Refined phenotyping of vaccine responses reveals transcriptomic determinants of neutralizing antibody heterogeneity.

Individuals exhibit considerable heterogeneity in vaccine-induced antibody responses, yet commonly used binary classifications may overlook intermediate patterns. More nuanced grouping could better capture inter-individual differences. Here, we analyzed longitudinal neutralizing antibody (NAb) trajectories in 73 adults after inactivated SARS-CoV-2 vaccination. Unsupervised analysis identified three phenotypes: Low-Delayed Responders (LR), with a modest, delayed NAb rise to day 30; Rapid-Stabilizing Responders (RS), peaking at day 7 and plateauing thereafter; and Continuous Increase Responders (CI), exhibiting sustained increases. Between days 0 and 7, these groups diverged in immune activation: LR showed limited pathway activation or cell shifts; RS exhibited early innate activation with reduced dendritic cells; CI mounted innate and adaptive responses with increased naive B cells. These differences culminated at day 7, when CI exhibited enhanced antigen presentation and Th1-related pathways, accompanied by higher IFN-γ and IL-2 T cell responses. CI also showed post-transcriptional regulation of innate signaling, including HLA-F/H splicing, 3'UTR shortening in IKBKE and HRAS, and biased IGHV4-59-IGHJ4 usage. Finally, we developed a baseline gene model accurately predicting LR individuals. Our work refines responder classification and provides molecular insights into antibody heterogeneity, laying groundwork for early stratification and personalized vaccination.