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. 2023 Jul 12;41(31):4561-4570.
doi: 10.1016/j.vaccine.2023.06.009. Epub 2023 Jun 5.

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

Gergely Tibor Kozma  1 , Tamás Mészáros  1 , Petra Berényi  1 , Réka Facskó  1 , Zsófia Patkó  2 , Csaba Zs Oláh  3 , Adrienne Nagy  4 , Tamás Gyula Fülöp  5 , Kathryn Anne Glatter  6 , Tamás Radovits  7 , Béla Merkely  7 , János Szebeni  8
Affiliations

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

Gergely Tibor Kozma et al. Vaccine. .

Abstract

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.

Keywords: Allergy; Anaphylaxis; Anti-PEG IgG; Complement; Covid-19; ELISA; Hypersensitivity reactions; IgM; Neutralizing antibodies; SARS-CoV-2; Spike protein; mRNA.

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Conflict of interest statement

Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Fig. 1
Fig. 1
Pre-vaccination anti-PEG antibody concentrations in a mixed population of blood donors. Anti-PEG-IgG (A, green) and anti-PEG-IgM (B, red) values were sorted in growing order. The bottom bars (which look like lines) are absolute Ab concentrations. The inserted probability distribution histograms are made from the log of absolute Ab levels, grouped into bins on the abscissa . The normality of log-transformed data was established by the Shapiro-Wilk test. The anti-PEG Ab levels were determined as described in the Methods, and the descriptive statistics of these data are shown in Table 2.
Fig. 2
Fig. 2
Use of cosmetics by women and men and blood anti-PEG antibody levels in the two genders. A) Ratio of frequent cosmetic users vs. no users or rare users in men and women. B) Blood levels of anti-PEG-IgG (B) and anti-PEG-IgM (C) in frequent vs. no/rare cosmetic users before COVID-19 vaccination. The anti-PEG Ab levels were determined as described in the Methods. *P < 0.05 by 2-tailed t-test of logarithmic transformed data.
Fig. 3
Fig. 3
Anti-PEG antibody levels in people before Covid-19 vaccinations. A) Changes over time in 6 subjects who gave blood at least 2 times before vaccination against Covid-19. The second/first anti-PEG IgG and IgM ratios were plotted against the time elapsed time between the 1st and 2nd blood withdrawal. The different symbols represent different individuals, and the filling color of symbols distinguishes IgG and IgM (as shown by the keys). The non-significant linear fits on the relative changes of anti-PEG IgG and IgM indicate no significant impact of time on inter-individual changes. Moreover, the smaller variation of the relative changes of anti-PEG IgG compared to IgM in most individuals suggest higher intra-individual stability of blood anti-PEG IgG levels compared to anti-PEG IgM. B) Plotting of plasma anti-PEG-IgG against anti-PEG IgM in healthy blood donors before vaccination (black dots), as well as those with allergy (red squares) and mastocytosis (green triangles), shows no linear correlation between these Ig classes. R2 of regression line is 0.0213 (p >0.1). The blue-framed extreme values on both axes are mainly from subjects with allergy or mastocytosis. C) Anti-PEG IgG and (D) anti-PEG IgM levels in the groups indicated on the X axis on panel D. Antibody levels were determined as described in the Methods.
Fig. 4
Fig. 4
Pre- and postvaccination anti-PEG IgG and IgM antibodies of non-allergic participants. Anti-PEG IgG (A, green rectangles) and anti-PEG IgM (B, red circles) levels in people vaccinated with different Covid-19 vaccines shown on the X axis, wherein the numbers (1, 2 and 3) represent the order of vaccinations. C) Relative rises of maximal postvaccination anti-PEG IgG and IgM levels relative to the respective preimmunization value in people undergoing serial (at least 2) immunizations with Comirnaty. Both absolute (A and B) and relative values (C) are presented on a log scale. Of note, the time elapsed between the pre- and postvaccination measurements differs for each point. *, P < 0.05, ***, P < 0.001, ****, P < 0.0001 by one-way ANOVA of logarithmic transformed data followed by Dunnett test (A and B) and Wilcoxon signed rank test of normalized data (C).
Fig. 5
Fig. 5
Anti-PEG IgG (A), IgM (B) in reactor people displaying HSRs (R) compared to non-reactor (NR) subjects. The symptoms observed in the NR (no adverse effects and Grade 1) and R (Grade 2 and 3) patients are detailed in Table 4. The time span between Ab determinations and vaccinations was 4 months. **P < 0.01 by t-test of logarithmic transformed data.
Fig. 6
Fig. 6
Anti-S Ab levels as a function of anti-PEG Abs within 100 days after the first or the second vaccination with Comirnaty. Donors with any sign of Covid-19 infection were excluded. Each points represent the highest Anti-S value obtained in serial plasma samples in each individual. The goodness of linear fitting is represented by R2 values on the figures. P < 0.05 implies that the slope is significantly non-zero after linear regression.
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References

    1. Fraiman J., Erviti J., Jones M., Greenland S., Whelan P., Kaplan R.M., et al. Serious adverse events of special interest following mRNA COVID-19 vaccination in randomized trials in adults. Vaccine. 2022;40:5798–5805. - PMC - PubMed
    1. Banerji A., Wickner P.G., Saff R., Stone C.A., Jr., Robinson L.B., Long A.A., et al. mRNA vaccines to prevent COVID-19 disease and reported allergic reactions: Current evidence and suggested approach. J Allergy Clin Immunol Pract. 2020 - PMC - PubMed
    1. Warren C.M., Snow T.T., Lee A.S., Shah M.M., Heider A., Blomkalns A., et al. Assessment of allergic and anaphylactic reactions to mRNA COVID-19 vaccines with confirmatory testing in a US regional health system. JAMA Netw Open. 2021;4 - PMC - PubMed
    1. Shimabukuro T. Allergic reactions including anaphylaxis after receipt of the first dose of Moderna COVID-19 vaccine - United States, December 21, 2020-January 10, 2021. Am J Transplant. 2021;21:1326–1331. - PMC - PubMed
    1. Shimabukuro T., Nair N. Allergic reactions including anaphylaxis after receipt of the first dose of Pfizer-BioNTech COVID-19 vaccine. JAMA. 2021 - PMC - PubMed

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