key: cord-0694497-16sumpdc authors: Cabanillas, Beatriz; Akdis, Cezmi A.; Novak, Natalija title: COVID‐19 vaccine anaphylaxis: IgE, complement or what else? A reply to: “COVID‐19 vaccine anaphylaxis: PEG or not?” date: 2021-06-15 journal: Allergy DOI: 10.1111/all.14725 sha: 42c260e1ba170d87299f3b92f789c57665aee8b4 doc_id: 694497 cord_uid: 16sumpdc nan To the Editor, Thank you for the correspondence of Krantz et al "COVID-19 vaccine anaphylaxis: PEG or not?". 1 We totally agree with the authors that patients previously allergic to polyethylene glycol (PEG) might react to PEGylated liposomes when exposed to them later on. 1 Since PEGs of different molecular weights are widely distributed, exposure and absorption depending on the size and mode of application can take place via the skin, the gastrointestinal mucosa, or other mucosal tissues including conjunctiva, while some substances containing PEG are administered intravenously, subcutaneously, or intramuscularly. 2 This broad range of likelihoods how PEG can be delivered to the immune system opens a wide range of possibilities, where and how to get sensitized to PEG. Interestingly, sensitization to PEG and PEG analogous occurs only very rarely in view of the extremely high rate of expositions to these substances. 2,3 ( Figure 1A ). Since hypersensitivity reactions take place more frequently after intravenous or intramuscular injection of PEGs, 2 both concentration and molecular weight might play a role. PEGs with lower molecular weights might require in some situations a higher concentration to induce hypersensitivity reactions, while PEGs with higher molecular weights could sometimes induce severe hypersensitivity reactions even at low concentrations ( Figure 1B ). The individual thresholds to react to PEGs of different molecular weight and at different concentrations in vivo and even during diagnostic skin prick testing varies, 4 so that a patient primarily sensitized to a PEG with lower molecular weight might react also to a PEG or even pegylated substance of higher molecular weight as described by Krantz et al. 5 If patients previously sensitized to PEGs of higher molecular weights may react with PEGs of lower molecular weights such as PEG2000 contained in the micellar delivery system of the BNT162b2 and mRNA-1273 COVID-19 vaccines, should be further analyzed. In this regards, attention should be also driven to the AZS1222 DNA vaccine or other COVID-19 vaccines in development, which contain polysorbat-80 as an excipient, since patients sensitized to PEG might be allergic to polysorbats as well, due to structural similarities, leading to cross-reactivity. In addition to IgE-mediated hypersensitivity reactions, complement activation-related pseudoallergy, called CARPA and mediated by PEGyated nanobodies, which induce anaphylatoxins (C3a and C5a) and anti-PEG IgM and IgG antibodies has been described. 6 The anti-drug antibodies are responsible for an accelerated blood COVID-19 vaccine anaphylaxis: PEG or not? Immediate-type hypersensitivity to polyethylene glycols: a review Immediate hypersensitivity to polyethylene glycols and polysorbates: more common than we have recognized Polyethylene glycol-induced systemic allergic reactions (anaphylaxis) Anaphylaxis to PEGylated liposomal echocardiogram contrast in a patient with IgE-mediated macrogol allergy Anti-PEG antibodies: properties, formation, testing and role in adverse immune reactions to PEGylated nano-biopharmaceuticals Intracellular RNA recognition pathway activates strong anti-viral response in human mast cells Safety and efficacy of the BNT162b2 mRNA covid-19 vaccine Vaccination management in children and adults with mastocytosis Cutaneous and systemic mastocytosis in children: a risk factor for anaphylaxis?