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

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

Zhou ZH ，Cortese MM ，Fang JL ，Wood R ，Hummell DS ，Risma KA ，Norton AE ，KuKuruga M ，Kirshner S ，Rabin RL ，Agarabi C ，Staat MA ，Halasa N ，Ware RE ，Stahl A ，McMahon M ，Browning P ，Maniatis P ，Bolcen S ，Edwards KM ，Su JR ，Dharmarajan S ，Forshee R ，Broder KR ，Anderson S ，Kozlowski S ... -  《-》

Serum polyethylene glycol-specific IgE and IgG in patients with hypersensitivity to COVID-19 mRNA vaccines.

The mechanism of allergic reactions to COVID-19 mRNA vaccines has not been clarified. Polyethylene glycol (PEG) is a potential antigen in the components of vaccines. However, there is little evidence that allergy after COVID-19 mRNA vaccination is related to PEG. Furthermore, the role of polysorbate (PS) as an antigen has also not been clarified. The objective of this study was to investigate whether PEG and PS allergies are reasonable causes of allergic symptoms after vaccination by detecting PEG-specific and PS-specific antibodies. Fourteen patients who developed immediate allergic reactions to BNT162b2 (Pfizer-BioNTech) or mRNA-1273 (Moderna) vaccines and nineteen healthy controls who did not present allergic symptoms were recruited. Serum PEG-specific immunoglobulin E (IgE) and immunoglobulin G (IgG) and PS-specific IgE and IgG were measured by enzyme-linked immunosorbent assay. Skin tests using PEG-2000 and PS-80 were applied to five patients and three controls. Serum levels of PEG-specific IgE and IgG in patients with immediate allergic reactions to the COVID-19 mRNA vaccine were higher than those in the control group. Serum levels of PS-specific IgE in patients with allergy to the vaccine were higher than those in patients of the control group. Intradermal tests using PEG verified the results for PEG-specific IgE and IgG. The results suggest that PEG is one of the antigens in the allergy to COVID-19 mRNA vaccines. Cross-reactivity between PEG and PS might be crucial for allergy to the vaccines. PEG-specific IgE and IgG may be useful in diagnosing allergy to COVID-19 mRNA vaccines.

Mouri M ，Imamura M ，Suzuki S ，Kawasaki T ，Ishizaki Y ，Sakurai K ，Nagafuchi H ，Matsumura N ，Uchida M ，Ando T ，Yoshioka K ，Ooka S ，Sugihara T ，Miyoshi H ，Mori M ，Okada T ，Yamaguchi M ，Kunishima H ，Kato M ，Kawahata K ... -  《-》

Allergic reactions to coronavirus disease 2019 vaccines and addressing vaccine hesitancy: Northwell Health experience.

Allergic and nonallergic adverse reactions have been reported with global coronavirus disease 2019 (COVID-19) vaccination. It was previously hypothesized that polyethylene glycol (PEG) may be responsible for anaphylactic reactions to messenger RNA (mRNA) COVID-19 vaccines. To report the workflow established at our institution, types, and frequency of adverse reactions to mRNA COVID-19 vaccines in patients presenting for allergy evaluation. A COVID-19 vaccine adverse reaction registry was established. We used PEG prick skin testing, followed by PEG challenges in selected cases, to ensure PEG tolerance and encourage completion of COVID-19 vaccination series. A total of 113 patients were included. Most vaccine reactions (86.7%) occurred in women. Anaphylaxis occurred only in women, all of which had a history of allergic disease and two-thirds had asthma. Anaphylaxis rate was 40.6 cases per million. None of the anaphylactic cases developed hypotension, required intubation, or required hospital admission. Systemic allergic symptoms, not fulfilling anaphylaxis criteria, were significantly more common in Pfizer-BioNTech than Moderna-vaccinated patients (P = .02). We observed a higher incidence of dermatologic nonurticarial reactions in men (P = .004). Among first-dose reactors, 86.7% received and tolerated the second dose. We observed a high rate of false-positive intradermal skin test results and frequent subjective symptoms with oral PEG challenge. Intradermal PEG testing has limited utility in evaluating anaphylaxis to mRNA vaccines. Most severe postvaccination allergic symptoms are not caused by hypersensitivity to PEG. Most people with reaction to the initial mRNA vaccine can be safely revaccinated. Patients with anaphylaxis to COVID-19 vaccines benefit from physician-observed vaccination.

Kaplan B ，Farzan S ，Coscia G ，Rosenthal DW ，McInerney A ，Jongco AM ，Ponda P ，Bonagura VR ... -  《-》

Role of anti-polyethylene glycol (PEG) antibodies in the allergic reactions to PEG-containing Covid-19 vaccines: Evidence for immunogenicity of PEG.

A small fraction of recipients who receive polyethylene-glycol (PEG)-containing COVID-19 mRNA-LNP vaccines (Comirnaty and Spikevax) develop hypersensitivity reactions (HSRs) or anaphylaxis. A causal role of anti-PEG antibodies (Abs) has been proposed, but not yet been proven in humans.We used ELISA for serial measurements of SARS-CoV-2 neutralizing Ab (anti-S) and anti-PEG IgG/IgM Ab levels before and after the first and subsequent booster vaccinations with mRNA-LNP vaccines in a total of 291 blood donors. The HSRs in 15 subjects were graded and correlated with anti-PEG IgG/IgM, just as the anti-S and anti-PEG Ab levels with each other. The impacts of gender, allergy, mastocytosis and use of cosmetics were also analyzed. Serial testing of two or more plasma samples showed substantial individual variation of anti-S Ab levels after repeated vaccinations, just as the levels of anti-PEG IgG and IgM, which were over baseline in 98-99 % of unvaccinated individuals. About 3-4 % of subjects in the strongly left-skewed distribution had 15-45-fold higher values than the median, referred to as anti-PEG Ab supercarriers. Both vaccines caused significant rises of anti-PEG IgG/IgM with >10-fold rises in about ∼10 % of Comirnaty, and all Spikevax recipients. The anti-PEG IgG and/or IgM levels in the 15 vaccine reactors (3 anaphylaxis) were significantly higher compared to nonreactors. Serial testing of plasma showed significant correlation between the booster injection-induced rises of anti-S and anti-PEG IgGs, suggesting coupled anti-S and anti-PEG immunogenicity.Conclusions: The small percentage of people who have extremelevels of anti-PEG Ab in their blood may be at increased risk for HSRs/anaphylaxis to PEGylated vaccines and other PEGylated injectables. This risk might be further increased by the anti-PEG immunogenicity of these vaccines. Screening for anti-PEG Ab "supercarriers" may help predicting reactors and thus preventing these adverse phenomena.

Kozma GT ，Mészáros T ，Berényi P ，Facskó R ，Patkó Z ，Oláh CZ ，Nagy A ，Fülöp TG ，Glatter KA ，Radovits T ，Merkely B ，Szebeni J ... -  《-》

Patients with previous immediate hypersensitivity reactions to polyethylene glycol can safely receive the BNT162b2 mRNA COVID-19 vaccine.

Previous anaphylaxis or immediate allergic reaction to polyethylene glycol (PEG; also known as macrogol) is considered a contraindication to the BNT162b2 mRNA COVID-19 vaccine, which contains 50 ug of PEG at a molecular weight of 2000, and this component is thought to account for the higher rate of anaphylaxis seen with this vaccine (4.7 per million doses) than with other non-mRNA vaccines. However, there is evidence that both anaphylaxis to PEG and anaphylaxis to the Pfizer COVID-19 reaction may not be IgE-mediated, with patients with anaphylaxis to first dose of the Pfizer COVID-19 vaccine receiving their second dose of vaccine without no or milder reactions in a high-risk clinic setting. In New Zealand, non-PEG-containing COVID-19 vaccines were not available until late 2021. Therefore, we offered patients with known or suspected PEG anaphylaxis their first dose of Pfizer COVID-19 vaccine in a high-risk hospital clinic. Eleven patients with previous hypersensitivity to PEG (including eight with anaphylaxis) successfully received their first dose with mild or no reactions; all have now had their second doses in the community without significant reaction. Record review also showed that most patients with previous hypersensitivity reactions to pegylated asparaginase have also been successfully vaccinated. This demonstrates that previous PEG hypersensitivity, including anaphylaxis, does not exclude immunisation with the Pfizer COVID-19 vaccine.

Hurst M ，Jordan A ，Capstick J ，Brewerton M ，Cockroft R ，Ingram J ... -  《-》