A randomized double-blinded trial to assess recurrence of systemic allergic reactions following COVID-19 mRNA vaccination

Abstract

BackgroundSystemic allergic reactions (sARs) following coronavirus disease-2019 (COVID-19) mRNA vaccines were initially reported at a higher rate than traditional vaccines. ObjectiveWe aimed to evaluate the safety of revaccination in these individuals and to interrogate mechanisms underlying these reactions. MethodsIn this randomized, double-blinded, phase 2 trial, individuals 16-69 years who previously reported a convincing sAR to their first dose of COVID-19 mRNA vaccine were randomly assigned to receive second dose of BNT162b2 (Pfizer-BioNTech; Comirnaty®) vaccine and placebo on consecutive days in a blinded, 1:1 cross-over fashion at the National Institutes of Health (NIH). Five months later, an open-label BNT162b2 booster was offered if the second dose did not result in severe sAR. None of the participants received the mRNA-1273 (Moderna; Spikevax®) vaccine during the study. The primary endpoint was recurrence of sAR following second dose and booster vaccination; exploratory endpoints included biomarker measurements. ResultsOf 111 screened individuals, 18 were randomized to receive study interventions. Eight received BNT162b2 second dose followed by placebo; eight received placebo followed by BNT162b2 second dose; two withdrew before receiving any study intervention. All 16 received the booster dose. Following second dose and booster vaccination, sARs recurred in two subjects (12.5%, 95% CI 1.6–38.3). No sAR occurred after placebo. An anaphylaxis mimic, immunization stress-related response (ISRR), occurred more commonly than sARs following both vaccine and placebo and was associated with higher pre-dose anxiety scores, paresthesias, and distinct vital sign and biomarker changes. ConclusionOur findings support revaccination of individuals who report sARs to COVID-19 mRNA vaccines. Distinct clinical and laboratory features may distinguish sARs from ISRRs.