{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,12]],"date-time":"2026-07-12T05:07:45Z","timestamp":1783832865558,"version":"3.55.0"},"reference-count":47,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2025,8,2]],"date-time":"2025-08-02T00:00:00Z","timestamp":1754092800000},"content-version":"vor","delay-in-days":1,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2025,8,1]],"date-time":"2025-08-01T00:00:00Z","timestamp":1754006400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal of Medical Virology"],"published-print":{"date-parts":[[2025,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:label\/>\n                    <jats:p>Despite adiposity's potential role in modulating immune responses, the causal effects of adiposity at different life stages on immune responses to COVID\u201019 vaccines remain poorly understood. Thus, we aimed to investigate the causal association between life\u2010course adiposity and the immune response to COVID\u201019 vaccination, and to explore the metabolic mechanisms underlying this association. We used a life\u2010course Mendelian randomization (MR) analytic framework, starting with univariable MR, to estimate the total effects of body mass index (BMI) and obesity in childhood and adulthood on the immune response to COVID\u201019 vaccination. We then used multivariable MR to distinguish the direct and indirect effects of childhood adiposity, adjusting for adulthood adiposity and lifestyle confounders. Furthermore, we conducted a metabolome\u2010wide mediation MR analysis to explore the potential links between adiposity at different life stages and immune responses to COVID\u201019 vaccination, mediated by 249 metabolic traits. The univariable MR results revealed that genetically predicted childhood and adulthood BMIs were significantly associated with an increased risk of anti\u2010spike IgG seronegativity after both the first and second doses of the COVID\u201019 vaccine. The multivariable MR analyzes further revealed that childhood BMI had a direct causal effect on anti\u2010spike IgG seronegativity after the first vaccine dose (OR 1.13, 95% CI 1.00\u20131.27), whereas adulthood BMI did not (OR 0.99, 95% CI 0.87\u20131.13). In contrast, adulthood BMI had a direct causal effect on anti\u2010spike IgG seronegativity after the second vaccine dose (OR 1.29, 95% CI 1.14\u20131.46). Mediation analyzes identified 71 metabolic traits that mediated the effects of childhood and adulthood BMI on the immune response to COVID\u201019 vaccination. Notably, branched\u2010chain amino acids (valine, leucine, and isoleucine) mediated over 20% of the causal effect between adulthood BMI and the vaccine\u2010induced immune response. Furthermore, the triglycerides to total lipids ratio in medium LDL was identified as a significant mediator of the causal relationship between childhood BMI and anti\u2010spike IgG seronegativity after the second vaccine dose, but not for adulthood BMI. The findings highlight the potential for targeted interventions to improve vaccine responses, particularly in individuals with a high childhood BMI.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/jmv.70540","type":"journal-article","created":{"date-parts":[[2025,8,2]],"date-time":"2025-08-02T14:20:21Z","timestamp":1754144421000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Causal Effects of Life\u2010Course Adiposity and Metabolic Mediators on the Immune Response to COVID\u201019 Vaccination"],"prefix":"10.1002","volume":"97","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0037-8356","authenticated-orcid":false,"given":"Pu","family":"Liang","sequence":"first","affiliation":[{"name":"National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, Beijing Ditan Hospital Capital Medical University Beijing China"},{"name":"Beijing Key Laboratory of Viral Infectious Disease, Institute of Infectious Diseases, Beijing Ditan Hospital Capital Medical University Beijing China"},{"name":"Beijing Institute of Infectious Diseases Shenzhen China"},{"name":"National Center for Infectious Diseases, Beijing Ditan Hospital Capital Medical University Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chi","family":"Li","sequence":"additional","affiliation":[{"name":"Section for AIDS\/STD Prevention &amp; Control Beijing Shijingshan District Center for Disease Control and Prevention Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Li","sequence":"additional","affiliation":[{"name":"Child and Adolescent Chronic Disease Prevention and Control Department Shenzhen Center for Chronic Disease Control Shenzhen China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingfan","family":"Xiong","sequence":"additional","affiliation":[{"name":"Child and Adolescent Chronic Disease Prevention and Control Department Shenzhen Center for Chronic Disease Control Shenzhen China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0630-8447","authenticated-orcid":false,"given":"Jie","family":"Mi","sequence":"additional","affiliation":[{"name":"Center for Non\u2010Communicable Disease Management, Beijing Children's Hospital Capital Medical University, National Center for Children's Health Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9976-7655","authenticated-orcid":false,"given":"Pei","family":"Xiao","sequence":"additional","affiliation":[{"name":"Center for Non\u2010Communicable Disease Management, Beijing Children's Hospital Capital Medical University, National Center for Children's Health Beijing 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