Vaccination is an effective prevention of influenza infection. However, certain individuals develop a lower antibody response after vaccination, which may lead to susceptibility to subsequent infection. An important challenge in human health is to find baseline gene signatures to help identify individuals who are at higher risk for infection despite influenza vaccination. We developed a multi-level machine learning strategy to build a predictive model of vaccine response using pre-vaccination antibody titers and network interactions between pre-vaccination gene expression levels. The first-level baseline-antibody model explains a significant amount of variation in post-vaccination response, especially for subjects with large pre-existing antibody titers. In the second level, we clustered individuals based on pre-vaccination antibody titers to focus gene-based modeling on individuals with lower baseline HAI where additional response variation may be predicted by baseline gene expression levels. In the third level, we used a gene-association interaction network (GAIN) feature selection algorithm to find the best pairs of genes that interact to influence antibody response within each baseline titer cluster. We used ratios of the top interacting genes as predictors to stabilize machine learning model generalizability. We trained and tested the multi-level approach on data with young and older individuals immunized against influenza vaccine in multiple cohorts. Our results indicate that the GAIN feature selection approach improves model generalizability and identifies genes enriched for immunologically relevant pathways, including B Cell Receptor signaling and antigen processing. Using a multi-level approach, starting with a baseline HAI model and stratifying on baseline HAI, allows for more targeted gene-based modeling. We provide an interactive tool that may be extended to other vaccine studies.