Systemic Allergic Reactions to mRNA COVID-19 Vaccines: A Randomized Placebo-controlled Trial

Why clinicians should know about it

• Picked for Immunology and Allergy (top studies of the week, 18 October 2026): Randomized placebo-controlled trial of systemic vaccine reactions

Abstract

BACKGROUND: COVID-19 mRNA vaccines were associated in early reports with more allergic reactions than most vaccines, especially in people with allergic histories. OBJECTIVE: To estimate the proportions of systemic allergic reactions to mRNA COVID-19 vaccines in people reporting prior severe allergic reactions to various allergens, and/or mast cell disorders (PSAR/MCD Group) and determine if proportions are higher than in non-PSAR/non-MCD (Comparison Group). METHODS: We conducted a multi-center, randomized, double-blinded (for the initial injection), placebo-controlled trial in PSAR/MCD vs Comparison adults and adolescents. Participants received a double-blinded injection with Pfizer-BioNTech or Moderna COVID-19 vaccine or placebo, followed by unblinded vaccine injections. The primary outcome was the incidence of clinically-determined systemic allergic reactions within 90 minutes after injection. RESULTS: The trial enrolled 723 participants of a planned 3400, with 664 (56% PSAR/MCD) receiving at least one injection. Within 90 minutes of injection, systemic allergic reactions occurred in 5/180 (3%) PSAR/MCD participants given Pfizer-BioNTech (vs 0/133 [0%] Comparison Group; p=0.063) and 2/173 (1%) PSAR/MCD participants given Moderna (vs 0/144 [0%] Comparison Group; p=0.27). Reactions were also reported >90 minutes and ≤48 hours only in PSAR/MCD. Among PSAR/MCD participants, reaction rates to vaccine within 90-minutes and 48-hours were similar to placebo. Extensive laboratory studies did not identify plausible reaction mechanisms. CONCLUSIONS: Systemic allergic reactions based solely on clinical determination within 90-minutes or 48-hours of vaccination were only observed in PSAR/MCD but failure to achieve planned enrollment limited statistical precision. Reactions to placebo and failure to identify underlying immunologic mechanisms suggest non-allergic or non-immunologic causes.

Abstract as published, via PubMed.