Comparative assessment of allergic reactions to COVID‐19 vaccines in Europe and the United States
Authors: Sophia Hatziantoniou, Cleo Anastassopoulou, Vicky Lampropoulou, Helena C. Maltezou, Evangelos Andreakos, Gregory A. Poland, Athanasios Tsakris
Journal: Allergy (2022)

Among the rare complications that may compromise vaccine acceptance are allergic reactions.1-3 Recently, we demonstrated that anaphylaxis rates associated with COVID-19 vaccines are within the range of those observed earlier with other vaccines, as indicated by passive reporting systems.4 Herein, we aimed to comparatively assess the incidence and potential underlying causes of the most common allergic reactions post-COVID-19 vaccination in Europe and the United States (US). To our knowledge, such a comparison has not been performed before. Allergic reaction data following COVID-19 vaccination reported from Week 52/2020 to Week 39/2021 were collected from EudraVigilance for the European Economic Area (EEA) and from Vaccine Adverse Event Reporting System (VAERS) for the United States and analyzed for all licensed vaccines. These included mRNA-1273 (Moderna), BNT162b2 (Pfizer-BioNTech), AD26.COV2.S (Janssen/Johnson & Johnson), and the not yet licensed in the US ChAdOx1-S (Oxford/AstraZeneca). Incidence rates were calculated using the corresponding administered vaccine doses as denominators. Vaccine composition was examined to identify potential allergic triggers. The most common allergic reactions after COVID-19 vaccination were anaphylactic reactions, with an overall incidence of 9.91/million doses (EEA: 13.69/million/US: 4.44/million, Figure 1). Anaphylactic shock followed, with much lower rates (overall incidence: 1.36/million, EEA: 2.01/million/US: 0.41/million). Other allergic symptoms post vaccination, which were infrequently reported in the two databases, included, among others, "anaphylactoid reactions" and "allergic edema." Sampath et al. and Alhumaid et al. also reported a similar spectrum of allergic and possibly non-allergic reactions post vaccination.2, 5 Higher anaphylactic reaction rates have been reported after the first than the second dose, especially when prior anaphylaxis was present, but that was not always the case.5, 6 The incidence of anaphylactic reactions reported in EudraVigilance varied considerably by vaccine and was threefold to fourfold higher for BNT162b2 or mRNA-1273 compared with VAERS. AD26.COV2.S-associated anaphylaxis did not differ between databases. The very low incidence of anaphylactic shock also varied by vaccine, particularly as captured in EudraVigilance. Considering vaccine platforms, the incidence of anaphylactic reactions post adenovirus-vectored vaccination was higher compared with mRNA-based vaccines (EudraVigilance: 15.62/ vs. 13.36/million and VAERS: 6.79/ vs. 4.34/million doses). Anaphylactic shock incidence rates were also higher for vectored compared with mRNA vaccines (EudraVigilance: 3.14/ vs. 1.81/million and VAERS: 1.20/ vs. 0.38). Detailed demographic data and outcomes of anaphylactic reaction and anaphylactic shock cases post-COVID-19 vaccination are presented in Tables S1 and S2, respectively. The vast majority of cases affected females (82% of anaphylactic reaction/75% of anaphylactic shock reports). The reasons why women have been implicated more frequently in hypersensitivity reactions throughout cohorts remain unknown. With regard to age, different patterns are evident. In EudraVigilance, both types of anaphylaxis were more common among working age (18–64 years) and older individuals; in VAERS, anaphylactic reactions were more frequent among subjects aged 30–59 years (69%), while the very rare anaphylactic shock cases were distributed across age groups. Regarding outcome, the vast majority of cases were resolved or resolving (90.0% of anaphylactic reaction/81.7% of anaphylactic shock cases as captured in EudraVigilance, Table S1). The disease course was complicated (life threatening or leading to permanent disability) in 25.5% of anaphylactic reaction and 31.3% of anaphylactic shock cases as captured in VAERS (Table S2). Fatalities from allergic reactions post-COVID-19 vaccination were extremely rare and twofold to sixfold higher for vectored than mRNA vaccines in both databases (Table 1). The anaphylactic reactions and anaphylactic shock cases reported to EudraVigilance compared with VAERS indicated significant differences to exist between reporting systems, vaccine platforms, and manufacturers. Conceivably, the reported variability may reflect population differences in the degree of sensitization to ingredients prior to vaccination and differences in the prevalence of atopy, which has been linked to anaphylactic incidents post vaccination.2, 7 Differences in implementation between the two reporting systems could also contribute to the observed differences between databases. The cause(s) that may trigger allergic reactions after vaccination remain elusive.2 Potential contributing factors include the following: (i) components of the final pharmaceutical product (i.e., the active ingredient and excipients); (ii) impurities or "related materials" unintentionally present in the final formula;1 and (iii) the packaging material, especially the rubber stopper.2 Cross-reactivity has been reported upon exposure between two of the main excipients of mRNA and vectored vaccines (polyethylene glycol 2000 and polysorbate 80, respectively).8 If true, should we anticipate increased anaphylaxis rates following first time or booster vaccination with vaccines of different platforms according to the so-called heterologous vaccination (mix-and-match) approach? A potential limitation of the study may be the likely underreporting of allergic reactions, including anaphylaxis that generally holds for passive surveillance systems; nonetheless, this may not hold for COVID-19 vaccines that have been under scrutiny by regulators and under the watchful eyes of healthcare professionals and the public since the beginning of their deployment. Other potential limitations, also related to passive reporting systems, entail possible reporting errors (e.g., duplicate or incomplete records), as well as the fact that recorded events only show temporal and not cause–effect relationships. In addition, the terminology used for the categorization of anaphylaxis post vaccination possibly introduces mechanistical explanations that may not be accurate. Nevertheless, for anaphylaxis and Guillain–Barré syndrome, the sensitivity of VAERS was found to be comparable to previous estimates for detecting important adverse events following vaccination.9 Our pragmatic analysis is based on imperfect, but real-world data of two of the world's largest and most reliable vaccine adverse event spontaneous reporting systems (EudraVigilance and VAERS). Our estimated rates from VAERS for anaphylactic reactions [4.34 for mRNA vaccines (5.41 for mRNA-1273 and 4.42 for BNT162b2) cases per million vaccinations] are in agreement with those reported largely in individuals with a history of allergy, by the Centers for Disease Control and Prevention (CDC), which were also based on passive spontaneous reporting methods (2.5–11.1 per million vaccinations).6 We found higher corresponding rates in EudraVigilance (13.36 per million vaccinations for mRNA vaccines overall) and more elevated for mRNA-1273 rather than BNT162b2 (20.39 vs. 12.36 per million vaccinations, respectively). Blumenthal et al.7 found larger incidence rates of confirmed anaphylaxis to mRNA vaccines using either the Brighton Criteria 10 or the National Institute of Allergy and Infectious Diseases/Food Allergy and Anaphylaxis Network (NIAID/FAAN) criteria11 (2.47 per 10000 vaccinations).7 Interestingly, this study also reported more frequently detecting acute allergic reactions with the Moderna rather than the Pfizer-BioNTech vaccine (2.20% [95% CI, 2.06%-2.35%] vs. 1.95% [95% CI, 1.79%- 2.13%]; p = 0.03).7 Relevant investigations in the literature report contradictory results, concluding on higher anaphylaxis incidence for mRNA-12737 or BNT162b2.5 These results emphasize the influence of the chosen datasets on the final conclusion. Our study revealed differences in anaphylaxis rates as captured in two of the world's largest pharmacovigilance databases between Europe and the United States, as well as between vaccines and vaccine platforms. Understanding the reasons behind true differences could lead to the further optimization of COVID-19 vaccines. Dr. Poland is the chair of a Safety Evaluation Committee for novel investigational vaccine trials being conducted by Merck Research Laboratories; holds patents related to vaccinia, influenza, and measles peptide vaccines; received grant funding from ICW Ventures for preclinical studies on a peptide-based COVID-19 vaccine; and provides consultative advice on vaccine development to Merck & Co., Medicago, GlaxoSmithKline, Sanofi Pasteur, Johnson & Johnson/Janssen Global Services LLC, Emergent Biosolutions, Dynavax, Genentech, Eli Lilly and Company, Kentucky Bioprocessing, Bavarian Nordic, AstraZeneca, Exelixis, Regeneron, Janssen, Vyriad, Moderna, and Genevant Sciences, Inc. These activities have been reviewed by the Mayo Clinic Conflict of Interest Review Board and are conducted in compliance with Mayo Clinic Conflict of Interest policies. This research has been reviewed by the Mayo Clinic Conflict of Interest Review Board and was conducted in compliance with Mayo Clinic Conflict of Interest policies. SH, CA, VL, HM, EA, and AT declare no conflict of interest in relation to this work. SH and CA designed the study, acquired the data, and wrote the manuscript. SH, CA, VL, and HM contributed to data analysis and interpretation. CA, VL, HM, EA, GP, and AT revised the manuscript critically for important intellectual content. All authors approved the final version of the manuscript. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.