Basophil reactivity to BNT162b2 is mediated by PEGylated lipid nanoparticles in patients with PEG allergy.

The mechanisms underpinning allergic reactions to the BNT162b2 (Pfizer) COVID-19 vaccine remain unknown, with polyethylene glycol (PEG) contained in the lipid nanoparticle suspected as being the cause. Our aim was to evaluate the performance of skin testing and basophil activation testing to PEG, polysorbate 80, and the BNT162b2 (Pfizer) and AZD1222 (AstraZeneca) COVID-19 vaccines in patients with a history of PEG allergy. Three known individuals with PEG allergy and 3 healthy controls were recruited and evaluated for hypersensitivity to the BNT162b2 and AZD1222 vaccines, and to related compounds by skin testing and basophil activation, as measured by CD63 upregulation using flow cytometry. We found that the BNT162b2 vaccine induced positive skin test results in patients with PEG allergy, whereas the result of traditional PEG skin testing was negative in 2 of 3 patients. One patient was found to be cosensitized to both the BNT162b2 and AZD1222 vaccines because of cross-reactive PEG and polysorbate allergy. The BNT162b2 vaccine, but not PEG alone, induced dose-dependent activation of all patients' basophils ex vivo. Similar basophil activation could be induced by PEGylated liposomal doxorubicin, suggesting that PEGylated lipids within nanoparticles, but not PEG in its native state, are able to efficiently induce degranulation. Our findings implicate PEG, as covalently modified and arranged on the vaccine lipid nanoparticle, as a potential trigger of anaphylaxis in response to BNT162b2, and highlight shortcomings of current skin testing protocols for allergy to PEGylated liposomal drugs.

Troelnikov A ，Perkins G ，Yuson C ，Ahamdie A ，Balouch S ，Hurtado PR ，Hissaria P ... -  《-》

PEGylated liposomes for diagnosis of polyethylene glycol allergy.

Polyethylene glycol (PEG) is a nonprotein polymer that is present in its native (unbound) form as an excipient in a range of products. It is increasingly being utilized clinically in the form of PEGylated liposomal medications and vaccines. PEG is the cause of anaphylaxis in a small percentage of drug reactions; however, diagnosis of PEG allergy is complicated by the variable and poor diagnostic performance of current skin testing protocols. We assessed the diagnostic performance of PEGylated lipid medications as an alternative to currently described tests that use medications containing PEG excipients. Nine patients with a strong history of PEG allergy were evaluated by skin testing with a panel of PEG-containing medications and with a PEGylated lipid nanoparticle vaccine (BNT162b2). Reactivity of basophils to unbound and liposomal PEG was assessed ex vivo, and specificity of basophil responses to PEGylated liposomes was investigated with a competitive inhibition assay. More detailed information is provided in this article's Methods section in the Online Repository available at www.jacionline.org. Despite compelling histories of anaphylaxis to PEG-containing medications, only 2 (22%) of 9 patients were skin test positive for purified PEG or their index reaction-indicated PEG-containing compound. Conversely, all 9 patients were skin test positive or basophil activation test positive to PEGylated liposomal BNT162b2 vaccine. Concordantly, PEGylated liposomal drugs (BNT162b2 vaccine and PEGylated liposomal doxorubicin), but not purified PEG2000, consistently induced basophil activation ex vivo in patients with PEG allergy but not in nonallergic controls. Basophil reactivity to PEGylated nanoparticles competitively inhibited by preincubation of basophils with native PEG2000. Presentation of PEG on the surface of a lipid nanoparticle increases its in vivo and ex vivo allergenicity, and improves diagnosis of PEG allergy.

Perkins GB ，Tunbridge MJ ，Hurtado PR ，Zuiani J ，Mhatre S ，Yip KH ，Le TA ，Yuson C ，Kette F ，Hissaria P ... -  《-》

Endotyping of IgE-Mediated Polyethylene Glycol and/or Polysorbate 80 Allergy.

Polyethylene glycol (PEG) and polysorbate 80 (PS80) allergy preclude from SARS-CoV-2 vaccination. The mechanism(s) governing cross-reactivity and PEG molecular weight dependence 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-spike 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, whereas 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.

Ieven T ，Coorevits L ，Vandebotermet M ，Tuyls S ，Vanneste H ，Santy L ，Wets D ，Proost P ，Frans G ，Devolder D ，Breynaert C ，Bullens DMA ，Schrijvers R ... -  《-》

Allergy to PEG (polyethylene glycol) - sensitivity of basophil activation test with COVID-19 mRNA-vaccine BNT162B2.

Eberlein B ，Mathes S ，Darsow U ，Biedermann T ，Brockow K ... -  《-》

The Polysorbate containing AstraZeneca COVID-19 vaccine is tolerated by polyethylene glycol (PEG) allergic patients.

Polyethylene glycol (PEG) is the excipient found in the mRNA COVID-19 vaccines. We previously demonstrated PEG allergy was a cause of severe anaphylaxis to the Pfizer/BioNTech COVID-19 vaccine. PEG is widely used in many household products, cosmetics and medicines. However PEG allergy is rare, there have been few confirmed cases of PEG allergy. The excipient of potential concern in the AstraZeneca COVID-19 vaccine is polysorbate 80 (PS80). Cross-reactivity between PEG and polysorbate has been suggested, based on their composition and skin-test data. The aim of this study was to determine whether PEG-allergic patients could be vaccinated with the PS80 containing AstraZeneca COVID-19 vaccine. Eight patients with PEG allergy were identified by the allergy clinic at Cambridge University Hospital. Patients underwent skin prick testing to PS80 (20%) and to the AstraZeneca COVID-19 vaccine prior to vaccination. All eight patients allergic to PEG tolerated the AstraZeneca COVID-19 vaccine, even in 2 patients where the PS80 skin prick test was positive and 1 with a positive skin prick test to the AstraZeneca COVID-19 vaccine. Patients allergic to PEG, previously denied COVID vaccination, may now be safely vaccinated with the PS80 containing AstraZeneca vaccine and need only avoid the PEG-containing mRNA COVID-19 vaccines. This opens up the possibility that these patients will also tolerate other vaccines containing PS80 such as the Janssen/Johnson and Johnson COVID-19 vaccine. Clinical cross-reactivity between PEG and PS80 did not occur in this vaccine setting.

Sellaturay P ，Gurugama P ，Harper V ，Dymond T ，Ewan P ，Nasser S ... -  《-》