Evaluation of association of anti-PEG antibodies with anaphylaxis after mRNA COVID-19 vaccination

Zhao-Hua Zhou; Margaret M Cortese; Jia-Long Fang; Robert Wood; Donna S Hummell; Kimberly A Risma; Allison E Norton; Mark KuKuruga; Susan Kirshner; Ronald L Rabin; Cyrus Agarabi; Mary A Staat; Natasha Halasa; Russell E Ware; Anna Stahl; Maureen McMahon; Peter Browning; Panagiotis Maniatis; Shanna Bolcen; Kathryn M Edwards; John R Su; Sai Dharmarajan; Richard Forshee; Karen R Broder; Steven Anderson; Steven Kozlowski

doi:10.1016/j.vaccine.2023.05.029

Evaluation of association of anti-PEG antibodies with anaphylaxis after mRNA COVID-19 vaccination

Vaccine. 2023 Jun 23;41(28):4183-4189. doi: 10.1016/j.vaccine.2023.05.029. Epub 2023 May 16.

Authors

Zhao-Hua Zhou¹, Margaret M Cortese², Jia-Long Fang³, Robert Wood⁴, Donna S Hummell⁵, Kimberly A Risma⁶, Allison E Norton⁵, Mark KuKuruga⁷, Susan Kirshner¹, Ronald L Rabin⁷, Cyrus Agarabi¹, Mary A Staat⁸, Natasha Halasa⁹, Russell E Ware¹⁰, Anna Stahl⁹, Maureen McMahon⁸, Peter Browning¹¹, Panagiotis Maniatis¹¹, Shanna Bolcen¹¹, Kathryn M Edwards⁹, John R Su², Sai Dharmarajan¹, Richard Forshee⁷, Karen R Broder², Steven Anderson⁷, Steven Kozlowski¹²

Affiliations

¹ Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA.
² Immunization Safety Office, Division of Healthcare Quality and Promotion, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA, USA.
³ National Center for Toxicological Research, FDA, Jefferson, AR, USA.
⁴ Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁵ Division of Pediatric Allergy, Immunology, and Pulmonary Medicine, Monroe Carell Jr. Children's Hospital at Vanderbilt, Vanderbilt University School of Medicine, Nashville, TN, USA.
⁶ Division of Allergy Immunology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
⁷ Center for Biologics Evaluation and Research, Food and Drug Administration, USA.
⁸ Division of Infectious Disease, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
⁹ Division of Infectious Diseases, Department of Pediatrics, Monroe Carell Jr. Children's Hospital at Vanderbilt, Vanderbilt University School of Medicine, Nashville, TN, USA.
¹⁰ Division of Hematology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
¹¹ Microbial Pathogenesis and Immune Response Laboratory, Division of Bacterial Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, GA, USA.
¹² Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA. Electronic address: steven.kozlowski@fda.hhs.gov.

Abstract

Background: The mechanism for anaphylaxis following mRNA COVID-19 vaccination has been widely debated; understanding this serious adverse event is important for future vaccines of similar design. A mechanism proposed is type I hypersensitivity (i.e., IgE-mediated mast cell degranulation) to polyethylene glycol (PEG). Using an assay that, uniquely, had been previously assessed in patients with anaphylaxis to PEG, our objective was to compare anti-PEG IgE in serum from mRNA COVID-19 vaccine anaphylaxis case-patients and persons vaccinated without allergic reactions. Secondarily, we compared anti-PEG IgG and IgM to assess alternative mechanisms.

Methods: Selected anaphylaxis case-patients reported to U.S. Vaccine Adverse Event Reporting System December 14, 2020-March 25, 2021 were invited to provide a serum sample. mRNA COVID-19 vaccine study participants with residual serum and no allergic reaction post-vaccination ("controls") were frequency matched to cases 3:1 on vaccine and dose number, sex and 10-year age category. Anti-PEG IgE was measured using a dual cytometric bead assay (DCBA). Anti-PEG IgG and IgM were measured using two different assays: DCBA and a PEGylated-polystyrene bead assay. Laboratorians were blinded to case/control status.

Results: All 20 case-patients were women; 17 had anaphylaxis after dose 1, 3 after dose 2. Thirteen (65 %) were hospitalized and 7 (35 %) were intubated. Time from vaccination to serum collection was longer for case-patients vs controls (post-dose 1: median 105 vs 21 days). Among Moderna recipients, anti-PEG IgE was detected in 1 of 10 (10 %) case-patients vs 8 of 30 (27 %) controls (p = 0.40); among Pfizer-BioNTech recipients, it was detected in 0 of 10 case-patients (0 %) vs 1 of 30 (3 %) controls (p >n 0.99). Anti-PEG IgE quantitative signals followed this same pattern. Neither anti-PEG IgG nor IgM was associated with case status with both assay formats.

Conclusion: Our results support that anti-PEG IgE is not a predominant mechanism for anaphylaxis post-mRNA COVID-19 vaccination.

Keywords: Anaphylaxis; Antibodies; COVID 19; IgE; Polyethylene glycol; mRNA vaccines.

Published by Elsevier Ltd.

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

MeSH terms

Anaphylaxis* / etiology
COVID-19 Vaccines* / adverse effects
COVID-19* / prevention & control
Female
Humans
Immunoglobulin E
Immunoglobulin G
Immunoglobulin M
Immunosuppressive Agents
Male
Polyethylene Glycols / adverse effects
RNA, Messenger
Vaccination / adverse effects

Substances

COVID-19 Vaccines
Immunoglobulin E
Immunoglobulin G
Immunoglobulin M
Immunosuppressive Agents
Polyethylene Glycols
RNA, Messenger