key: cord-0690807-clk482qk
authors: TURNER, Paul J.; ANSOTEGUI, Ignacio J.; CAMPBELL, Dianne E.; CARDONA, Victoria; EBISAWA, Motohiro; EL-GAMAL, Yehia; FINEMAN, Stanley; GELLER, Mario; GONZALEZ-ESTRADA, Alexei; GREENBERGER, Paul A.; LEUNG, Agnes S.Y.; LEVIN, Michael E.; MURARO, Antonella; SÁNCHEZ BORGES, Mario; SENNA, Gianenrico; TANNO, Luciana K.; Yu-Hor THONG, Bernard; WORM, Margitta
title: COVID-19 VACCINE-ASSOCIATED ANAPHYLAXIS: A STATEMENT OF THE WORLD ALLERGY ORGANIZATION ANAPHYLAXIS COMMITTEE
date: 2021-02-03
journal: World Allergy Organ J
DOI: 10.1016/j.waojou.2021.100517
sha: d7fc1cdf96a91cb2b35a9563ce9473203c006699
doc_id: 690807
cord_uid: clk482qk

Vaccines against COVID-19 (and its emerging variants) are an essential global intervention to control the current pandemic situation. Vaccines often cause adverse events; however, the vast majority of adverse events following immunization (AEFI) are a consequence of the vaccine stimulating a protective immune response, and not allergic in etiology. Anaphylaxis as an AEFI is uncommon, occurring at a rate of less than 1 per million doses for most vaccines. However, within the first days of initiating mass vaccination with the Pfizer-BioNTech COVID-19 vaccine BNT162b2, there were reports of anaphylaxis from the UK and USA. More recent data implies an incidence of anaphylaxis closer to 1:125,000 doses with respect to the Pfizer-BioNTech vaccine. In this position paper, we discuss the background to reactions to the current COVID-19 vaccines and relevant steps to mitigate against the risk of anaphylaxis as an AEFI. We propose a global surveillance strategy led by allergists in order to understand the potential risk and generate data to inform evidence-based guidance, and thus provide reassurance to public health bodies and members of the public.

are a consequence of the vaccine stimulating a protective immune response, and not 10 allergic in etiology. Anaphylaxis as an AEFI is uncommon, occurring at a rate of less 11 than 1 per million doses for most vaccines. However, within the first days of initiating 12 mass vaccination with the Pfizer-BioNTech COVID-19 vaccine BNT162b2, there 13 were reports of anaphylaxis from the UK and USA. More recent data implies an 14 incidence of anaphylaxis closer to 1:125,000 doses with respect to the Pfizer-15

BioNTech vaccine. 16 17

In this position paper, we discuss the background to reactions to the current COVID-18 19 vaccines and relevant steps to mitigate against the risk of anaphylaxis as an 19 AEFI. We propose a global surveillance strategy led by allergists in order to 20 understand the potential risk and generate data to inform evidence-based guidance, 21 and thus provide reassurance to public health bodies and members of the public. Adverse event following immunization; Anaphylaxis; COVID-19; polyethylene glycol; 26

vaccine. 27

Vaccines against COVID-19 (and its emerging variants) are an essential global 29 intervention to control the current pandemic situation. Vaccines often cause adverse 30 events; however, the vast majority of adverse events following immunization (AEFI) 31 are due to the protective immune response induced by the vaccine, and not due to 32 an allergic reaction. 33 34 Anaphylaxis as an AEFI is uncommon, occurring at a rate of less than 1 per million 35 doses for most vaccines. [1] [2] [3] [4] [5] However, within the first days of initiating mass 36 vaccination with the Pfizer-BioNTech COVID-19 vaccine BNT162b2, there were 37 reports of 2 and 6 anaphylaxis events in the UK and USA, respectively. 6,7 Further 38 surveillance data reported for the UK 7 and USA 8 suggest a rate closer to 1:125,000 39 doses for the Pfizer-BioNTech vaccine (while the USA publication reported 21 cases 40 of anaphylaxis, in 6 cases the reactions described refer only to cutaneous 41 symptoms; thus the true rate of anaphylaxis (15 cases) is closer to 1:125,000 42 doses). 8 The vaccines against COVID-19 are new and some (for example, the 43 mRNA vaccines) have a novel mechanism of action; thus the risk of allergic 44 reactions may be greater than for conventional vaccines. Moreover, it is not 45 surprising that anaphylaxis has not been reported in the clinical trials to date, given 46 the very low incidence and the exclusion of individuals with a history of 47 hypersensitivity reactions in most studies. 48

In this position paper, we discuss the background to reactions to the current COVID-50 19 vaccines and relevant steps to mitigate against the risk of anaphylaxis as an 51 AEFI. We propose a global surveillance strategy led by allergists in order to 52 understand the potential risk and generate data to inform evidence-based guidance. 53

Allergic reactions to vaccines are generally due to adjuvants and other 56 excipients/components in the vaccine such as preservatives and antibiotics, rather 57 than to the active ingredient itself. Vaccines may also contain small amounts of 58 protein present due to the production process (e.g. embryonic cells). 3 59 60 In the UK, there was an initial concern that patients with atopic disease might be 61 more at risk of allergic reactions. This is because the two recipients in the UK who 62 were reported to experience anaphylaxis had a history of epinephrine auto-injector 63 carriage due to prior anaphylaxis. The UK regulator issued an advisory statement 64 which listed prior anaphylaxis to a vaccine, medicine or food as a contra-indication. 6 65

The FDA did not make the same stipulation, nor did the US Centers for Disease 66

Control and Prevention (CDC), although both the UK regulator and CDC 67 recommended that all vaccine recipients (regardless of atopic history) should be 68 observed for 15 minutes following vaccination, and that facilities (and trained staff) 69 must be available in all vaccination centres. 9 However, subsequent surveillance data 70 provided further reassurance and the UK regulator lifted the contra-indication three 71 weeks later. 10 72 73

The Pfizer-BioNTech vaccine contains two novel lipid nanoparticles, one of which is 75 "pegylated" (Polyethylene glycol, molecular weight 2000 Daltons, abbreviated to 76 (also a PEG2000) ( Table 1) Skin testing for the investigation of PEG allergy has also been reported to induce 105 anaphylaxis. 13 106 107

The mechanism(s) which underly PEG allergy are unclear. IgE antibodies to PEG 108 have been detected in some patients with a history of PEG-induced anaphylaxis. 15 109

PEGs have also been shown to induce complement activation, at least in vitro, 16 However, in contrast to PEG, polysorbate 80 is an excipient in many existing 130 vaccines (e.g. DTaP and its analogues, HepB, HPV, pneumococcal conjugate 131 vaccine, influenza vaccines, zoster) and many medicines; it is also in widespread 132 use as an emulsifier in foods (E433). At least 70% of injectable biological agents and 133 monoclonal antibody treatments contain polysorbates, usually polysorbate 80. 17 134

Polysorbates are derived from PEGs, but tend to be of lower molecular weights (e.g. The speed and necessity with which vaccines against COVID-19 are being rolled-out 231 requires additional surveillance in order for the community to be able to provide 232 reassurance to the vast majority of individuals and identify potential risk factors for 233 those very few who do experience allergic reactions to the vaccines. This is 234

particularly important in the current climate of vaccine hesitancy. Furthermore, there 235 is a concern as to whether the first dose of vaccine might cause IgE-sensitization, 236 and thus increase the risk of anaphylaxis to a subsequent booster dose of vaccine. 237

In addition, the 2 nd dose of the Pfizer vaccine causes a higher rate of AEFI; 26 this is 238 not uncommon for non-live vaccines, and is generally thought to be due to a priming 239 effect of the first dose. Whether this impacts on the risk of allergic reactions to the 240 new COVID-19 vaccines is unclear. 241 242 Whilst many countries have their own surveillance system, the incidence of 243 anaphylaxis to vaccines is so small that we propose a global strategy. Therefore, 244

Registration of Anaphylaxis (NORA) has established a system for healthcare 246 professionals to register potential cases of anaphylaxis and allergic reactions to the 247 different COVID-19 vaccines. We encourage our colleagues around the world to 248 provide de-identified information which will then be assessed against the validated 249 criteria published by the Brighton Collaboration with respect to Anaphylaxis as an 250 AEFI, 27 as summarized in Appendix B. These data will allow us, as a community, to 251 monitor the occurrence of allergic reactions to the different COVID-19 vaccines in 252 use. We intend to make this information public via the WAO and NORA websites. In the current climate where widespread uptake of vaccines against COVID-19 is a 261 key global intervention to control the pandemic, it is essential that vaccination 262 proceeds safely and with as few barriers as possible. Both the public and healthcare 263 workers need reassurance that the vaccines are safe. We hope guidance such as 264 this document, and the collection of anonymized patient data relating to possible 265 allergic reactions to the vaccines will play a constructive role in achieving this aim. Table 1 )

• Proceed with vaccination as normal, according to local guidelines

• An observation period of 15-30 minutes may be advisable.

• Assess risk and possibility of PEG-allergy

• Consider referral to allergist-immunologist

• Consider observation for 30 minutes if vaccination proceeds

• There are no data to inform recommendations regarding pretreatment e.g. with antihistamine.

• Pretreatment with antihistamines may mask initial symptoms of a reaction.

• Do not vaccinate with the vaccine in question.

• Ideally choose a different COVID-19

vaccine if available and not contraindicated

• Consider referral to allergist-immunologist J o u r n a l P r e -p r o o f

Risk of anaphylaxis after vaccination in children and adults

Anaphylaxis after 285 vaccination reported to the Vaccine Adverse Event Reporting System

International Consensus (ICON): allergic reactions to vaccines

Vaccination 291 and allergy: EAACI position paper, practical aspects

Anaphylaxis as an adverse 294 event following immunisation in the UK and Ireland

Anaphylaxis Following m-RNA COVID-19 Vaccine Receipt. Presentation 297 to ACIP COVID-19 Vaccines Work Group

Confirmation of guidance to vaccination centres on managing allergic 301 reactions following COVID-19 vaccination with the Pfizer/BioNTech vaccine 302 (press release)

CDC COVID-19 Response Team; Food and Drug Administration

Reactions Including Anaphylaxis After Receipt of the First Dose of Pfizer-309

BioNTech COVID-19 Vaccine -United States

Interim clinical considerations for use of mRNA COVID-19 vaccines currently 313 authorized in the United States -Appendix B

Available at: cdc.gov/vaccines/covid-19/info-by-product/clinical-316 considerations.html 317 10. Medicines and Healthcare products Regulatory Agency (MHRA)

University/ AstraZeneca COVID-19 vaccine approved (press release)

Immediate-type hypersensitivity to polyethylene glycols: 322 a review

Fruijtier-Polloth C. Safety assessment on polyethylene glycols (PEGs) and their 324 derivatives as used in cosmetic products

Reactions (Anaphylaxis)

Allergy to polyethylene glycol 329 has significant impact on daily life

PEG IgE in anaphylaxis associated with polyethylene glycol

Epub ahead of print

Poly(ethylene glycol)s generate 336 complement activation products in human serum through increased alternative 337 pathway turnover and a MASP-2-dependent process

Vaccines to Prevent COVID-19 Disease and Reported Allergic Reactions

Current Evidence and Approach

Polysorbates, biotherapeutics and anaphylaxis: a review

Hypersensitivity to Polyethylene Glycols and Polysorbates: More Common Than 349

We Have Recognized

Hypersensitivity reaction to human 351 papillomavirus vaccine due to polysorbate 80

Available at: 355 assets.publishing.service.gov

Proposed Diagnostic Algorithm for Patients with Suspected Mast Cell Activation 359

Vaccination 361 management in children and adults with mastocytosis

World allergy organization anaphylaxis guidance 2020

Polyethylene glycol as a cause of anaphylaxis

Safety and efficacy of the BNT162b2 369 mRNA Covid-19 vaccine

Anaphylaxis: case definition 372 and guidelines for data collection, analysis, and presentation of immunization 373 safety data