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Published on: September 20, 2024
Time-Resolved Multi-Omics Identify Biomarkers of Immediate Reactions to mRNA Vaccination
Ana Olivera1, Benjamin Schwarz2, Brittany Dulek3
1Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland, USA.
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.
