2OCT52025.pdf Supplemental Table 5A.2 FigureS3exS5JAN19.pdf Extended Figure 3 Supplementaltable6NOV52024.pdf Supplemental Table 6 FigureS1JAN19.pdf Extended Figure 1 Supplementaltable2BNOV52024.pdf Supplemental Table 2B FigureS2JAN19.pdf Extended Figure 2 Supplementaltable8OCT52025.pdf Supplemental Table 8 Supplementaltable3NOV52024.pdf Supplemental Table 3 Supplementaltable5bOCT52025.pdf Supplemental Table 5B Supplementaltable2ANOV52024.pdf Supplemental Table 2A Supplementaltable1NOV52024.pdf Supplemental Table 1 FigureS52k25SEPT21.pdf Extended Figure 5 FigureS4exS3JAN19.pdf Extended Figure 4 Supplementaltable5dOCT52025.pdf Supplemental Table 5D FigureS6JAN19.pdf Extended Figure 6 Supplementaltable7NOV52024.pdf Supplemental Table 7 Supplementaltable5a.1OCT52025.pdf Supplemental Table 5A.1 FigureS72k25SEPT22.pdf Extended Figure 7 Supplementaltable5cOCT52025.pdf Supplemental Table 5C FigureS82k25SEPT21.pdf Extended Figure 8 Cite Share Download PDF Status: Under Review Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4294379","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":535822283,"identity":"66c4dd81-58b4-43ae-8dca-bf20c485440c","order_by":0,"name":"Laurence Zitvogel","email":"data:image/png;base64,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","orcid":"https://orcid.org/0000-0003-1596-0998","institution":"Gustave Roussy Cancer Campus, ClinicObiome","correspondingAuthor":true,"prefix":"","firstName":"Laurence","middleName":"","lastName":"Zitvogel","suffix":""},{"id":535822284,"identity":"495c5e2d-e1d0-4f11-a40f-e16ca6ce284d","order_by":1,"name":"Agathe Carrier","email":"","orcid":"https://orcid.org/0000-0002-3177-5736","institution":"Gustave Roussy","correspondingAuthor":false,"prefix":"","firstName":"Agathe","middleName":"","lastName":"Carrier","suffix":""},{"id":535822285,"identity":"ccc326b1-c88d-4fa1-a0e3-01e440ad7eb6","order_by":2,"name":"Paolo Manghi","email":"","orcid":"https://orcid.org/0000-0003-0846-6529","institution":"Edmund Mach Foundation","correspondingAuthor":false,"prefix":"","firstName":"Paolo","middleName":"","lastName":"Manghi","suffix":""},{"id":535822286,"identity":"4bd9e181-36f6-463a-aa71-ef2c466231c4","order_by":3,"name":"Carolina Alves Costa Silva","email":"","orcid":"","institution":"Gustave Roussy Cancer Campus","correspondingAuthor":false,"prefix":"","firstName":"Carolina","middleName":"Alves Costa","lastName":"Silva","suffix":""},{"id":535822287,"identity":"e18f2e04-5721-4d63-b0b7-91da3f9f9edc","order_by":4,"name":"Imran Lahmar","email":"","orcid":"","institution":"Gustave Roussy","correspondingAuthor":false,"prefix":"","firstName":"Imran","middleName":"","lastName":"Lahmar","suffix":""},{"id":535822288,"identity":"0c0f3d36-0bfe-4cc1-a69c-23b4d06d7453","order_by":5,"name":"Roxanne Birebent","email":"","orcid":"","institution":"Gustave Roussy","correspondingAuthor":false,"prefix":"","firstName":"Roxanne","middleName":"","lastName":"Birebent","suffix":""},{"id":535822289,"identity":"c453d708-7eb5-4600-bf34-3a32d536dd43","order_by":6,"name":"Deborah Suissa","email":"","orcid":"","institution":"2.\tGustave Roussy Cancer Campus (GRCC), Clinicobiome, 94800 Villejuif Cedex, France.","correspondingAuthor":false,"prefix":"","firstName":"Deborah","middleName":"","lastName":"Suissa","suffix":""},{"id":535822290,"identity":"dfed1b88-34e3-448a-9fe4-3fcb612840a1","order_by":7,"name":"Caroline Laheurte","email":"","orcid":"","institution":"Univ. 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18:05:05","extension":"pdf","order_by":13,"title":"","display":"","copyAsset":false,"role":"supplement","size":113924,"visible":true,"origin":"","legend":"Supplemental Table 5C","description":"","filename":"Supplementaltable5cOCT52025.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4294379/v1/ee6389d269226e79936bcb1d.pdf"},{"id":94568413,"identity":"23081600-e1b7-45f4-af23-039a12cbb186","added_by":"auto","created_at":"2025-10-28 18:05:52","extension":"pdf","order_by":15,"title":"","display":"","copyAsset":false,"role":"supplement","size":640007,"visible":true,"origin":"","legend":"Extended Figure 8","description":"","filename":"FigureS82k25SEPT21.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4294379/v1/f9ffc8f0b935be726c31f133.pdf"}],"financialInterests":"\u003cb\u003eYes\u003c/b\u003e there is potential Competing Interest.\nLZ is a cofounder of everImmune, a biotech company devoted to the use of commensal microbes for the treatment of cancers. LD is a SAB member of everImmune. LZ has received a research support from BIOMERIEUX for the implementation of the VIDAS in monitoring Th1/Tc1 immune responses to the vaccine. ES is inventor of the patent filed by LZ regarding ‘The Polarity and Specificity Of Sars-Cov2 -Specific T Lymphocyte Responses As A Biomarker Of Disease Susceptibility’. SF is a consultant for: Bristol Myers Squibb, Varian, ViewRay, Elekta, Regeneron, Eisai, Astra Zeneca, MedImmune, Merck US, EMD Serono/Merck, Boehringer Ingelheim, Genentech/ROCHE, EMBioSys, Telix. SF received grant/research support from: Bristol Myers Squibb, Varian, Regeneron, Merck, Celldex, Arcus. FB is a bioMérieux employee. EG is PI of Investigator Initiated Trial sponsored by Arcus Biosciences. KFB received consultancy fees (all paid to the institute) from MSD, Pierre Fabre, Merck and Framingham. GK is a scientific co-founder of EverImmune, Osasuna Therapeutics, Samsara Therapeutics and Therafast Bio. GK is in the scientific advisory boards of Hevolution, Institut Servier and Longevity Vision Funds. GK is the inventor of patents covering therapeutic targeting of aging, cancer, cystic fibrosis and metabolic disorders. GK’s brother, Romano Kroemer, was an employee of Sanofi and now consults for Boehringer-Ingelheim. SK has received honoraria from Cymab, Plectonic, TCR2 Inc, Novartis, BMS, Miltenyi and GSK. SK is inventor of several patents in the field of immuno-oncology. SK received license fees from TCR2 Inc and Carina Biotech. AG received research support from Tabby Therapeutics and Plectonic for work unrelated to the manuscript. SK received research support from Tabby Therapeutics, TCR2 Inc., Plectonic GmBH, Catalym GmBH and Arcus Bioscience for work unrelated to the manuscript. J.A.W. reports compensation for speaker’s bureau and honoria from PeerView and serves as a consultant and/or advisory board member for Gustave Roussy Cancer Center, OSE Immunotherapeutics, Bayer Therapeutics, James Cancer Center OSU, and Daiichi Sankyo. The remaining authors declare no competing interests.","formattedTitle":"Gut microbiota: a new factor modulating the immunizing potential of \r\nviral and cancer vaccines","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"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":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-4294379/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4294379/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Vaccines represent a major public health intervention against infectious diseases and potentially cancer. Surrogate markers of vaccine efficacy usually rely on neutralizing antibody titers afflicted by high interindividual variabilities. Automated multiplexed T cell assays currently allow to test the clinical relevance of T lymphocyte responses during vaccine rollout. We examined cellular and/or humoral immune responses in five independent cohorts of health care workers, young healthy individuals and patients with cancer (melanoma or lung cancer) receiving various immunizing formulations (non-replicating, viral/tumoral, mRNA/peptides/cellular/viral particles). Here we show that about 20% of vaccinees to non-replicating formulations fail to mount protective antibody and Th1/Tc1 responses while 9% receiving a live vaccine were hyperresponders. Vaccine outliers could at least in part be attributed to gut dysbiosis at baseline, evaluated by shotgun metagenomics-based machine learning or the TOPOSCORE. These findings highlight the requirement of diagnostic tools to identify intestinal dysbiosis, as well as microbiota-centered interventions to optimize the efficiency of mass vaccinations.","manuscriptTitle":"Gut microbiota: a new factor modulating the immunizing potential of \nviral and cancer vaccines","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-28 11:01:50","doi":"10.21203/rs.3.rs-4294379/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-communications","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"NCOMMS","sideBox":"Learn more about [Nature Communications](http://www.nature.com/ncomms/)","snPcode":"","submissionUrl":"https://mts-ncomms.nature.com/","title":"Nature Communications","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Communications","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"1573eab1-ce0c-4d03-b705-3c0b9b615464","owner":[],"postedDate":"October 28th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":56970639,"name":"Biological sciences/Cancer"},{"id":56970640,"name":"Biological sciences/Immunology/Vaccines"},{"id":56970641,"name":"Biological sciences/Immunology/Adaptive immunity"},{"id":56970642,"name":"Biological sciences/Microbiology/Virology"},{"id":56970643,"name":"Biological sciences/Microbiology/Bacteria/Metagenomics"}],"tags":[],"updatedAt":"2025-11-18T14:11:24+00:00","versionOfRecord":[],"versionCreatedAt":"2025-10-28 11:01:50","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4294379","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4294379","identity":"rs-4294379","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}