Title: Anti-PEG IgE in anaphylaxis associated with polyethylene glycol

Abstract

Polyethylene glycol (PEG) with its unique properties, including solubility in water and non-polar solvents, has been used in many medical and pharmaceutical products including LNP/mRNA COVID vaccines as an active ingredient or excipient. Despite the success of these products, acute drug allergic reactions associated with PEG have been observed in both clinical trials and practice, with many cases occurring without a known prior PEG exposure. Many cases of PEG associated anaphylaxis may not be recognized, especially for products where PEG is not identified as an active ingredient. Although skin testing suggested a potential IgE-mediated type 1 hypersensitivity reaction in some cases, a reliable lab assay to sensitively detect specific anti-PEG IgE was not available to evaluate these events. Studies with ELISA-based anti-PEG assays have reported high background and lack of specificity and thus, could only detect higher levels of IgG and IgM. To fill this important gap in assessing the increasing risks associated with the use of PEG and PEGylated drugs, we developed a dual cytometric beads assay (DCBA, with built-in specificity control) for the detection of anti-PEG antibodies, with a 100-fold greater sensitivity than conventional assays. This increased assay sensitivity allows for reliable detection of anti-PEG IgE. This assay was used to test samples from patients who had developed clinical anaphylaxis upon PEG exposure (cases) and those who did not (controls). The DCBA method and results enabled us to first confirm the long-considered hypothesis that PEG-associated acute allergy can be due to IgE-mediated type 1 hypersensitivity. We also demonstrated pre-existing antibodies to PEG in normal sera that can explain allergic responses on apparently initial exposures.