Allergo J Int (2021) 30:51–55 https://doi.org/10.1007/s40629-020-00160-4 position article Severe allergic reactions after COVID-19 vaccination with the Pfizer/BioNTech vaccine in Great Britain and USA Position statement of the German Allergy Societies: Medical Association of German Allergologists (AeDA), German Society for Allergology and Clinical Immunology (DGAKI) and Society for Pediatric Allergology and Environmental Medicine (GPA) Ludger Klimek · Natalija Novak · Eckard Hamelmann · Thomas Werfel · Martin Wagenmann · Christian Taube · Andrea Bauer · Hans Merk · Uta Rabe · Kirsten Jung · Wolfgang Schlenter · Johannes Ring · Adam Chaker · Wolfgang Wehrmann · Sven Becker · Norbert Mülleneisen · Katja Nemat · Wolfgang Czech · Holger Wrede · Randolf Brehler · Thomas Fuchs · Thilo Jakob · Tobias Ankermann · Sebastian M. Schmidt · Michael Gerstlauer · Christian Vogelberg · Thomas Zuberbier · Karin Hartmann · Margitta Worm Accepted: 17 December 2020 / Published online: 24 February 2021 © The Author(s) 2021 Summary Two employees of the National Health Ser- vice (NHS) in England developed severe allergic reac- tions following administration of BNT162b2 vaccine against COVID-19 (coronavirus disease 2019). The British SmPC for the BNT162b2 vaccine already in- cludes reference to a contraindication for use in indi- viduals who have had an allergic reaction to the vac- cine or any of its components. As a precautionary measure, the Medicines and Healthcare products Reg- ulatory Agency (MHRA) has issued interim guidance to the NHS not to vaccinate in principle in “patients with severe allergies”. Allergic reactions to vaccines are very rare, but vaccine components are known to cause allergic reactions. BNT162b2 is a vaccine based on an mRNA embedded in lipid nanoparticles and blended with other substances to enable its transport L. Klimek Center for Rhinology and Allergology Wiesbaden, Wiesbaden, Germany N. Novak Clinic and Polyclinic for Dermatology and Allergology, University Hospital Bonn, Bonn, Germany E. Hamelmann Pediatric and Adolescent Medicine, Children’s Center Bethel, University Hospital OWL of Bielefeld University, Bielefeld, Germany T. Werfel Department of Dermatology, Allergology and Venereology, Hannover Medical School, Hannover, Germany M. Wagenmann Department of Ear, Nose and Throat Medicine, University Hospital Düsseldorf, Düsseldorf, Germany C. Taube Clinic for Pneumology, University Medicine Essen-Ruhrlandklinik, West German Lung Center, Essen, Germany A. Bauer Clinic and Polyclinic for Dermatology, University Allergy Center, University Clinic Carl Gustav Carus, Technical University Dresden, Dresden, Germany H. Merk Department of Dermatology and Allergology, RWTH Aachen, Aachen, Germany U. Rabe Clinic for Allergology, Johanniter Hospital in Fläming Treuenbrietzen GmbH, Treuenbrietzen, Germany K. Jung Practice for Dermatology, Immunology and Allergology, Erfurt, Germany W. Schlenter Medical Association of German Allergologists, Dreieich, Germany J. Ring Skin and Laser Center at the Opera, Munich, Germany K Severe allergic reactions after COVID-19 vaccination with the Pfizer/BioNTech vaccine in Great Britain and. . . 51 position article into the cells. In the pivotal phase III clinical trial, the BNT162b2 vaccine was generally well tolerated, but this large clinical trial, used to support vaccine approval by the MHRA and US Food and Drug Ad- ministration, excluded individuals with a “history of a severe adverse reaction related to the vaccine and/or a severe allergic reaction (e.g., anaphylaxis) to a com- ponent of the study medication”. Vaccines are recog- nized as one of the most effective public health in- terventions. This repeated administration of a foreign protein (antigen) necessitates a careful allergological history before each application and diagnostic clarifi- cation and a risk–benefit assessment before each in- jection. Severe allergic reactions to vaccines are rare but can be life-threatening, and it is prudent to raise awareness of this hazard among vaccination teams and to take adequate precautions while more expe- rience is gained with this new vaccine. Keywords BNT162b2 · Severe allergic reactions · Anaphylaxis · Vaccines · mRNA Abbreviations EUA FDA Emergency Use Authorization Food and Drug Administration LNP MHRA NHS PEG SmPC S-Protein Lipid-based nano particles Medicines and Healthcare products Reg- ulatory Agency National Health Service Polyethylenglycol Summary of Product Characteristics Spike-protein Background On December 9, 2020, the Medicines and Healthcare products Regulatory Agency (MHRA) in the United Kingdom informed of severe allergic reactions in two employees of the National Health Service (NHS) in England following administration of BNT162b2 vac- cine against COVID-19 (Coronavirus disease 2019). Both patients had a history of anaphylaxis, and as far as is currently known both recovered rapidly and completely from these severe allergic reactions. Since it is not clear which component of the vaccine trig- gered the reaction, an investigation was initiated to fully understand the two incidents and their causes. The British summary of product characteristics (SmPC) for the BNT162b2 vaccine already includes reference to a contraindication for use in individu- als who have had an allergic reaction to the vaccine A. Chaker Ear, Nose and Throat Clinic, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany Center for Allergy and Environment (ZAUM), Klinikum rechts der Isar, Technical University of Munich, Munich, Germany W. Wehrmann Dermatological Group Practice Wehrmann, Münster, Germany S. Becker Ear, Nose and Throat Clinic, University of Tübingen, Tübingen, Germany N. Mülleneisen Asthma and Allergy Center Leverkusen, Leverkusen, Germany K. Nemat Practice for Pediatric Pneumology/Allergology at the Children’s Center Dresden (Kid), Dresden, Germany W. Czech Practice and Clinic for Allergology/Dermatology Schwarzwald-Baar Clinic, Villingen-Schwenningen, Germany H. Wrede Ear, Nose and Throat Specialist, Herford, Germany R. Brehler Department of Skin Diseases, Outpatient Clinic for Allergology, Occupational Dermatology and Environmental Medicine, Münster University Hospital, Münster, Germany T. Fuchs Department of Dermatology, Venereology and Allergology, University Medical Center, Georg-August University, Göttingen, Germany T. Jakob Department of Dermatology and Allergology, University Hospital Gießen, UKGM Justus Liebig University Gießen, Gießen, Germany T. Ankermann Clinic for Pediatric and Adolescent Medicine, Pneumology, Allergology, Neonatology, Intensive Care Medicine, Infectiology, Schleswig-Holstein University Medical Center, Kiel, Germany S. M. Schmidt Center for Pediatric and Adolescent Medicine, Clinic and Polyclinic for Pediatric and Adolescent Medicine, University Medicine Greifswald, Greifswald, Germany M. Gerstlauer Pediatric Pneumology/Pediatric Allergology, 2nd Clinic for Children and Adolescents, University Hospital Augsburg, Augsburg, Germany C. Vogelberg Department of Pediatric Pneumology/Allergology, Clinic and Polyclinic for Pediatric and Adolescent Medicine, Carl Gustav Carus University Hospital, Dresden, Germany T. Zuberbier Clinic for Dermatology, Venereology and Allergology, Charité—University Medicine Berlin, Berlin, Germany K. Hartmann Clinic for Dermatology and Allergology, University Hospital Basel, Basel, Switzerland Univ.-Prof. Dr. M. Worm ((cid:2)) Allergologie und Immunologie, Klinik für Dermatologie, Venerologie und Allergologie, Charité – Universitätsmedizin Berlin, Campus Mitte, Charitéplatz 1, 10117 Berlin, Germany margitta.worm@charite.de Severe allergic reactions after COVID-19 vaccination with the Pfizer/BioNTech vaccine in Great Britain and. . . K 52 or any of its components [1]. As a precautionary measure, the MHRA has issued interim guidance to the NHS not to vaccinate in principle “patients with severe allergies”. It is likely that the restriction on indications now imposed by the MHRA will result in significantly fewer patients being able to receive the vaccine. Further adverse reaction reports can be expected from the U.S. Food and Drug Administration’s (FDA) Emergency Use Authorization (EUA) for BNT162b2 granted on December 11, 2020, as very large vaccina- tion numbers are now likely to be achieved rapidly. Allergic reactions to vaccines Allergic reactions to vaccines are very rare, occurring at 1 per 1,000,000 to 30 per 100,000 vaccinations [2–6]. Vaccine components known to cause allergic reac- tions include residues of animal proteins, antimicro- bial agents, preservatives, stabilizers, and adjuvants in addition to the active component of the vaccine (the actual antigen) that elicit the immune response [2–6]. Individual vaccine components associated with causing vaccine anaphylaxis include chicken egg pro- tein, gelatin, cow’s milk proteins, and other additives and trace compounds left over from the manufactur- ing process, in addition to latex components from the sealing plugs in multiple vaccine vials [3–6]. The vaccine BNT162b2 BNT162b2 is “temporarily licensed” in the United Kingdom for active immunization to prevent COVID- 19 disease caused by the SARS-CoV-2 virus in persons 16 years of age and older [7]. The vaccine is administered intramuscularly in two doses of 0.3 ml each, 21 days apart. Thawed COVID-19 mRNA vaccine BNT162b2 requires dilution in its orig- inal vial (0.45 ml) with 1.8 ml of unpreserved sodium chloride 0.9% solution for injection, prior to with- drawing a 0.3 ml dose [7, 8]. The listed excipients in BNT162b2 are ALC-0315 ((4-hydroxybutyl)azanediyl)bis(hexane-6,1-diyl)bis(2- hexyl decanoate), ALC-0159 (2-((polyethylene glycol)- 2000)-N,N-ditetradecylacetamide), 1,2-distearoyl-sn- glycero-3-phosphocholine, cholesterol, potassium chloride, potassium dihydrogen phosphate, sodium chloride, disodium hydrogen phosphate dihydrate, sucrose, and water for injection [7, 8]. One vial (0.45 ml) contains five doses of 30 µg of highly purified, single-stranded, 5(cid:2)-capped mRNA (BNT162b2 RNA) produced by cell-free in vitro tran- scription on an appropriate DNA template and en- coding the viral spike(S) protein of SARS-CoV-2 [7, 8]. This mRNA is embedded in lipid nanoparticles. mRNA is rapidly degraded by ribonucleases, readily taken up by mononuclear phagocytes, and has poor ability to penetrate cell membranes due to its negative position article electrical charge and high molecular weight. There- fore, mRNA requires a protective envelope for use In the BioNTech vaccine, lipid-based as a vaccine. nanoparticles (LNPs) are used as nonviral vectors for this purpose, containing cationic lipids that coat the polyanionic mRNA with its tertiary or quaternary amines, complemented by zwitterionic lipids that mimic cell membrane phospholipids, and cholesterol that stabilizes the lipid bilayer of the nanoparticle. Finally, polyethylene glycol (PEG)-modified lipids en- able the assembly of a hydrate shell, increasing the solubility of the LNPs. types ranging from 200 g/mol PEG or macrogol is a polyether compound com- monly used as an additive in cosmetics, pharmaceu- ticals, and also in foods [9]. PEG exists in molecular to weight 10,000,000 g/mol and allergic reactions have been reported after its use in a variety of drugs and cos- metic products [10, 11]. There is cross-reactivity to polysorbate 80 due to common chemical motifs [12, 13]. Allergic reactions to PEG are probably diag- nosed too rarely, so PEG is also considered a “hidden” allergen [11]. Severe allergic reactions have been de- scribed in diagnostic skin testing, so this should only be performed in allergy-specialized centers according to published standard regimens. In the pivotal phase III clinical trial, the BNT162b2 vaccine was generally well tolerated [8]. A total of 43,548 participants were randomized, of whom 43,448 received one injection, 21,720 with BNT162b2 and 21,728 with placebo 18,556 received a second dose of BNT162b2 [8]. The most common adverse reactions were local reactions at the injection site (84.7%), fatigue (62.8%), headache (55.1%), muscle pain (38.3%), chills (31.9%), joint pain (23.6%), fever (14.2%) [7, 8]. Most reactions were mild to moderate in severity. Severe adverse reactions occurred in up to 4.6% and were more common after the second dose and less common in adults > 55 years of age. Lymphadenopathy was reported in 0.3%. Systemic adverse reactions were usually mild or moderate in severity, generally occurring the day after vaccination and lasting one to two days thereafter [7, 8]. The occurrence of allergic reaction was reported in simi- lar numbers in both the vaccine-verum and placebo groups (0.63% vs. 0.51%) [7, 8]. However, this large clinical trial, used to support vaccine approval by the MHRA and FDA, excluded individuals with a “history of a severe adverse reaction related to the vaccine and/or a severe allergic reaction (e.g., anaphylaxis) to a component of the study medication” [7, 8]. Based on this the UK package insert based on this states that the vaccine should not be administered to individuals who are allergic to the active ingredient or any of the other ingredients listed. In this respect, the patient information complies with the exclusion criteria of the clinical trial. K Severe allergic reactions after COVID-19 vaccination with the Pfizer/BioNTech vaccine in Great Britain and. . . 53 position article Evaluation and outlook Vaccines are recognized as one of the most effective public health interventions. The primary goal of vac- cination programs is the protection of the vaccinated individuals. In addition, in many cases they also aim to protect unvaccinated individuals. The ultimate goal is creating herd immunity, i.e., resistance to the spread of a contagious disease in a population, which occurs when a sufficiently high proportion of individuals are immune to that disease, especially through vaccina- tion [14]. The development of such herd immunity requires vaccination rates of > 60% of the total population [14]. However, to achieve effective individual immuniza- tion of > 95% with BNT162b2, a second vaccination (“booster”) is necessary. This repeated administration of a foreign protein (antigen) necessitates a careful al- lergological history before each application and diag- nostic clarification, if necessary, and risk–benefit as- sessment before each injection. Against this background we state that (cid:2) Patients and people who are to receive a vaccination against COVID-19 must also be regularly informed about possible severe allergic/anaphylactic reac- tions and questioned with regard to such incidents in the past. (cid:2) Allergic reactions to additives, in particular PEG and cross-reactive PEG analogues, must be systemati- cally queried in order to identify patients at risk. (cid:2) In suspected cases, allergological clarification (skin prick test, laboratory diagnostics) and consultation of an allergist should be carried out. (cid:2) Personnel performing vaccination against COVID- 19 must always be prepared for the possibility of severe allergic/anaphylactic reactions and vacci- nation teams and vaccination centers should be trained in the treatment of anaphylaxis according to the recommendations of the current AWMF guide- line on the acute therapy and management of ana- phylaxis [15]. (cid:2) It will be important to understand the specific cause of the two reported severe allergic reactions and the medical history of the individuals involved so that any risks of allergic reactions can be more accurately defined and, if possible, circumvented. (cid:2) Current authority guidelines in the UK exclude pa- tients with severe allergies from vaccination with BNT162b2. (cid:2) More precise definitions of the type, cause, and severity of severe allergic reactions are needed be- cause, given the high incidence of patients with “severe” allergies (a significant proportion of the total population in Europe and the US, depend- ing on the definition), excluding all such patients from vaccination could have a significant impact on achieving the goal of herd immunity. On the other hand, a more precise definition (e.g., “ana- phylaxis-prone patients”) would suggest only 1–3% of the population for whom vaccination would be impossible or only possible with special protective measures. (cid:2) More data need to be collected from both clini- cal trials and clinical practice that will improve our knowledge of the safety profile of COVID-19 vaccines, particularly with regard to severe allergic reactions. Severe allergic reactions to vaccines are rare but can be life-threatening, and it is prudent to raise aware- ness of this hazard among vaccination teams and to take adequate precautions while more experience is gained with this new vaccine. Patients with a history of severe allergic reactions may be vaccinated with adequate medication and by physicians experienced in the management of anaphylactic reactions if the ongoing investigation in the UK allows this recom- mendation. PEG is currently considered to have most likely triggered the severe allergic reactions in the 2 af- fected patients in the UK, but further investigations are awaited. If confirmed, it would only be necessary to exclude patients with known allergic reactions to PEG, PEG analogs, and other additives from vaccination with BNT162b2, but not all patients with a history of se- vere allergic reactions, which would significantly ex- pand the pool of potentially vaccinatable individuals. For BNT162b2, safety monitoring will continue for 2 years after administration of the second vaccine dose within the study [8]. Funding Open Access funding enabled and organized by Projekt DEAL Conflict of interest L. Klimek reports grants and personal fees from Allergopharma, grants and personal fees from MEDA/ Mylan, personal fees from HAL Allergie, personal fees from ALK Abelló, grants and personal fees from LETI Pharma, grants and personal fees from Stallergenes, grants from Quin- tiles, grants and personal fees from Sanofi, grants from ASIT biotech, grants from Lofarma, personal fees from Allergy Therapeut., grants from AstraZeneca, grants and personal fees from GSK, grants from Inmunotek, personal fees from Cassella med, personal fees from Novartis, outside the sub- mitted work; and Membership: AeDA, DGHNO, Deutsche Akademie für Allergologie und klinische Immunologie, HNO- BV, GPA, EAACI. K. Hartmann has received research funding from Euroimmun and Thermofisher and consultancy or lec- ture fees from Allergopharma, ALK-Abelló, Blueprint, Deci- phera, Menarini, Novartis and Takeda. J. Ring reports per- sonal fees from Mylan, personal fees from Allergika, outside the submitted work. A. Chaker reports grants and other from Allergopharma, grants and other from ALK Abello, grants and other from Bencard/Allergen Therapeutics, grants and other from ASIT Biotech, other from Lofarma, grants and other from GSK, grants and other from Novartis, grants and other from LETI, grants and other from Roche, grants and other from Zeller, other from Sanofi Genzyme, grants from European Institute of Technology, grants and other from AstraZeneca, grants and other from Immunotek, outside the submitted work; in addition, Dr. Chaker has a patent A ratio of immune Severe allergic reactions after COVID-19 vaccination with the Pfizer/BioNTech vaccine in Great Britain and. . . K 54 cells as prognostic indicator of therapeutic success in allergen- specificimmunotherapy: 17 177 681.8 licensedto none. M. Wa- genmann has received fees for advice, lectures or research support from the following companies in the past 3 years: ALK-Abelló, Allergopharma, AstraZeneca, Bencard Allergie, Genzyme, GSK, HAL Allergie, Infectopharm, LETI Pharma, MEDA Pharma, Novartis, Regeneron, Sanofi Aventis, Staller- genes, Teva—all outside of the present work. T. Ankermann has received fees and accommodation and travel expenses for lectures and publications from the following companies and institutions: Abbvie, Aimmune, Allergopharma, Chiesi, Infectopharm, Novartis, UKSH Academy, RG, Springer pub- lishing house, Scientific publishing company, GPP e. V, GPA e. V., nappa e. V., ÖGKJ e. V. Dr. Ankermann has received fees for advisory boards from Boehringer Ingelheim, Aimmune, and fees for safety board from Allergopharma, all outside of the present work. C. Vogelberg has received lecture fees or consultant fees or travel and accommodation costs from: ALK, Allergopharma, Aimmune, DBV, LETI, Novartis, Stal- lergenes, HAL, Bencard, Sanofi, Aimmune, GPA e. V., APPA e. V. all outside of the present work. T. Werfel reports grants and/or fees from AbbVie, ALK Abello, Almirall, Astellas, Ben- card, Galderma, Janssen/JNJ, Leo Pharma, Leti, Lilly, Novartis, Pfizer, Regeneron/Sanofi, Stallergen, all outside of the present work. A. Bauer reports grants and personal fees from Novartis, Leo Pharma, Sanofi/Regeneron, Shire/Takeda, Genentech, outside the submitted work. T. Zuberbier reports personal fees and/or fees for talk from Bayer Health Care, FAES, No- vartis, Henkel, AstraZeneca, AbbVie, ALK, Almirall, Astellas, Bencard, Berlin Chemie, HAL, Leti, Meda, Menarini, Merck, MSD, Pfizer, Sanofi, Stallergenes, Takeda, Teva, UCB, Kryolan, L’Oréal outside the submitted work. T. Jakob reports grants, personal fees and non-financial support from Novartis, grants, personal fees and non-financial support from ALK-Abello, personal fees and non-financial support from Allergy Ther- apeutics/Bencard, personal fees from Allergopharma, per- sonal fees from Thermo Fisher, outside the submitted work. M. Worm reports honorarium for advisory boards and lecture activities from Regeneron Pharmaceuticals, DBV Technolo- gies S.A, Stallergenes GmbH, HAL Allergie GmbH, Bencard Allergie GmbH, Allergopharma GmbH & Co. KG, ALK-Abelló Arzneimittel GmbH, Mylan Germany GmbH, Leo Pharma GmbH, Sanofi-Aventis Deutschland GmbH, Aimmune Ther- apeutics UK Limited, Actelion Pharmaceuticals Deutschland GmbH, Novartis AG, Biotest AG, AbbVie Deutschland GmbH & Co. KG, Lilly Deutschland GmbH, outside the submitted work. N. Novak, E. Hamelmann, C. Taube, H. Merk, U. Rabe, K. Jung, W. Schlenter, W. Wehrmann, S. Becker, N. Mülleneisen, K. Ne- mat, W. Czech, H. Wrede, R. Brehler, T. Fuchs, S. M. Schmidt and M. Gerstlauer declare that they have no competing in- terests. Open Access This article is licensed under a Creative Com- mons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permis- sion directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. position article References 1. England NHS. 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