Time-Resolved Multi-Omics Identify Biomarkers of Immediate Reactions to mRNA Vaccination [RNA-Seq]

Background: Immediate vaccine reactions, including systemic allergic reactions (sARs) and immunization stress-related responses (ISRRs) require distinct management and contribute to vaccine hesitancy; improved molecular understanding may enhance patient care and vaccine implementations. Objective: To compare early immune and metabolic signatures and downstream immunity after vaccination in participants who experienced sARs, ISSRs, or no-reaction to second and booster doses of BNT162b2. Methods: We analyzed samples from a double-blind, placebo-controlled re-vaccination trial of BNT162b2 in individuals with suspected allergic reactions to a first dose of mRNA vaccine. Whole-blood transcriptomics, plasma proteomics, metabolomics, blood counts, and flow cytometry were measured 0.5–24 hours after second vaccine dose, booster, and placebo. Anti-spike antibodies were measured longitudinally; anti-nucleocapsid antibodies indicated intercurrent infection. Results: Interferon and antiviral transcriptional programs were conserved across reaction groups 24 h after vaccination. Early neutrophil activation and degranulation signatures peaked at 6 hours in no-reaction participants but were diminished in ISRR despite similar early neutrophil mobilization. ISRRs also showed reduced basophil activation and recruitment markers and early increases in norepinephrine with sustained elevations of bisphosphoglycerate and 2/3-phosphoglycerate. sARs showed opposite metabolite trajectories and trended towards early upregulation of neutrophil CD63. Anti-spike antibody responses after the second dose and booster were robust across reaction groups, although longer time intervals between the first and second vaccine dose were associated with lower anti-spike antibody levels. Conclusion: Time-resolved immune and metabolic signatures revealed candidate biomarkers that distinguished ISRRs from sARs. Vaccine-induced antiviral transcriptional responses and humoral immunity were preserved in all reaction groups.