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

J Allergy Clin Immunol. 2021 Jul;148(1):91-95. doi: 10.1016/j.jaci.2021.04.032. Epub 2021 May 12.


Background: 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.

Objective: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords: COVID-19; Pfizer BNT162b2; SARS-CoV-2; basophil activation testing; lipid nanoparticles; liposomes; polyethylene glycol and polysorbate allergy; skin testing; vaccine allergy.

MeSH terms

  • Adult
  • Anaphylaxis / immunology*
  • BNT162 Vaccine
  • Basophils / immunology*
  • COVID-19 / immunology*
  • COVID-19 Vaccines / immunology*
  • Cell Degranulation
  • Cells, Cultured
  • ChAdOx1 nCoV-19
  • Doxorubicin / adverse effects
  • Doxorubicin / analogs & derivatives*
  • Doxorubicin / chemistry
  • Drug Hypersensitivity / immunology*
  • Female
  • Humans
  • Lipids / chemistry
  • Male
  • Middle Aged
  • Nanoparticles / adverse effects*
  • Nanoparticles / chemistry
  • Polyethylene Glycols / adverse effects*
  • Polyethylene Glycols / chemistry
  • SARS-CoV-2 / physiology*
  • Skin Tests
  • Young Adult


  • COVID-19 Vaccines
  • Lipids
  • liposomal doxorubicin
  • Polyethylene Glycols
  • Doxorubicin
  • ChAdOx1 nCoV-19
  • BNT162 Vaccine