Time‐Resolved Multi‐Omics Identify Biomarkers of Immediate Reactions to <scp>mRNA</scp> Vaccination

BACKGROUND: Systemic allergic reactions (sARs) after vaccination are life-threatening and can erode vaccine confidence. Distinguishing sARs from immunization stress-related responses (ISRRs), which require different management, remains a clinical challenge. We sought to identify biomarkers distinguishing sARs from ISRRs, characterize their early immune and metabolic pathways, and determine whether immediate reactions alter subsequent vaccine-induced immunity. METHODS: We profiled samples from a double-blind, placebo-controlled BNT162b2 re-vaccination trial (NCT04977479) in individuals with allergic reactions to a first mRNA vaccine dose. Whole-blood transcriptomics, plasma proteomics and metabolomics, blood counts, and flow cytometry were assessed 0.5-24 h after the second dose, booster, and placebo. Anti-spike antibodies were measured longitudinally; anti-nucleocapsid antibodies identified intercurrent infection. RESULTS: Interferon and antiviral transcriptional programs 24 h post-vaccination and subsequent anti-spike antibody responses were preserved across reaction groups. However, longer-than-recommended intervals between first and second doses were associated with lower antibody titers. In participants with mild to no reactions, neutrophil activation and degranulation signatures peaked at 6 h; these responses were blunted in ISRRs despite comparable early neutrophil mobilization. ISRRs were also marked by a stress-metabolic state with early norepinephrine increases; sustained bisphosphoglycerate and 2/3-phosphoglycerate elevations; reduced basophil activation/recruitment markers (CD63, CD193); downregulation of basophil-associated transcripts (CPA3, HDC, MS4A3); and upregulation of stress-linked genes (OTOF, SNORD3). sARs showed opposite metabolic trajectories and trended toward early neutrophil CD63 upregulation. CONCLUSION: Time-resolved immune and metabolic signatures identified candidate biomarkers distinguishing ISRRs from sARs, with implications for diagnosis, management, and vaccine adherence. Notably, reactions did not impair vaccine-elicited antiviral responses or humoral immunity.