key: cord-0942583-uzlgdgqq
authors: Giavina-Bianchi, Pedro; Kalil, Jorge
title: May polyethylene glycol be the cause of anaphylaxis to mRNA COVID-19 vaccines?
date: 2021-03-15
journal: World Allergy Organ J
DOI: 10.1016/j.waojou.2021.100532
sha: 88a205e28a8acb5b8b644efcc348c15a7c82da48
doc_id: 942583
cord_uid: uzlgdgqq

Vaccination against coronavirus is essential to minimize COVID-19 pandemic. Rare cases of anaphylaxis associated with the mRNA COVID-19 vaccines are being described, and the mechanisms involved in these reactions are poorly understood. A potential culprit agent of these vaccine-induced anaphylaxis is the polyethylene glycol, which has been reported as a cause of anaphylaxis. However, a cause-effect association has not been demonstrated and the cases of anaphylaxis to mRNA COVID-19 vaccines should be further investigated. In this scenario, the recommendations are inaccurate and can lead to misinterpretation. At the moment, a more accurate recommendation would be the contraindication of mRNA COVID-19 vaccines in patients with immediate hypersensitivity reaction to polyethylene glycol or polysorbate. Patients with history of anaphylaxis to other or unknown causes should be referral to an allergist-immunologist to further orientation.

Vaccination against coronavirus is essential to minimize COVID-19 pandemic. Rare cases of 4 anaphylaxis associated with the mRNA COVID-19 vaccines are being described, and the 5 mechanisms involved in these reactions are poorly understood. A potential culprit agent of these 6 vaccine-induced anaphylaxis is the polyethylene glycol, which has been reported as a cause of 7 anaphylaxis. However, a cause-effect association has not been demonstrated and the cases of 8 anaphylaxis to mRNA COVID-19 vaccines should be further investigated. In this scenario, the 9 recommendations are inaccurate and can lead to misinterpretation. 10

At the moment, a more accurate recommendation would be the contraindication of mRNA 11 COVID-19 vaccines in patients with immediate hypersensitivity reaction to polyethylene glycol 12 or polysorbate. Patients with history of anaphylaxis to other or unknown causes should be 13 referral to an allergist-immunologist to further orientation. 14 15 Keywords: BNT162b2 mRNA COVID-19 vaccine; polyethylene glycol; macrogol; polysorbate; 16 anaphylaxis, immediate hypersensitivity reaction; immunization. 17

To the Editor, 19

The COVID-19 pandemic has been plaguing the world for one year. In this period, there 20 were about 100 million people infected and two million dead. The effects of the pandemic on 21 public health, economy and society have been devastating, and vaccination against coronavirus is 22 essential to minimize this catastrophe. Therefore, the clinical trials showing the efficacy and 23 safety of the BNT162b2 mRNA COVID-19 (Pfizer/BioNTech) and the mRNA-1273 COVID-19 24 (Moderna) vaccines are encouraging and revolutionary (1, 2) . Several countries around the world 25 started vaccinating their citizens. 26

After two cases of anaphylaxis associated with the Pfizer/BioNTech vaccine were 27 described, the National Health Service (NHS) of United Kingdom stated: "Any person with a 28 history of anaphylaxis to a vaccine, medicine or food should not receive the Pfizer/BioNTech 29 vaccine"(3). We consider this statement vague and very generalist. It may cause fear and 30 confusion, depriving patients with a history of anaphylaxis from being vaccinated. Right after the and also detected rare cases of anaphylaxis to both mRNA vaccines(4, 5). The recommendations 33 of the Center for Disease Control (CDC) were that, while cases of anaphylaxis are investigated, 34 "History of severe allergic reaction to any vaccine or any injectable therapy is a precaution, but 35 not contraindication, to vaccination"(6). 36

Anaphylaxis is a serious, life-threatening immediate systemic hypersensitivity reaction 37 (HR) induced by mast cells and basophils degranulation. Anaphylaxis can be classified as 38 allergic, in which there is a specific immune response mediated by IgE, or nonallergic, with 39 direct degranulation of mast cells/basophils induced by the culprit agent. The three main causes 40 of anaphylaxis are drugs, food and hymenoptera venom. Incidence, prevalence and fatalities of 41 drug-induced anaphylaxis have been increasing (7). Risk of anaphylaxis after all vaccines is 42 estimated to be 1.31 (95% CI, 0.90-1.84) per million vaccine doses, but it differs depending on 43 the vaccine involved and allergies to latex, gelatin and eggs should be considered(8). In these 44 cases, concomitant use of non-steroidal anti-inflammatory drugs, a major cause of drug-induced 45 anaphylaxis, must also be ruled out(9). mRNA COVID-19 vaccines do not contain eggs or 46 gelatin. 47

Looking at the constituents of the mRNA COVID-19 vaccines, there is a possible cause 48 of these vaccine-induced anaphylaxis: the polyethylene glycol (PEG). In the vaccine, the 49 nucleoside-modified RNA encoding the SARS-CoV-2 full-length spike protein is formulated 50 into lipid nanoparticles, which contain PEG. Immediate HRs to PEG, also known as macrogol, 51 are underrecognized and poorly understood. PEGs constitute a family of hydrophilic polymers of 52 ethylene oxide (H(OCH2CH2)nOH), and these substances are present in thousands of 53 medications, cosmetics, and food products. Although rare, anaphylaxis to PEG has been 54 described in the literature, mainly in patients using bowel preparation solutions or steroid depot 55 formulations(10). Recently, a case series of five patients with PEG allergy was described, 56 warning that "PEG is a high-risk "hidden" allergen, usually unsuspected, and can cause frequent 57 allergic reactions due to inadvertent reexposure"(11). The mechanisms of PEG-induced 58 anaphylaxis are not fully understood and may involve IgE-and non IgE-mediated immediate 59

HRs. Serum specific-IgE was detected in patients with anaphylaxis to PEG, showing that at least 60 J o u r n a l P r e -p r o o f cross-reactive hypersensitivity between these compounds may occur(10, 12). 62

Recently, two case series were published bringing more information on anaphylaxis to 63 mRNA vaccines of Pfizer/BioNTech(4) and Moderna(5). They were based on notifications and 64 reports of immediate HRs following mRNA vaccination, which were captured in the Vaccine 65

Adverse Event Reporting System (VAERS), the United States passive surveillance system for 66 adverse events after immunization(13). Table 1 shows the incidence of anaphylaxis to mRNA 67 SARS-CoV-2 vaccines(4, 5), the vaccine constituents and the current Centers for Disease 68

Control and Prevention (CDC) recommendations regarding adverse reactions(6). 69

Analyzing these case series, 87.1% and 96.8% of the immediate HRs started within 30 70 and 60 minutes of vaccination, respectively. They were characterized by diffuse erythematous 71 rash; generalized urticaria; wheezing; stridor; hoarseness; difficulty swallowing; lips, eyelids, 72 tongue and throat swelling; dry cough; hypotension; decreased peripheral perfusion; and 73 anaphylaxis. Patients who had anaphylaxis to the mRNA COVID-19 vaccines reported past 74 history of immediate HRs and anaphylaxis in 80.6% and 38.7% of the cases, respectively (Table  75 2). There was an association between anaphylaxis to mRNA COVID-19 vaccines and past 76 history of anaphylaxis to several etiologies, including drugs, food and Hymenoptera venom 77 ( Figure 1) . None of the patients had history of previous immediate HR to PEG. There are many 78 questions to be answered: Is PEG-anaphylaxis underdiagnosed? Are patients with PEG-79 anaphylaxis misdiagnosed and the reaction is associated with wrong causes? If PEG-anaphylaxis 80 is an allergic reaction, with a specific immune response mediated by IgE, why anaphylaxis to 81 several unrelated etiologies is a risk factor for PEG-anaphylaxis? If PEG-anaphylaxis is a non-82 allergic reaction, why anaphylaxis to several unrelated etiologies is a risk factor for PEG-83 anaphylaxis? 84

It is essential to prevent vaccination against coronavirus from being harmful and, 85 consequently, being hampered by public opinion. Hipocatres stated "Primun non nocere", which 86 ironically was published in his work "Epidemic". mRNA COVID-19 vaccines should be 87 administered in settings with an appropriate structure and with trained health professionals for 88 the prompt treatment of any anaphylaxis(14). 89 J o u r n a l P r e -p r o o f mRNA COVID-19 vaccines in patients with immediate HR to polyethylene glycol or 91 polysorbate. Patients with history of immediate HR to other or unknown causes should be 92 referral to an allergist-immunologist to further orientation. Here we suggest an algorithm to 93 manage individuals intending to be vaccinated with a mRNA COVID-19 vaccine (Figure 2) . J o u r n a l P r e -p r o o f

Safety and 121 Efficacy of the BNT162b2 mRNA Covid-19 Vaccine

Efficacy and 123 Safety of the mRNA-1273 SARS-CoV-2 Vaccine

Drug-Induced Anaphylaxis. Immunol Allergy Clin 125 North Am

Allergic Reactions Including Anaphylaxis After Receipt of the 127 First Dose of Pfizer-BioNTech COVID-19 Vaccine. JAMA. 2021. 128 5. Team CC-R, Administration FaD

Interim Clinical Considerations for 132 Use of mRNA COVID-19 Vaccines Currently Authorized in the United States

Drug-induced anaphylaxis: is it an epidemic? Curr 137 Opin

Vaccine-associated hypersensitivity

Nonsteroidal anti-141 inflammatory drugs are major causes of drug-induced anaphylaxis

Polyethylene Glycol Is a Cause of IgE-Mediated 144

Polyethylene Glycol-Induced Systemic Allergic 146 Reactions (Anaphylaxis)

Immediate 148 Hypersensitivity to Polyethylene Glycols and Polysorbates: More Common Than We Have 149 Recognized

Safety monitoring in the Vaccine 151

Adverse Event Reporting System (VAERS)