Liang Pu, Li Chi, Li Yan, Xiong Jingfan, Mi Jie, Xiao Pei
National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China.
Beijing Key Laboratory of Viral Infectious Disease, Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China.
J Med Virol. 2025 Aug;97(8):e70540. doi: 10.1002/jmv.70540.
Despite adiposity's potential role in modulating immune responses, the causal effects of adiposity at different life stages on immune responses to COVID-19 vaccines remain poorly understood. Thus, we aimed to investigate the causal association between life-course adiposity and the immune response to COVID-19 vaccination, and to explore the metabolic mechanisms underlying this association. We used a life-course 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-19 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-wide mediation MR analysis to explore the potential links between adiposity at different life stages and immune responses to COVID-19 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-spike IgG seronegativity after both the first and second doses of the COVID-19 vaccine. The multivariable MR analyzes further revealed that childhood BMI had a direct causal effect on anti-spike IgG seronegativity after the first vaccine dose (OR 1.13, 95% CI 1.00-1.27), whereas adulthood BMI did not (OR 0.99, 95% CI 0.87-1.13). In contrast, adulthood BMI had a direct causal effect on anti-spike IgG seronegativity after the second vaccine dose (OR 1.29, 95% CI 1.14-1.46). Mediation analyzes identified 71 metabolic traits that mediated the effects of childhood and adulthood BMI on the immune response to COVID-19 vaccination. Notably, branched-chain amino acids (valine, leucine, and isoleucine) mediated over 20% of the causal effect between adulthood BMI and the vaccine-induced 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-spike 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.
尽管肥胖在调节免疫反应中可能发挥作用，但不同生命阶段的肥胖对新冠疫苗免疫反应的因果影响仍知之甚少。因此，我们旨在研究生命历程中的肥胖与新冠疫苗接种免疫反应之间的因果关联，并探索这种关联背后的代谢机制。我们采用了生命历程孟德尔随机化（MR）分析框架，从单变量MR开始，以估计儿童期和成年期体重指数（BMI）及肥胖对新冠疫苗接种免疫反应的总体影响。然后，我们使用多变量MR来区分儿童期肥胖的直接和间接影响，并对成年期肥胖和生活方式混杂因素进行调整。此外，我们进行了全代谢组中介MR分析，以探索不同生命阶段的肥胖与新冠疫苗接种免疫反应之间的潜在联系，这种联系由249种代谢特征介导。单变量MR结果显示，基因预测的儿童期和成年期BMI与两剂新冠疫苗接种后抗刺突IgG血清阴性风险增加显著相关。多变量MR分析进一步显示，儿童期BMI对第一剂疫苗接种后抗刺突IgG血清阴性有直接因果效应（OR 1.13，95% CI 1.00 - 1.27），而成年期BMI则没有（OR 0.99，95% CI 0.87 - 1.13）。相比之下，成年期BMI对第二剂疫苗接种后抗刺突IgG血清阴性有直接因果效应（OR 1.29，95% CI 1.14 - 1.46）。中介分析确定了71种代谢特征介导了儿童期和成年期BMI对新冠疫苗接种免疫反应的影响。值得注意的是，支链氨基酸（缬氨酸、亮氨酸和异亮氨酸）介导了成年期BMI与疫苗诱导免疫反应之间超过20%的因果效应。此外，中等密度脂蛋白中甘油三酯与总脂质的比率被确定为儿童期BMI与第二剂疫苗接种后抗刺突IgG血清阴性因果关系的显著中介因素，但成年期BMI并非如此。这些发现突出了针对性干预措施改善疫苗反应的潜力，特别是对于儿童期BMI较高的个体。
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