Background: The newly developed mRNA-based COVID-19 vaccines can provoke anaphylaxis, possibly induced by polyethylene glycol (PEG) contained in the vaccine. The management of persons with a history of PEG allergy or with a suspected allergic reaction after the first dose remains to be defined.

Methods: In this real-life study, we defined two cohorts of individuals: one pre-vaccination including 187 individuals with high-risk profiles for developing anaphylaxis and a second post-vaccination including 87 individuals with suspected allergic reactions after the COVID-19 mRNA vaccine. Upon negative skin test with an mRNA vaccine, a two-step (10-90%) vaccination protocol was performed. Positive skin tests were confirmed with the basophil activation test (BAT).

Results: Among 604,267 doses of vaccine, 87 suspected allergic reactions (5 after the booster) were reported to our division for further investigations: 18/87 (21%) were consistent with anaphylaxis, 78/87 (90%) were female, and 47/87 (54%) received the BNT162b2 mRNA vaccine. Vaccine skin tests were negative in 96% and 76% of the pre- and post-vaccination cohorts, respectively. A two-step vaccination was tolerated in 232/236 (98%) of individuals with negative tests. Four individuals experienced isolated asthmatic reactions during the two-step challenge. Vaccine-positive skin tests were consistently confirmed by BAT; CD63 and CD203c expression was selectively inhibited with ibrutinib, suggesting an IgE-dependent mechanism.

Conclusion: Sensitization to SARS-CoV-2 mRNA vaccines can be detected with intradermal testing. Significantly more individuals were sensitized to mRNA vaccines in the post-vaccination cohort. A two-step 10-90%-vaccination protocol can be safely administered upon negative skin testing.