Advanced Machine Learning Across Multiple Vaccines to Predict Durable Immunogenicity using the Immune Signatures Data Resource 2260430

Abstract Introduction Understanding vaccine durability is key to designing immunizations with long-term efficacy. Leveraging the Immune Signatures Data Resource, a compendium of transcriptomic and immunological responses from 1405 healthy adults (18+ years) across 24 vaccines, we investigated shared immune mechanisms underlying durable antibody responses. The dataset spans live (yellow fever, smallpox), recombinant viral-vector (Ebola), inactivated (influenza), and glycoconjugate (pneumococcal) vaccines. Methods Data preprocessing included imputation, normalization, and alignment across post-vaccination time points. We applied advanced machine learning (ML) frameworks to predict antibody immunogenicity and durability. Feature selection for high-dimensional, low-sample-size multi-omics datasets was performed using HSIC Lasso to identify predictors of antibody responses. Selected features served as input to ensemble, regularized regression, and gradient-boosting models (e.g. DT, RF, LASSO, XGB, CatBoost). We compared single-target and multi-output approaches, evaluating stacked, chained, and wrapper-based strategies, and implemented multi-layer neural networks to capture complex relationships among immune features. Results Post-vaccination time points explained ∼15% of the total variance, indicating shared immune kinetics across vaccine types, while age and sex contributed minimally. Gradient-boosting and multi-output modeling approaches achieved the highest predictive accuracy across vaccines, highlighting the value of integrating correlated outcomes. Neural network models similarly captured complex, nonlinear immune signatures, albeit with reduced explainability. Conclusion Conserved transcriptional modules, particularly interferon-signaling and plasmablast-related pathways, emerged as strong predictors of antibody durability. This integrative ML framework enables identification of key immune signatures critical for developing vaccines with durable responses, advancing data-driven strategies for systems vaccinology. Funding Source n/a Topic Categories Computational and Systems Immunology (COMP)