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Despite widespread administration, their long-term systemic effects on human metabolism remain inadequately understood. This longitudinal study aims to evaluate IgG responses, 34 cytokines, 112 lipoproteins, and 21 low-molecular-weight metabolites in 33 individuals receiving two to four COVID-19 vaccine doses. Changes in metabolic profiles for the first 16\u00a0days post each dose of vaccine, and up to 480\u00a0days post-initial dose, were compared to baseline (before vaccination). Additionally, metabolic\u00a0profiles of vaccinated participants\u00a0were compared\u00a0to a reference cohort of unvaccinated individuals without prior exposure to SARS-CoV-2 infection (controls) and SARS-CoV-2 cases. Positive IgG responses were observed in 78.8% (<jats:italic>N<\/jats:italic>\u2009=\u200926) of participants after the first dose, reaching 100% with subsequent doses. The most common side effects were localized pain at the injection site and \u201cflu-like\u201d symptoms, reported by\u2009&gt;\u200950% of participants. Systemic side effects, e.g., sore lymph nodes, fatigue, and brain fog, were reported but showed no significant correlations to IgG responses. Transient temporal changes were observed for cytokine IP10 (CXCL10) and glutamic acid around the third vaccine dose. Compared to the reference cohort, 497 vaccinated samples (95.0%) had profiles similar to the controls, while the remaining 26 samples with prior infection exposures were similar to mild cases of SARS-CooV-2 infection. In conclusion, COVID-19 vaccination did not induce lasting changes in inflammatory and metabolic responses, nor did it induce changes similar to mild cases of SARS-CoV-2 infection. This supports the metabolic safety of the vaccine and contributes to increased vaccine confidence.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Key messages<\/jats:title>\n            <jats:p>\n              <jats:list list-type=\"bullet\">\n                <jats:list-item>\n                  <jats:p>Minimal changes in inflammatory\/metabolic markers up to 480\u00a0days post-vaccination.<\/jats:p>\n                <\/jats:list-item>\n                <jats:list-item>\n                  <jats:p>Transient increase in IP10 (CXCL10) and glutamic acid around the third dose.<\/jats:p>\n                <\/jats:list-item>\n                <jats:list-item>\n                  <jats:p>Post-vaccination IgG response did not alter metabolic profiles like SARS-CoV-2 cases.<\/jats:p>\n                <\/jats:list-item>\n                <jats:list-item>\n                  <jats:p>Our findings provide insights into the safety of repeated COVID-19 vaccinations.<\/jats:p>\n                <\/jats:list-item>\n              <\/jats:list>\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1007\/s00109-025-02527-y","type":"journal-article","created":{"date-parts":[[2025,3,12]],"date-time":"2025-03-12T16:28:04Z","timestamp":1741796884000},"page":"421-433","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Longitudinal study on immunologic, lipoproteomic, and inflammatory responses indicates the safety of sequential COVID-19 vaccination"],"prefix":"10.1007","volume":"103","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-3959-0946","authenticated-orcid":false,"given":"Jurissa","family":"Lang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1668-7225","authenticated-orcid":false,"given":"Andres","family":"Bernal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3416-2572","authenticated-orcid":false,"given":"Julien","family":"Wist","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4395-4069","authenticated-orcid":false,"given":"Siobhon","family":"Egan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3313-5097","authenticated-orcid":false,"given":"Sze How","family":"Bong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8748-4105","authenticated-orcid":false,"given":"Oscar","family":"Millet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9188-7097","authenticated-orcid":false,"given":"Monique","family":"Ryan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9692-9396","authenticated-orcid":false,"given":"Aude-Claire","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6562-2335","authenticated-orcid":false,"given":"Drew","family":"Hall","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5814-7529","authenticated-orcid":false,"given":"Philipp","family":"Nitschke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4891-7830","authenticated-orcid":false,"given":"Reika","family":"Masuda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4715-6662","authenticated-orcid":false,"given":"Allison","family":"Imrie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0556-8389","authenticated-orcid":false,"given":"Elaine","family":"Holmes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8123-8349","authenticated-orcid":false,"given":"Jeremy","family":"Nicholson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5307-5709","authenticated-orcid":false,"given":"Ruey Leng","family":"Loo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,3,12]]},"reference":[{"key":"2527_CR1","unstructured":"WHO (n.d.) 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