Identifying biomarkers of immunocompetence that predict vaccine response is crucial for preventing diseases, reducing the need for antibiotics, and enhancing vaccine efficacy in pigs. In this study, we aimed to identify immune traits at weaning (28 days of age) that predispose pigs to a subsequent strong humoral response to vaccination. A cohort of 189 Large White pigs was vaccinated against Mycoplasma hyopneumoniae at weaning and received a booster 21 days later. The vaccine response was assessed by measuring serum-specific antibody (Ab) levels at 28, 35, and 118 days post-vaccination (dpv). Pigs were classified as high and low responders based on their Ab levels at different time points. At weaning, key immune traits, including blood cell composition, hematocrit, plasma coloration, immunoglobulins, natural antibodies, enzymatic activities, and vitamin D, were measured to identify potential predictors of the vaccine response. To assess the predictive performance, we applied Partial Least Squares Discriminant Analysis (PLS-DA) and Random Forest (RF). We found that both methods yielded nearly similar accuracies, ranging from 53% to 67% and 62% to 78% for PLS-DA and RF, respectively. Interestingly, prediction accuracy was found to be higher at 35dpv and 118dpv compared to 28dpv in both methods. Notably, traits such as Mean Corpuscular Hemoglobin concentration (MCHC), hemoglobin, peroxidase activity, and microRBC were consistently associated with extreme Ab responders at both 35dpv and 118dpv across both analytical approaches. These findings indicate that certain early-life immune traits may serve as reliable indicators of vaccine response. Integrating such biomarkers into breeding programs may improve vaccine efficacy and contribute to overall animal health. Further research will deepen our understanding by incorporating additional immune traits. Additionally, we will investigate a vaccine for swine influenza, which will provide a more comprehensive understanding of individual variability in vaccine responses in pigs.