Role of anti-polyethylene glycol (PEG) antibodies in the allergic reactions and immunogenicity of PEG-containing Covid-19 vaccines

Abstract

The polyethylene-glycol (PEG)-containing Covid-19 vaccines can cause hypersensitivity reactions (HSRs), or rarely, life-threatening anaphylaxis. A causal role of anti-PEG antibodies (Abs) has been proposed, but not yet proven in humans. The 191 blood donors in this study included 10 women and 5 men who displayed HSRs to Comirnaty or Spikevax Covid-19 vaccines with 3 anaphylaxis. 118 donors had pre-vaccination anti-PEG IgG/IgM values as measured by ELISA, of which >98% were over background regardless of age, indicating the presence of these Abs in almost everyone. Their values varied over 2-3 orders of magnitude and displayed strong left-skewed distribution with 3-4% of subjects having >15-30-fold higher values than the respective median. First, or booster injections with both vaccines led to significant rises of anti-PEG IgG/IgM with >10-fold rises in about ~10% of Comirnaty, and all Spikevax recipients, measured at different times after the injections. The anti-PEG Ab levels measured within 4-months after the HSRs were significantly higher than those in nonreactors. Serial testing of plasma (n=361 tests) showed the SARS-CoV-2 neutralization IgG to vary over a broad range, with a trend for biphasic dose dependence on anti-PEG Abs. The highest prevalence of anti-PEG Ab positivity in human blood reported to date represents new information which can most easily be rationalized by daily exposure to common PEG-containing medications and/or household items. The significantly higher, HSR-non-coincidental blood level of anti-PEG Abs in hypersensitivity reactor vs. non-reactors, taken together with relevant clinical and experimental data in the literature, suggest that anti-PEG Ab supercarrier people might be at increased risk for HSRs to PEG-containing vaccines, which themselves can induce these Abs via bystander immunogenicity. Our data also raise the possibility that anti-PEG Abs might also contribute to the reduction of these vaccines' virus neutralization efficacy. Thus, screening for anti-PEG Ab supercarriers may identify people at risk for HSRs or reduced vaccine effectiveness.

The COVID-19 mRNA vaccine Comirnaty induces anaphylactic shock in an anti-PEG hyperimmune large animal model: Role of complement activation in cardiovascular, hematological and inflammatory mediator changes

“…Regarding the prevalence of anaphylaxis, which entails death or disability in 1.7%, 40 the ~1.8 billion mRNA-LNP injections given worldwide in 3 years places even the lowest estimate of the sheer number of anaphylaxis cases in the multiple thousand range. Calculating with the median of estimated anaphylaxis rate (123 cases/million), 32 yields 223,200 anaphylaxis with ~3,800 death or disability worldwide, placing vaccine-induced anaphylaxis as the first pandemic of an iatrogenic rare (orphan) disease. To prevent its occurrence in the future, when new infection diseases and vaccines arise, the phenomenon needs to be understood.…”

“…28 Regardless of C activation, the likely causal role of anti-PEG Abs in mRNA-LNP vaccineinduced HSRs/anaphylaxis was raised by many groups, 1,8,15,16,18,31 and we found significant correlation between the blood levels of anti-PEG Abs and rise of HSR/anaphylaxis in recipients of Comirnaty and Spikevax. 32 Nevertheless, all above facts provide only indirect proofs of a causal role of anti-PEG Abs in Comirnaty-induced HSRs; conclusive experimental or clinical evidence is still lacking. Accordingly, the goal of the present study was to obtain such evidence using the anti-PEG hyperimmune pig model, 33 which showed the acceleration of HSR to anaphylaxis to PEGylated liposomal doxorubicin (Doxil) if the blood level of anti-PEG IgM had been increased by prior vaccination with drug-free Doxil (Doxebo).…”

Investigating Generation of Antibodies against the Lipid Nanoparticle Vector Following COVID-19 Vaccination with an mRNA Vaccine

“…Generation of anti-PEG antibodies following vaccination with Spikevax (the mRNA vaccine manufactured by Moderna) and Comirnaty has been studied in four other recent studies, employing ELISA to detect the presence of the antibodies. − While all of these studies (as well as a MedRxiv pre-print) found an increase in anti-PEG antibodies following vaccinations with Spikevax, , only two of the peer-reviewed studies reported an increase in anti-PEG antibodies following vaccination with Comirnaty, , and this increase was more modest compared to what was observed for the Moderna vaccine. We here expand on that knowledge, carried out in Southern European, Australian, North American, and Middle-Eastern populations, with a study performed in a Scandinavian population using a methodology looking at antibodies against the actual LNP as a whole entity and not against the individual lipid components alone.…”

Covid-19 vaccines elicit effective IgG responses in an elderly thymus cancer patient with chemotherapy

“…In fact, the anti-PEG IgM measurements in our patient was done as part of a different project aimed to establish the risk of allergic people to develop anaphylactic reaction to Comirnaty, which contains PEG. 15 , 16 High blood levels of such antibodies have been implicated in the anaphylactic reactions to numerous PEGylated drugs, 17–19 , 33 , 34 Furthermore there is a suspicion that the increased occurrence of such reactions after mRNA vaccines 35–40 may be due, at least in part, to the presence of high levels of anti-PEG antibodies. 15 , 16 , 41 In fact, a recent study on 55 people receiving Comirnaty showed the common presence of anti-PEG IgG and IgM, which were boosted by vaccination by a mean of 2–3-fold, up to 13–17-fold in some individuals.…”

“…The anti-PEG IgM titers in blood were determined using a sandwich ELISA, as described previously. 17 …”