COVID‐19 vaccine anaphylaxis: PEG or not?

Abstract

To the Editor, We read the editorial by Cabanillas et al1 with great interest. We agree that great consideration needs to be given to the possibility that the polyethylene glycol [PEG])-2000]-N,N-ditetradecylacetamide micellar carrier system for the active mRNA spike protein component of the Pfizer–BioNTech BNT162b2 mRNA vaccine, sometimes referred to as the lipid nanoparticle (LNP) delivery system, could be evoked in the recent immediate reactions post-emergency use authorization (EUA). In our prior work, we have described patients with immediate reactions to PEG3350. These reactions were consistent with anaphylaxis to PEG3350 bowel preparations and corticosteroids containing both PEG3350 and polysorbate (PS) 80 as an excipient (Table 1). Aside from clinical presentation consistent with anaphylaxis, the case for these being IgE-mediated was supported by positive skin tests to both PEG3350 and PS80 (which we believe to be cross-reactive when primary sensitization occurs through PEG3350) as well as the presence of specific IgE (sIgE) against PEG by two independent methods.2, 3 We would also like to highlight a case of anaphylaxis to an intravenous medication that might be mechanistically relevant. We observed a patient with a history to suggest preexisting PEG3350 anaphylaxis who also developed anaphylaxis when later exposed to a PEGylated liposome (PEGLip) microbubble, PEGLip 5000 perflutren echocardiogram contrast (Definity®). This case was also skin test positive to PEG3350 and PS80 as well as having demonstrable anti-PEG sIgE.4, 5 In post-marketing surveillance of PEGLip perflutren, first approved by the Food and Drug Administration (FDA) in 2001, a multi-center retrospective analysis observed four cases of anaphylaxis out of 66 164 doses of PEGLip perflutren administered.6 In this same study, an alternative formulation of perflutren conjugated to human albumin (Optison™), FDA approved in 1997, was also monitored and had no cases of anaphylaxis observed out of 12,219 doses administered.7 Both formulations of perflutren carry a FDA black box warning for the risk of severe hypersensitivity reactions, but a hypothetical mechanism underlying these reactions had not been clearly elucidated or attributed prior to our report. While anaphylactic reactions to PEGLip perflutren appears to be rare overall, occurring in 0.006% of patients in the study by Wei et al, these reactions do occur.6 PEG and/or lipid complexes in vitro have been shown to cause complement activation, and given the importance of these technologies for developing new therapeutics and vaccines, there is a science behind “PEG pairing” to minimize this effect.8 However, our clinical and laboratory observations do support that IgE-mediated reactions can occur to a PEG-containing product presumably due to previous subclinical sensitization. These patients can notably be labeled as “idiopathic anaphylaxis” or multiple drug allergy if multiple episodes to different products occur over time without knowledge of the shared excipients. An additional observation by our group and others is that for immediate reactions associated with PEG there appears to be a molecular weight (MW) threshold.9 This was seen in our skin test-positive patients who were positive to PEG3350 but negative to PEG300 who then tolerated oral challenge with PEG300.2, 9 This MW predisposition may also vary by patient. To support this hypothesis, we have observed increasing binding avidity of anti-PEG sIgG as the molecular weight of the PEG increases.2 Currently, IgE-mediated reactions associated with PEG appear to both uncommon and underrecognized.2, 4 PEG2000 is crucial to the formation of micelles used as the delivery system for the mRNA vaccines. It will be important to determine whether PEG2000 is implicated in the IgE-mediated reactions in PEG allergic patients, both as a separate ingredient or as a lipid reagent as formulated in the Moderna, Pfizer–BioNTech, and future mRNA vaccines. Cases clinically compatible with anaphylaxis to the Pfizer–BioNTech mRNA vaccine have occurred on the first dose in the post-EUA phase of surveillance in healthcare workers. It is possible that these could be IgE-mediated reactions related to preexisting sensitization to a different PEG product. Until we understand more, patients with previous immediate reactions compatible with PEG anaphylaxis will be excluded from receiving the SARS-CoV-2 mRNA vaccines. Similarly, we need to understand the risk of immediate reactions to PEG products in those who have experienced anaphylaxis with the Pfizer–BioNTech SARS-CoV-2 mRNA vaccine and other mRNA vaccines if these occur. Until assessed by an allergist, it would be recommended that these individuals also avoid not only future vaccination with an mRNA SARS-CoV-2 vaccine but all components of the vaccine which would include PEG products (Table 1). Understanding the mechanisms of immediate reactions associated with the Pfizer–BioNtech and any other mRNA vaccines that utilize different lipids in their PEG2000-micellar delivery system (Table 1), should they occur, will be crucial not only for the safety of the current COVID-19 mRNA vaccine program but for mRNA vaccines in earlier stages of development for other viruses and cancer. The authors declare that they have no conflicts of interest to disclose.

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