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

Abstract

Background: Systemic allergic reactions (sARs) following coronavirus disease 2019 (COVID-19) mRNA vaccines were initially reported at a higher rate than after traditional vaccines.

Objective: We aimed to evaluate the safety of revaccination in these individuals and to interrogate mechanisms underlying these reactions.

Methods: In this randomized, double-blinded, phase 2 trial, participants aged 16 to 69 years who previously reported a convincing sAR to their first dose of COVID-19 mRNA vaccine were randomly assigned to receive a second dose of BNT162b2 (Comirnaty) vaccine and placebo on consecutive days in a blinded, 1:1 crossover fashion at the National Institutes of Health. An open-label BNT162b2 booster was offered 5 months later if the second dose did not result in severe sAR. None of the participants received the mRNA-1273 (Spikevax) vaccine during the study. The primary end point was recurrence of sAR following second dose and booster vaccination; exploratory end points included biomarker measurements.

Results: Of 111 screened participants, 18 were randomly assigned to receive study interventions. Eight received BNT162b2 second dose followed by placebo; 8 received placebo followed by BNT162b2 second dose; 2 withdrew before receiving any study intervention. All 16 participants received the booster dose. Following second dose and booster vaccination, sARs recurred in 2 participants (12.5%; 95% CI, 1.6 to 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 predose anxiety scores, paresthesias, and distinct vital sign and biomarker changes.

Conclusions: Our findings support revaccination of individuals who report sARs to COVID-19 mRNA vaccines. Distinct clinical and laboratory features may distinguish sARs from ISRRs.

Keywords: Anaphylaxis; COVID-19; ISRR; PEG; allergic reaction; immunization stress-related response; mRNA; vaccine.

Fig 1:. Study design: Screening, randomization and follow-up

The data cut-off for primary analysis occurred on June 17, 2022. Participants who received blinded doses (second BNT162b2 dose and placebo) and unblinded BNT162b2 booster dose were included in the full analysis. Additional screening procedures included spirometry (n=8), otolaryngology consult (n=2), echocardiogram (n=2), electrocardiogram (n=2) and chest x-ray (n=1). Additional psychiatric assessment included evaluation by a psychiatrist for acute neuropsychiatric symptoms, in addition to per-protocol baseline psychiatric assessment for all participants performed before Visit 1 (n=13) or Visit 4 (n=3). Neurologic assessment included evaluation by consultant neurologist for neuropsychiatric symptoms and additional imaging such as magnetic resonance imaging if clinically indicated. Cardiac assessment was performed to exclude myocarditis or pericarditis, and included evaluation by a consultant cardiologist, serial serum troponins, electrocardiogram, echocardiogram and additional investigations as indicated. All 6 grade-3 adverse events (AEs) following second dose of vaccine and placebo were unlikely or not related to study intervention. Only one of the 5 grade-3 AEs (CoFAR grade-3 systemic allergic reaction) following booster was definitely related; other 4 were unlikely or not related. Migraine was the only AE following booster that remain unresolved and was not related to study intervention. Complete description of AEs is available in Tables E5–E9. Created with biorender.com.

Fig 2:. Frequency and characteristics of in-study reactions

A) Summary of reactions following first dose of mRNA vaccine (pre-study Dose 1) and all in-study doses, ordered by reaction type. Participant C, only male participant, had a mixed reaction (non-systemic mild allergic reaction [CoFAR grade-1] and mild Immunization Stress-Related Response [ISRR]) following BNT162b2 second dose (blinded). Created with Biorender.com B) Frequency of reactions following all in-study doses (n=48) including second BNT162b2 dose (blinded), placebo (blinded), and booster (unblinded). One participant who had mixed reaction is included with ISRRs (*). C) Frequency of reaction types following individual in-study doses. D) Frequency of all in-study ISRRs (n=34) based on severity grades irrespective of dose. E) Frequency of ISRRs based on severity grades following individual in-study doses. F) Frequency of prolonged (lasting ≥ 30 minutes), episodic (>1 episode of symptoms), chronic (lasting >48hrs) and mixed (>1 organ symptoms) in total (n=34), very mild-mild (n=20) and moderate-severe ISRRs following all in-study doses. G) Mean heart rate ([HR], beats per minute) change (SEM): difference of maximal HR (within 60 minutes post-dose) from same day baseline. H) Mean systolic ([SBP], mmHg) change (SEM): difference of maximal SBP change (within 60 minutes of dosing) from same day baseline. sAR: systemic Allergic Reaction, ISRR: Immunization Stress-Related Response, P: Placebo (blinded), V: second dose of mRNA vaccine (blinded), B: Booster (unblinded). Vm: very mild ISRR, m: mild ISRR, M: Moderate ISRR, S: Severe ISRR

Fig 3:. Clinical reactions phenotype

A) NIAID Immunization Stress-Related Response (ISRR) Classification. B) Frequency of symptoms or signs following all in-study ISRRs (n=34). Symptoms marked with asterisk (*) were subjective only (patient-reported without changes on physical examination or measurements) and obelisk (†) were confirmed on examination. C) Frequency of symptoms following in-study allergic reactions (n=5) to second and booster vaccine doses. No allergic reactions occurred following placebo. For the one participant who had mixed reaction, only the allergic symptom (generalized flushing) was included here; all other symptoms were attributed to and included with ISRRs. Signs or vital sign changes marked with obelisk (†) were confirmed on physical examination or measurements. Symptoms uniquely reported with in-study ISRRs and sARs are indicated by purple and red box, respectively.

Fig 4:. Biomarkers, airway resistance, and anxiety score measurements

A) Plasma histamine (normal reference: <1 ng/mL) was measured within 60 minutes pre-dose (n=44), and at 35 minutes (± 15, n=43) and 120 minutes (± 30, n=48) post-dose. B) Urine leukotriene E4 (normal reference: ≤ 104 pg/mg Cr) was measured for all in-study doses in a pre-dose (n=47, within 60 minutes) and first post-dose void (n=46, ~ 2 hours post-dose). C) Plasma free metanephrine ([epinephrine metabolite], reference: <0.50 nmol/L) was measured for all in-study doses within 60 minutes pre-dose (n=39), and at 35 minutes (± 15, n=40) and 120 minutes (± 30, n=40) post-dose. One sAR, where participant received epinephrine 12 minutes following the dose, was excluded from analysis due to iatrogenic elevation of metanephrine, an epinephrine metabolite. D) Serum cortisol ([total], reference <10 am: 3.7–19.4; >5 pm: 2.9–17.3 mcg/dL) was measured for all in-study doses within 60 minutes pre-dose (n=41) and at 35 minutes (± 15, n=42) and 120 minutes (± 30, n=42) post-dose. E) Mean percent change at 15 minutes post-dose from baseline of difference between resistance (cmH2O/[L/s]) at 5 and 19 Hz (small airway resistance change, n=25). F) Pre-dose anxiety rating score (scale 1–10) for all in-study doses (n=48) administered within 60 minutes before doses, as response to single question “How anxious are you right now about the COVID-19 Vaccine?”. The measure of distribution for A-F is represented by the standard error of mean (SEM).