Systemic Transcriptional Responses to Clinical Vaccine Formulations and Live-Attenuated Vaccination: Comparative Kinetics and Hypotheses for Therapeutic Cancer Vaccine Monitoring

Background/Objectives: Therapeutic cancer vaccination requires innate sensing, antigen presentation, lymphocyte priming, tumor access, cytotoxicity, and persistence. Prophylactic studies cannot demonstrate these antitumor functions but can compare systemic formulation responses. We tested whether blood transcription extended beyond innate responses to cancer-immunity-cycle programs. Methods: From 385 GEO records, we retained six human blood cohorts (five bulk-RNA and one sorted-cell) and one mouse blood/lymph-node study. We percentile-ranked 23 modules and compared baseline changes across 17 formulation questions. A separate screen of 35 poly-ICLC cancer-vaccine studies yielded NCT01204684; all arms received a tumor-lysate-pulsed dendritic-cell vaccine. Results: At 24 h after dose 2, AS01B, AS01E, and AS03 increased type I interferon-associated transcription relative to aluminum salt; the AS04 change was negligible. MF59 increased this score by 3.2 points (95% confidence interval, 1.2–5.1) relative to unadjuvanted antigen. Responsive comparisons also showed higher transcription of genes associated with antigen-presenting-cell costimulation, type 1 conventional dendritic cells, and MHC-I antigen processing/presentation. Yellow fever 17D produced a multicomponent trajectory, but the comparison did not isolate viral replication, antigen persistence, viral sensing, or tissue distribution. Of 390 evaluable module–formulation combinations, 278 had no result after false discovery rate (FDR) correction. Sensitivity estimates agreed (r = 0.998; 97.8% directional agreement). In NCT01204684, poly-ICLC recipients showed within-arm interferon and antigen-processing changes, but none of 46 agonist-versus-placebo module contrasts survived FDR correction. Conclusions: Early systemic transcription differed among formulations, whereas later cancer-immunity programs were infrequently detected in bulk blood RNA. Therapeutic studies should add draining-node or tumor measurements and antigen-specific functional assays.