May polyethylene glycol be the cause of anaphylaxis to mRNA COVID-19 vaccines?

Vaccination against coronavirus is essential to minimize the impact of the 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 events is 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 referred to an allergist-immunologist for further orientation.

To the Editor,

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

After two cases of anaphylaxis associated with the Pfizer/BioNTech vaccine were described, the National Health Service (NHS) of United Kingdom stated: “Any person with a history of anaphylaxis to a vaccine, medicine or food should not receive the Pfizer/BioNTech vaccine”. We consider this statement vague and very generalist. It may cause fear and confusion, depriving patients with a history of anaphylaxis from being vaccinated. Right after the vaccination started in England, the United States started immunizing their population and also detected rare cases of anaphylaxis to both mRNA vaccines., The recommendations of the US Centers for Disease Control and Prevention (CDC) were that, while cases of anaphylaxis are investigated, “History of severe allergic reaction to any vaccine or any injectable therapy is a precaution, but not contraindication, to vaccination”.

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

Looking at the constituents of the mRNA COVID-19 vaccines, there is a possible cause of these vaccine-induced anaphylaxis events: the polyethylene glycol (PEG). In the vaccine, the nucleoside-modified RNA encoding the SARS-CoV-2 full-length spike protein is formulated into lipid nanoparticles, which contain PEG. Immediate HRs to PEG, also known as macrogol, are underrecognized and poorly understood. PEGs constitute a family of hydrophilic polymers of ethylene oxide (H(OCH2CH2)nOH), and these substances are present in thousands of medications, cosmetics, and food products. Although rare, anaphylaxis to PEG has been described in the literature, mainly in patients using bowel preparation solutions or steroid depot formulations. Recently, a case series of five patients with PEG allergy was described, warning that “PEG is a high-risk 'hidden' allergen, usually unsuspected, and can cause frequent allergic reactions due to inadvertent reexposure”. The mechanisms of PEG-induced anaphylaxis are not fully understood and may involve IgE- and non IgE-mediated immediate HRs. Serum specific-IgE was detected in patients with anaphylaxis to PEG, showing that at least some of these immediate HRs could be allergic. PEG is structurally related to polysorbate, and cross-reactive hypersensitivity between these compounds may occur.,

Recently, two case series were published bringing more information on anaphylaxis to the mRNA vaccines of Pfizer/BioNTech (4) and Moderna. They were based on notifications and reports of immediate HRs following mRNA vaccination, which were captured in the Vaccine Adverse Event Reporting System (VAERS), the passive surveillance system in the United States for adverse events after immunization. Table 1 shows the incidence of anaphylaxis to mRNA SARS-CoV-2 vaccines,, the vaccine constituents and the current CDC recommendations regarding adverse reactions.

Table 1

MRNA SARS-CoV-2 vaccines, incidence of anaphylaxis and current CDC recommendations regarding adverse reactions (4–6)

mRNA vaccine to SARS-CoV-2	Constituents	Incidence of anaphylaxis per doses administered	CDC recommendations regarding adverse reactions
BNT162b2 mRNA COVID-19 (Pfizer/BioNTech)	• Nucleoside-modified mRNA encoding the viral spike (S) glycoprotein of SARS-CoV-2 • 2 [(polyethylene glycol)-2000]-N,N-ditetradecylacetamide • 1,2-distearoyl-sn-glycero-3-phosphocholine • Cholesterol • (4-hydroxybutyl)azanediyl)bis (hexane-6,1-diyl)bis (2-hexyldecanoate) • Potassium chloride • Monobasic potassium phosphate • Sodium chloride • Dibasic sodium phosphate dihydrate • Sucrose	11.1:1 million	• Contraindication Immediate allergic reaction of any severity to a previous dose of an mRNA COVID-19 vaccine or any of its components (including polyethylene glycol [PEG]). Immediate allergic reaction of any severity to polysorbate (due to potential cross-reactive hypersensitivity with the vaccine ingredient PEG)
mRNA-1273 COVID-19 (Moderna)	• Nucleoside-modified mRNA encoding the viral spike (S) glycoprotein of SARS-CoV-2 • PEG2000-DMG: 1,2-dimyristoyl-rac-glycerol, methoxypolyethylene glycol • 1,2-distearoyl-sn-glycero-3-phosphocholine • Cholesterol • SM-102: heptadecan-9-yl 8-((2-hydroxyethyl) (6-oxo-6-(undecyloxy) hexyl) amino) octanoate • Tromethamine • Tromethamine hydrochloride • Acetic acid • Sodium acetate • Sucrose	2.5:1 million	• Precautions History of any immediate allergic reaction to other vaccines or injectables therapies

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

Table 2

Immediate hypersensitivity reactions following mRNA SARS-CoV-2 vaccination (4, 5)

mRNA SARS-CoV-2 vaccine	n patients (n women)	Mean age (range)	Past history of immediate HRs (%)	Past history of anaphylaxis (%)
BNT162b2 mRNA COVID-19 (Pfizer/BioNTech)	21 (19)	40.5 (27–60)	76.2%	33.3%
mRNA-1273 COVID-19 (Moderna)	10 (10)	46.2 (31–63)	90%	50%
Total	31 (29)	42.3 (27–63)	80.6%	38.7%

Fig. 1

Cause of previous immediate hypersensitivity reaction in patients with anaphylaxis to mRNA COVID-19 vaccines

It is essential to prevent vaccination against coronavirus from being harmful and, consequently, being hampered by public opinion. Hippocrates stated “Primum non nocere”, which ironically was published in his work “Epidemic”. The mRNA COVID-19 vaccines should be administered in settings with an appropriate structure and with trained health professionals for the prompt treatment of any anaphylaxis event.

At the moment, a more accurate recommendation would be the contraindication of mRNA COVID-19 vaccines in patients with immediate HR to polyethylene glycol or polysorbate. Patients with history of immediate HR to other or unknown causes should be referred to an allergist-immunologist for further orientation. Here we suggest an algorithm to manage individuals intending to be vaccinated with an mRNA COVID-19 vaccine (Fig. 2). Evidence-based decisions are crucial to increase the confidence and adherence of the world population in vaccination for COVID-19. Further studies on anaphylaxis associated with the mRNA COVID-19 vaccines are needed.

Fig. 2

Algorithm to manage individuals intending to be vaccinated with an mRNA COVID-19 vaccine. Legend: immediate HR – Immediate Hypersensitivity Reaction (anaphylactic type reaction)

Abbreviations

National Health Service, NHS; Center for Disease Control, CDC; hypersensitivity reaction, HSR; polyethylene glycol, PEG; Vaccine Adverse Event Reporting System, VAERS.

Funding

Own Department funding.

Availability of data and materials

Availability of data and materials do not apply.

Ethics

Ethics approval does not apply.

Conflict of interest

The authors have no financial or conflicts of interest to disclose. All authors participated in the design of the present study and wrote the manuscript. All authors read, approved, and consented to the publication of this manuscript.

The study was done at the Clinical Immunology and Allergy Division of the University of São Paulo School of Medicine, Brazil, in 2020.