COVID-19 vaccine reactions occurred at similar rates with placebo among participants with severe allergy histories or mast cell disorders.
A randomized, placebo-controlled trial found clinically determined systemic allergic reactions only in participants with these histories, with none observed in the comparison group. However, similar reaction rates after vaccination and placebo, together with laboratory findings, suggested that some reactions could have nonallergic or nonimmunologic causes.
The multicenter trial enrolled adults and adolescents with reported prior severe allergic reactions to various allergens, mast cell disorders, or both. A comparison group included participants without either history.
Participants initially received a blinded injection containing one of two mRNA COVID-19 vaccines or placebo, followed by unblinded vaccine injections. The primary outcome was clinically determined systemic allergic reactions within 90 minutes of injection.
Enrollment reached 723 of the planned 3,400 participants. Of the 664 who received at least one injection, 56% belonged to the group with severe allergy histories or mast cell disorders.
Within 90 minutes, systemic allergic reactions occurred in five of 180 participants, approximately 3%, receiving one mRNA vaccine in the allergy history or mast cell disorder group. No reactions occurred among 133 comparison participants receiving that vaccine (p=0.063).
For the other mRNA vaccine, reactions occurred in two of 173 participants, approximately 1%, in the allergy history or mast cell disorder group, compared with none of 144 comparison participants (p=0.27). Neither comparison reached statistical significance.
Reactions occurring more than 90 minutes and up to 48 hours after injection were also reported only in participants with severe allergy histories or mast cell disorders.
Within this group, COVID-19 vaccine reactions occurred at rates similar to placebo during both assessment windows. Extensive laboratory investigations did not identify plausible mechanisms underlying the reactions.
For clinicians evaluating suspected vaccine hypersensitivity, the findings highlight the distinction between clinically identified reactions and demonstrated immunologic causation. They suggest that nonallergic or nonimmunologic processes may contribute, without establishing a specific alternative explanation.
The substantial enrollment shortfall limited statistical precision. Consequently, the trial does not establish equivalent reaction rates between groups or exclude immunologic mechanisms in individual patients.
Reference
Wheatley LM et al. Systemic allergic reactions to mRNA COVID-19 vaccines: a randomized placebo-controlled trial. J Allergy Clin Immunol. 2026;doi:10.1016/j.jaci.2026.09.024.
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