Publication date: Jun 26, 2023

Polyethylene glycol (PEG) and polysorbate 80 (PS80) allergy preclude from SARS-CoV-2 vaccination. The mechanism(s) governing cross-reactivity and PEG molecular weight-dependency remain unclear. To evaluate PEGylated lipid nanoparticle (LNP) vaccine (BNT162b2) tolerance, and explore the mechanism of reactivity in PEG and/or PS80 allergic patients. PEG/PS80 dual- (n=3), PEG mono- (n=7) and PS80 mono-allergic patients (n=2) were included. Tolerability of graded vaccine challenges was assessed. Basophil activation testing on whole blood (wb-BAT) or passively sensitized donor basophils (allo-BAT) was performed using PEG, PS80, BNT162b2, and PEGylated lipids (ALC-0159). Serum PEG-specific IgE was measured in patients (n=10) and controls (n=15). Graded BNT162b2 challenge in dual- and PEG mono-allergic patients (n=3/group) was well-tolerated and induced anti-S IgG seroconversion. PS80 mono-allergic patients (n=2/2) tolerated single-dose BNT162b2 vaccination. Wb-BAT reactivity to PEG-containing antigens was observed in dual- (n=3/3) and PEG mono- (n=2/3), but absent in PS80 mono-allergic patients (n=0/2). BNT162b2 elicited the highest in vitro reactivity. BNT162b2 reactivity was IgE-mediated, complement-independent, and inhibited in allo-BAT by preincubation with short PEG motifs, or detergent-induced LNP degradation. PEG-specific IgE was only detectable in dual-allergic (n=3/3) and PEG mono-allergic (n=1/6) serum. PEG and PS80 cross-reactivity is determined by IgE recognizing short PEG motifs, whilst PS80 mono-allergy is PEG-independent. PS80 skin test positivity in PEG allergics was associated with a severe and persistent phenotype, higher serum PEG-specific IgE levels and enhanced BAT reactivity. Spherical PEG-exposure via LNP enhances BAT sensitivity through increased avidity. All PEG and/or PS80 excipient allergic patients can safely receive SARS-CoV-2 vaccines.

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