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While it is known that the transcriptional activity of various genes is altered following mRNA vaccination, identifying and studying gene networks could reveal important scientific insights that might inform future vaccine designs. In this study, we conducted an in\u2010depth weighted gene correlation network analysis of the blood transcriptome before and 24\u00a0h after the second and third vaccination with licensed mRNA vaccines against COVID\u201019 in humans, following a prime vaccination with either mRNA or ChAdOx1 vaccines. Utilizing this unsupervised gene network analysis approach, we identified distinct modular networks of co\u2010varying genes characterized by either an expressional up\u2010 or downregulation in response to vaccination. Downregulated networks were associated with cell metabolic processes and regulation of transcription factors, while upregulated networks were associated with myeloid differentiation, antigen presentation, and antiviral, interferon\u2010driven pathways. Within this interferon\u2010associated network, we identified highly connected hub genes such as\n                    <jats:italic>STAT2<\/jats:italic>\n                    and\n                    <jats:italic>RIGI<\/jats:italic>\n                    and associated upstream transcription factors, potentially playing important regulatory roles in the vaccine\u2010induced immune response. The expression profile of this network significantly correlated with S1\u2010specific IgG levels at the follow\u2010up visit in vaccinated individuals. Those findings could be corroborated in a second, independent cohort of mRNA vaccine recipients. Collectively, results from this modular gene network analysis enhance the understanding of mRNA vaccines from a systems immunology perspective. Influencing specific gene networks could lead to optimized vaccines that elicit augmented vaccine responses.\n                  <\/jats:p>","DOI":"10.1002\/eji.202451236","type":"journal-article","created":{"date-parts":[[2024,10,15]],"date-time":"2024-10-15T01:05:36Z","timestamp":1728954336000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Blood transcriptome profiling reveals distinct gene networks induced by mRNA vaccination against COVID\u201019"],"prefix":"10.1002","volume":"54","author":[{"given":"Lennart","family":"Riemann","sequence":"first","affiliation":[{"name":"Institute of Immunology Hannover Medical School  Hannover Germany"},{"name":"Department of Paediatric Pneumology, Allergology and Neonatology Hannover Medical School  Hannover Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1175-7354","authenticated-orcid":false,"given":"Leonie M.","family":"Weskamm","sequence":"additional","affiliation":[{"name":"Institute for Infection Research and Vaccine Development (IIRVD) University Medical Centre Hamburg\u2010Eppendorf  Hamburg 20246 Germany"},{"name":"Department for Clinical Immunology of Infectious Diseases Bernhard Nocht Institute for Tropical Medicine  Hamburg 20246 Germany"},{"name":"German Centre for Infection Research partner site Hamburg\u2010L\u00fcbeck\u2010Borstel\u2010Riems  Hamburg 20246 Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonie","family":"Mayer","sequence":"additional","affiliation":[{"name":"Institute for Infection Research and Vaccine Development (IIRVD) University Medical Centre Hamburg\u2010Eppendorf  Hamburg 20246 Germany"},{"name":"Department for Clinical Immunology of Infectious Diseases Bernhard Nocht Institute for Tropical Medicine  Hamburg 20246 Germany"},{"name":"German Centre for Infection Research partner site Hamburg\u2010L\u00fcbeck\u2010Borstel\u2010Riems  Hamburg 20246 Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0408-5091","authenticated-orcid":false,"given":"Ivan","family":"Odak","sequence":"additional","affiliation":[{"name":"Institute of Immunology Hannover Medical School  Hannover Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0718-0422","authenticated-orcid":false,"given":"Swantje","family":"Hammerschmidt","sequence":"additional","affiliation":[{"name":"Institute of Immunology Hannover Medical School  Hannover Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inga","family":"Sandrock","sequence":"additional","affiliation":[{"name":"Institute of Immunology Hannover Medical School  Hannover 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Lung Research (DZL) BREATH  Hannover Germany"},{"name":"Cluster of Excellence RESIST (EXC 2155) Hannover Medical School  Hannover Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marylyn M.","family":"Addo","sequence":"additional","affiliation":[{"name":"Institute for Infection Research and Vaccine Development (IIRVD) University Medical Centre Hamburg\u2010Eppendorf  Hamburg 20246 Germany"},{"name":"Department for Clinical Immunology of Infectious Diseases Bernhard Nocht Institute for Tropical Medicine  Hamburg 20246 Germany"},{"name":"German Centre for Infection Research partner site Hamburg\u2010L\u00fcbeck\u2010Borstel\u2010Riems  Hamburg 20246 Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reinhold","family":"F\u00f6rster","sequence":"additional","affiliation":[{"name":"Institute of Immunology Hannover Medical School  Hannover Germany"},{"name":"German Centre for Infection Research partner site 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