Features of chronic urticaria after COVID-19 mRNA vaccine over time

Abstract

Background: New onsets of chronic urticaria (CU) have been reported after repeated immunizations, mainly with the Moderna mRNA-1273 vaccine (Spikevax). This study aims to evaluate patients with CU after COVID-19 mRNA vaccination. The contribution of SARS-Cov2 infection, atopy and IgE against the vaccine was analyzed.

Methods: We monitored the features of patients who developed CU after vaccination through two surveys conducted in 2022 and 2023. Fifty individuals with CU underwent blood tests, and their results were compared with individuals without a history of urticaria (N = 135). The presence of anti-vaccine IgE was tested in 185 individuals with basophil activation tests (BAT). We assessed anti-SARS-Cov2 humoral response, and the presence of IgEs against common respiratory allergens (Phadiatop) as a surrogate for atopy.

Results: Post-vaccination CU occurs after a median interval of 10 days and significantly more after the Spikevax booster, affecting middle-aged individuals (median 41, 66% females). In 2023, CU was still active in 53% of the cases. Inducible forms of CU, primarily dermographism, are reported in 54% (2022) and 61% (2023) of the cases. BAT positivity is not specific to CU, anti-nucleocapsid positivity, or atopy but is significantly associated with higher anti-spike neutralizing activities and younger age. Four CU patients tolerate an additional dose of mRNA vaccine with no disease exacerbation/recurrence.

Conclusions: The spikevax booster induces anti-vaccine IgE independently of CU, the latter being not directly associated with COVID-19 infection nor atopy. The tolerance to a new booster in 4/4 patients suggests that the Spikevax vaccine indirectly triggers CU in predisposed individuals.

Fig. 1. Flowchart of the study and patients’ characteristics.

a Flowchart of the patients included in the COVURT study. b Patients characteristics across the three groups. Foot note *cohort COVURT, §cohort COSED, ^cohort Immunovax.

Fig. 2. Timing between the vaccine, COVID-19 and chronic urticaria onset.

a Distribution per participant of the days before (negative values) and after (positive values) the onset of chronic urticaria for the latest SARS-Cov-2 vaccination (black circles) and COVID-19 infection (gray squares) (n = 84, 4 missing values for onset date). b Peak incidence of the first booster (n = 312,723), new-onset chronic urticaria after booster (n = 74), and COVID-19 cases over time (n = 260,802). Only patients who developed CU after November 1st, 2021 without missing values were included in the analysis. VD, canton of Vaud.

Fig. 3. Contribution of vaccine sensitization and atopy to chronic urticaria.

a Table summarizing the percentage of patients across the different cohort studies with positive versus negative basophil activation tests (BAT). Associations between the different variables were assessed using a Fisher exact test. b Age (mean and SD) of patients with a positive (+) (n = 45) or negative (−) BAT (n = 132). c CU duration in patients with a positive (+) (n = 19) or negative (−) BAT (n = 12). d CD63 expression (BAT condition shown 0.1%, missing data n = 8) in patients with a positive BAT who received the Spikevax (n = 32) and the BNT 16b2 (n = 4). e CD63 expression in CU patients with a positive (≥10 μg/ml) (n = 19) versus negative (n = 14) serology for the nucleocapsid (BAT condition shown 0.1%, missing data n = 11). Anti-nucleocapsid (f) and anti-spike (g) titers in patients with positive (+) (n = 45) or negative (−) BAT (n = 132). h Neutralizing activities against the different SARS-COV2 variants in patients with a positive (+) (n = 45) or negative (−) BAT (n = 132), or (i) with (n = 45) /without CU (n = 61) among patients who received the booster. j Table summarizing the percentages of patients across the different cohort studies with positive or negative Phadiatop results. For 13 patients, not sufficient material to perform the analysis. k Phadiatop titer in patients with a negative (−) (n = 55) or positive (+) (n = 16) BAT. l Phadiatop titer correlated to CD63 expression in patients with a positive BAT and phadiatop result (n = 12, BAT condition shown 0.1%, missing data n = 4). BAT, basophil activation tests; Nucl, nucleocapsid, CU chronic urticaria; ns non-significant. Statistics. Mean and SD are shown. Unpaired two-sided T tests or two-way ANOVAs were used for statistical analysis. For the tables, Fisher’s exact test was performed for each vaccine on a contingency table comparing the number of donors who received one, two, or three doses with the number of unvaccinated donors in the BAT-negative and BAT-positive groups (as a reference). In (a), Fisher’s exact test was performed on a contingency table comparing the number of donors who received the mRNA-1273 booster in the BAT-negative and BAT-positive groups, along with their cohort or gender.

Fig. 4. Spikevax to Comirnaty administration ratios across Europe compared to Switzerland.

The map of Europe shows the proportion of individuals who received Spikevax (black) and the Comirnaty (blue circles) vaccines for each country. The larger the circle is, the larger the frequency is. The red arrow indicates Switzerland. Data were downloaded from the European Centre for Disease Prevention and Control (ECDC) and Federal Office of Public health (FOPH) of Switzerland on November 27th. Bivalent vaccines were not included in the analysis.