Anti-PEG Antibodies Boosted in Humans by SARS-CoV-2 Lipid Nanoparticle mRNA Vaccine

Abstract

Humans commonly have low level antibodies to poly(ethylene) glycol (PEG) due to environmental exposure. Lipid nanoparticle mRNA vaccines for SARS-CoV-2 contain small amounts of PEG but it is not known if PEG antibodies are enhanced by vaccination and if there are any consequences. We studied plasma from 55 people receiving the Comirnaty (Pfizer-BioNTech) mRNA vaccine for PEG-specific antibodies. Anti-PEG IgG was commonly detected prior to vaccination and was boosted a mean of 1.78-fold (range 0.68 to 16.6) by vaccination. Anti-PEG IgM increased 2.64-fold (0.76 to 12.84) following vaccination. PEG antibodies did not impact the neutralizing antibody response to vaccination. Pre-existing levels of anti-PEG IgM correlated with increased reactogenicity. A rise in PEG antibodies following vaccination was associated with an increase in the association of PEG-based nanoparticles to blood immune cells ex vivo. We conclude that low level PEG-specific antibodies can be modestly boosted by a lipid nanoparticle mRNA-vaccine and that PEG-specific antibodies are associated with higher reactogenicity. The longer-term clinical impact of the increase in PEG-specific antibodies induced by lipid nanoparticle mRNA-vaccines should be monitored.

mRNA-1273 but not BNT162b2 induces antibodies against polyethylene glycol (PEG) contained in mRNA-based vaccine formulations

“…Moreover, serum from mRNA-1273 vaccine recipients was able to recognize components of both formulations in a prime-boost dependent manner. Importantly, similar outcomes to our findings have been recently described [37] . It remains to be explored whether the anti-PEG antibodies induced following vaccination are directed towards the backbone of the PEG molecule, or the methoxy group present in PEG from both formulations.…”

“…First, the sample size of the side effect cohort did not allow us to confidently evaluate the relationship between PEG reactive antibodies and adverse reactions induced by vaccination. A recent report from Ju and colleagues [37] suggests that the elevated levels of vaccine-induced anti-PEG antibodies correlated with increased systemic reactogenicity after two vaccine doses. In addition, we did not detect a significant increase in anti-PEG antibodies in BNT162b2 recipients, which might be due to the limited number of subjects studied in our cohort.…”

Protein precoating modulates biomolecular coronas and nanocapsule–immune cell interactions in human blood

“…However, studies have shown that healthy humans have pre-existing anti-PEG antibodies, which can affect the fate and utility of PEGylated nanomedicines. [25][26][27] Therefore, alternative strategies are needed to endow nanoparticles with stealth properties. Owing to the intrinsic biocompatibility and low immunogenicity of biomolecules, precoating nanoparticles with biomolecules (prior to their administration in the body/contact with blood) is emerging as a promising strategy for providing a protective coating on nanoparticles.…”

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

“…Most recently, two studies reported the rise of anti-PEG Abs in Spikevax-vaccinated people, 21,22 implying specific binding of these Abs to PEG in the vaccine. In earlier studies, anti-PEG Abs were shown to cause rapid loss of efficacy along with increased the risk of HSRs to PEGylated urate oxidase, 23,24 and in another example, 3 anaphylactic reactions in patients having very high pre-existing anti-PEG Abs led to early termination of a Phase II clinical trial with the PEGylated RNA aptamer, Pegnivacogin.…”

“…These anti-PEG Abs were also correlated with the levels of SARS-CoV-2 neutralizing Abs, taken as endpoint for vaccine efficacy, and relating the postvaccination anti-PEG Ab levels to the pre-vaccination values allowed us to investigate "bystander" anti-PEG immunogenicity, similar to that reported for Spikevax. 21,22…”