Causal Effects of Life-Course Adiposity and Metabolic Mediators on the Immune Response to COVID-19 Vaccination

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.