{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,25]],"date-time":"2026-04-25T07:13:29Z","timestamp":1777101209746,"version":"3.51.4"},"reference-count":51,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,12,18]],"date-time":"2024-12-18T00:00:00Z","timestamp":1734480000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010877","name":"ViiV Healthcare","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100010877","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>During the COVID-19 pandemic, major events with immune-modulating effects at population-level included COVID-19 infection, lockdowns, and mass vaccinations campaigns. As immune responses influence many immune-mediated diseases, population scale immunological changes may have broad consequences.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We investigated the impact of lockdowns, COVID-19 infection and vaccinations on immune responses in the 2000HIV study including 1895 asymptomatic virally-suppressed people living with HIV recruited between October 2019 and October 2021. Their inflammatory profile was assessed by targeted plasma proteomics, immune responsiveness by cytokine production capacity of circulating immune cells, and epigenetic profile by genome-wide DNA methylation of immune cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Past mild COVID-19 infection had limited long-term immune effects. In contrast, COVID-19 vaccines and especially lockdowns significantly altered both the epigenetic profile in immune cells at DNA methylation level and immune responses. Lockdowns resulted in a strong overall exaggerated immune responsiveness, while COVID-19 vaccines moderately dampened immune responses. Lockdown-associated immune responsiveness alterations were confirmed in 30 healthy volunteers from the 200FG cohort that, like the 2000HIV study, is part of the Human Functional Genomics Project.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>Our data suggest that lockdowns have unforeseen immunological effects. Furthermore, COVID-19 vaccines have immunological effects beyond anti-SARS-CoV-2 activity, and studies of their impact on non-COVID-19 immune-mediated pathology are warranted.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2024.1459593","type":"journal-article","created":{"date-parts":[[2024,12,18]],"date-time":"2024-12-18T04:22:41Z","timestamp":1734495761000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Impact of COVID-19, lockdowns and vaccination on immune responses in a HIV cohort in the Netherlands"],"prefix":"10.3389","volume":"15","author":[{"given":"Twan","family":"Otten","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xun","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manoj Kumar","family":"Gupta","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nadira","family":"Vadaq","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maartje","family":"Cleophas-Jacobs","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J\u00e9ssica C.","family":"dos Santos","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Albert","family":"Groenendijk","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wilhelm","family":"Vos","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Louise E.","family":"van Eekeren","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marc J. T.","family":"Blaauw","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elise M.G.","family":"Meeder","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Olivier","family":"Richel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vasiliki","family":"Matzaraki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jan","family":"van Lunzen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leo A. B.","family":"Joosten","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yang","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cheng-Jian","family":"Xu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andre","family":"van der Ven","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mihai G.","family":"Netea","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2024,12,18]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2008-3","article-title":"A new coronavirus associated with human respiratory disease in China","volume":"579","author":"Wu","year":"2020","journal-title":"Nature"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2012-7","article-title":"A pneumonia outbreak associated with a new coronavirus of probable bat origin","volume":"579","author":"Zhou","year":"2020","journal-title":"Nature"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1126\/science.abh1823","article-title":"Cross-reactive CD4(+) T cells enhance SARS-CoV-2 immune responses upon infection and vaccination","author":"Loyal","year":"2021","journal-title":"Sci 374 eabh1823"},{"key":"B4","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1038\/s41591-021-01643-9","article-title":"A guide to immunotherapy for COVID-19","volume":"28","author":"van de Veerdonk","year":"2022","journal-title":"Nat Med"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciac180","article-title":"Molnupiravir and nirmatrelvir-ritonavir: oral coronavirus disease 2019 antiviral drugs","volume":"76","author":"Saravolatz","year":"2023","journal-title":"Clin Infect Dis"},{"key":"B6","doi-asserted-by":"publisher","first-page":"109518","DOI":"10.1016\/j.celrep.2021.109518","article-title":"Long-term SARS-CoV-2-specific immune and inflammatory responses in individuals recovering from COVID-19 with and without post-acute symptoms","volume":"36","author":"Peluso","year":"2021","journal-title":"Cell Rep"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-019-0675-0","article-title":"Chronic inflammation in the etiology of disease across the life span","volume":"25","author":"Furman","year":"2019","journal-title":"Nat Med"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1038\/nm.4140","article-title":"Understanding human immune function using the resources from the Human Functional Genomics Project","volume":"22","author":"Netea","year":"2016","journal-title":"Nat Med"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.982746","article-title":"The 2000HIV study: Design, multi-omics methods and participant characteristics","volume":"13","author":"Vos","year":"2022","journal-title":"Front Immunol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1038\/nm.4139","article-title":"Inter-individual variability and genetic influences on cytokine responses to bacteria and fungi","volume":"22","author":"Li","year":"2016","journal-title":"Nat Med"},{"key":"B11","doi-asserted-by":"publisher","first-page":"696","DOI":"10.4049\/jimmunol.2000133","article-title":"Seasonal and nonseasonal longitudinal variation of immune function","volume":"207","author":"Ter Horst","year":"2021","journal-title":"J Immunol"},{"key":"B12","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1186\/s13059-016-1131-9","article-title":"Controlling bias and inflation in epigenome- and transcriptome-wide association studies using the empirical null distribution","volume":"18","author":"van Iterson","year":"2017","journal-title":"Genome Biol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.20532","article-title":"Differential methylation between ethnic sub-groups reflects the effect of genetic ancestry and environmental exposures","volume":"6","author":"Galanter","year":"2017","journal-title":"Elife"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3721","article-title":"Disease variants alter transcription factor levels and methylation of their binding sites","volume":"49","author":"Bonder","year":"2017","journal-title":"Nat Genet"},{"key":"B15","doi-asserted-by":"publisher","first-page":"D607","DOI":"10.1093\/nar\/gky1131","article-title":"STRING v11: protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets","volume":"47","author":"Szklarczyk","year":"2019","journal-title":"Nucleic Acids Res"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1038\/s41562-022-01453-0","article-title":"Social isolation and the brain in the pandemic era","volume":"6","author":"Bzdok","year":"2022","journal-title":"Nat Hum Behav"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-022-02078-6","article-title":"Human leukocyte antigen alleles associate with COVID-19 vaccine immunogenicity and risk of breakthrough infection","volume":"29","author":"Mentzer","year":"2023","journal-title":"Nat Med"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1136\/bmjopen-2020-045343","article-title":"Impact of COVID-19 pandemic on utilisation of healthcare services: a systematic review","volume":"11","author":"Moynihan","year":"2021","journal-title":"BMJ Open"},{"key":"B19","doi-asserted-by":"publisher","first-page":"114705","DOI":"10.1016\/j.psychres.2022.114705","article-title":"Effects of the COVID-19 pandemic on psychological health in a sample of Italian adults: A three-wave longitudinal study","volume":"315","author":"Fioravanti","year":"2022","journal-title":"Psychiatry Res"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2019.10.001","article-title":"Impact of historic migrations and evolutionary processes on human immunity","volume":"40","author":"Dom\u00ednguez-Andr\u00e9s","year":"2019","journal-title":"Trends Immunol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1556\/1886.2016.00036","article-title":"Dissecting the interplay between intestinal microbiota and host immunity in health and disease: lessons learned from germfree and gnotobiotic animal models","volume":"6","author":"Fiebiger","year":"2016","journal-title":"Eur J Microbiol Immunol (Bp)"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1038\/nri2515","article-title":"The gut microbiota shapes intestinal immune responses during health and disease","volume":"9","author":"Round","year":"2009","journal-title":"Nat Rev Immunol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.299.6710.1259","article-title":"Hay fever, hygiene, and household size","volume":"299","author":"Strachan","year":"1989","journal-title":"Bmj"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1038\/nri.2017.111","article-title":"The hygiene hypothesis in autoimmunity: the role of pathogens and commensals","volume":"18","author":"Bach","year":"2018","journal-title":"Nat Rev Immunol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra020100","article-title":"The effect of infections on susceptibility to autoimmune and allergic diseases","volume":"347","author":"Bach","year":"2002","journal-title":"N Engl J Med"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03791-x","article-title":"Systems vaccinology of the BNT162b2 mRNA vaccine in humans","volume":"596","author":"Arunachalam","year":"2021","journal-title":"Nature"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-022-01163-9","article-title":"Mechanisms of innate and adaptive immunity to the Pfizer-BioNTech BNT162b2 vaccine","volume":"23","author":"Li","year":"2022","journal-title":"Nat Immunol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1172\/JCI162581","article-title":"Trained immunity is induced in humans after immunization with an adenoviral vector COVID-19 vaccine","volume":"133","author":"Murphy","year":"2023","journal-title":"J Clin Invest"},{"key":"B29","doi-asserted-by":"publisher","first-page":"103479","DOI":"10.1016\/j.isci.2021.103479","article-title":"The mRNA-LNP platform\u2019s lipid nanoparticle component used in preclinical vaccine studies is highly inflammatory","volume":"24","author":"Ndeupen","year":"2021","journal-title":"iScience"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1010830","article-title":"Pre-exposure to mRNA-LNP inhibits adaptive immune responses and alters innate immune fitness in an inheritable fashion","volume":"18","author":"Qin","year":"2022","journal-title":"PloS Pathog"},{"key":"B31","doi-asserted-by":"publisher","first-page":"2005.2003.21256520","DOI":"10.1016\/j.clim.2023.109762","article-title":"The impact of BNT162b2 mRNA vaccine on adaptive and innate immune responses","volume":"2021","author":"F\u00f6hse","year":"2023","journal-title":"medRxiv"},{"key":"B32","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1038\/npp.2012.112","article-title":"DNA methylation and its basic function","volume":"38","author":"Moore","year":"2013","journal-title":"Neuropsychopharmacology"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2016.02.019","article-title":"DNA methylation in newborns and maternal smoking in pregnancy: genome-wide consortium meta-analysis","volume":"98","author":"Joubert","year":"2016","journal-title":"Am J Hum Genet"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1289\/EHP36","article-title":"Epigenome-wide meta-analysis of methylation in children related to prenatal NO2 air pollution exposure","volume":"125","author":"Gruzieva","year":"2017","journal-title":"Environ Health Perspect"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-2600(18)30052-3","article-title":"DNA methylation in childhood asthma: an epigenome-wide meta-analysis","volume":"6","author":"Xu","year":"2018","journal-title":"Lancet Respir Med"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.145928","article-title":"Chronic HIV infection induces transcriptional and functional reprogramming of innate immune cells","volume":"6","author":"van der Heijden","year":"2021","journal-title":"JCI Insight"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.3390\/ijerph181910025","article-title":"Changes to physical activity, sitting time, eating behaviours and barriers to exercise during the first COVID-19 \u2018Lockdown\u2019 in an english cohort","volume":"18","author":"Kass","year":"2021","journal-title":"Int J Environ Res Public Health"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.3389\/fnut.2021.626432","article-title":"The impact of lockdown during the COVID-19 outbreak on dietary habits in various population groups: A scoping review","volume":"8","author":"Bennett","year":"2021","journal-title":"Front Nutr"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1128\/spectrum.00231-23","article-title":"Differences in immune responses in individuals of Indian and european origin: relevance for the COVID-19 pandemic","volume":"11","author":"Geckin","year":"2023","journal-title":"Microbiol Spectr"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0095192","article-title":"Homogenous 96-plex PEA immunoassay exhibiting high sensitivity, specificity, and excellent scalability","volume":"9","author":"Assarsson","year":"2014","journal-title":"PloS One"},{"key":"B41","doi-asserted-by":"publisher","first-page":"1111","DOI":"10.1016\/j.cell.2016.10.018","article-title":"Host and environmental factors influencing individual human cytokine responses","volume":"167","author":"Ter Horst","year":"2016","journal-title":"Cell"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkv007","article-title":"limma powers differential expression analyses for RNA-sequencing and microarray studies","volume":"43","author":"Ritchie","year":"2015","journal-title":"Nucleic Acids Res"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btu049","article-title":"Minfi: a flexible and comprehensive Bioconductor package for the analysis of Infinium DNA methylation microarrays","volume":"30","author":"Aryee","year":"2014","journal-title":"Bioinformatics"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.838132","article-title":"Multi-omics integration reveals only minor long-term molecular and functional sequelae in immune cells of\u00a0individuals recovered from COVID-19","volume":"13","author":"Liu","year":"2022","journal-title":"Front Immunol"},{"key":"B45","doi-asserted-by":"publisher","first-page":"208","DOI":"10.1186\/s13059-016-1066-1","article-title":"Critical evaluation of the Illumina MethylationEPIC BeadChip microarray for whole-genome DNA methylation profiling","volume":"17","author":"Pidsley","year":"2016","journal-title":"Genome Biol"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.2217\/epi.12.21","article-title":"Complete pipeline for Infinium(\u00ae) Human Methylation 450K BeadChip data processing using subset quantile normalization for accurate DNA methylation estimation","volume":"4","author":"Touleimat","year":"2012","journal-title":"Epigenomics"},{"key":"B47","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1186\/s13059-018-1448-7","article-title":"An optimized library for reference-based deconvolution of whole-blood biospecimens assayed using the Illumina HumanMethylationEPIC BeadArray","volume":"19","author":"Salas","year":"2018","journal-title":"Genome Biol"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.0030161","article-title":"Capturing heterogeneity in gene expression studies by surrogate variable analysis","volume":"3","author":"Leek","year":"2007","journal-title":"PloS Genet"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btq340","article-title":"METAL: fast and efficient meta-analysis of genomewide association scans","volume":"26","author":"Willer","year":"2010","journal-title":"Bioinformatics"},{"key":"B50","doi-asserted-by":"publisher","first-page":"100141","DOI":"10.1016\/j.xinn.2021.100141","article-title":"clusterProfiler 4.0: A universal enrichment tool for interpreting omics data","volume":"2","author":"Wu","year":"2021","journal-title":"Innovation (Camb)"},{"key":"B51","doi-asserted-by":"publisher","first-page":"D638","DOI":"10.1093\/nar\/gkac1000","article-title":"The STRING database in 2023: protein-protein association networks and functional enrichment analyses for any sequenced genome of interest","volume":"51","author":"Szklarczyk","year":"2023","journal-title":"Nucleic Acids Res"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2024.1459593\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,12,18]],"date-time":"2024-12-18T04:22:46Z","timestamp":1734495766000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2024.1459593\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,18]]},"references-count":51,"alternative-id":["10.3389\/fimmu.2024.1459593"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2024.1459593","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,12,18]]},"article-number":"1459593"}}