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

Ju, Yi; Lee, Wen Shi; Pilkington, Emily H.; Kelly, Hannah G.; Li, Shiyao; Selva, Kevin J.; Wragg, Kathleen; Subbarao, Kanta; Nguyen, Thi H. O.; Rowntree, Louise C.; Allen, Lilith F; Bond, Katherine; Williamson, Deborah A; Truong, Nghia P.; Plebanski, Magdalena; Kedzierska, Katherine; Mahanty, Siddhartha; Chung, Amy W.; Caruso, Frank; Wheatley, Adam K.; Juno, Jennifer A; Kent, Stephen J.

doi:10.1021/acsnano.2c04543

Cited by 147 publications

(174 citation statements)

References 42 publications

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“…1 shows the anti-PEG IgG (A) and IgM (B) levels and distribution in the blood of Covid-19 unvaccinated participants, and Table 1 lists the main statistical parameters derived from these data. Contrary to the 10-76% range of anti-PEG Ab positivity in various studies, 21,25,26,[30][31][32][33][34] we found detectable levels of these Abs in 98-99% blood donors. Their distribution was highly left-skewed, with considerable, 2-3 orders of magnitude span between the lowest and highest values.…”

Section: Resultscontrasting

confidence: 99%

“…The discrepancy may partly be due to the diverse quantitation methods for anti-PEG Abs in these studies, 36 and partly to the different inclusion criteria of blood donors. For example, each referred reports on the prevalence of anti-PEG Abs in the healthy population or drug-treated patients 21,25,26,[30][31][32][33][34] used different antigens and/or differing test conditions in the anti-PEG Ab ELISA assays. As for the inclusion criteria of blood donors, we had a mixed population "enriched" with sporadic and chronic allergic people and patients with mastocytosis.…”

Section: Resultsmentioning

confidence: 99%

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

Kozma

Mészáros

Berenyi

et al. 2022

Preprint

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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.

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Section: Resultscontrasting

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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

Kozma

Mészáros

Berenyi

et al. 2022

Preprint

View full text Add to dashboard Cite

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“…The mechanism underlying PEG immunogenicity is not completely understood, but two recent reviews have discussed the application of general knowledge regarding T-independent antigens to PEG immunogenicity through the passive immunization resulting from environmental exposure and food ( 153 , 154 ). Interestingly, two recent reports demonstrated anti-PEG IgG and IgM induction via active immunization with mRNA-PEG-LNPs in a pig model ( 155 ) and humans ( 156 ).…”

Section: Immunogenicitymentioning

confidence: 99%

Lessons learned from immunological characterization of nanomaterials at the Nanotechnology Characterization Laboratory

Dobrovolskaia

2022

Front. Immunol.

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Nanotechnology carriers have become common in pharmaceutical products because of their benefits to drug delivery, including reduced toxicities and improved efficacy of active pharmaceutical ingredients due to targeted delivery, prolonged circulation time, and controlled payload release. While available examples of reduced drug toxicity through formulation using a nanocarrier are encouraging, current data also demonstrate that nanoparticles may change a drug’s biodistribution and alter its toxicity profile. Moreover, individual components of nanoparticles and excipients commonly used in formulations are often not immunologically inert and contribute to the overall immune responses to nanotechnology-formulated products. Said immune responses may be beneficial or adverse depending on the indication, dose, dose regimen, and route of administration. Therefore, comprehensive toxicology studies are of paramount importance even when previously known drugs, components, and excipients are used in nanoformulations. Recent data also suggest that, despite decades of research directed at hiding nanocarriers from the immune recognition, the immune system’s inherent property of clearing particulate materials can be leveraged to improve the therapeutic efficacy of drugs formulated using nanoparticles. Herein, I review current knowledge about nanoparticles’ interaction with the immune system and how these interactions contribute to nanotechnology-formulated drug products’ safety and efficacy through the lens of over a decade of nanoparticle characterization at the Nanotechnology Characterization Laboratory.

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“…Nanoparticle (NP)-based drug delivery systems that are capable of reducing nonspecific biodistribution in organs and tissues while specifically targeting tumors are needed to reduce systemic toxicity and improve drug delivery efficacy. − Surface modification with poly(ethylene glycol) (PEG), known as PEGylation, is a widely used approach to increase the colloidal stability of NPs and to reduce their interactions with a variety of components (e.g., proteins and immune cells) in biological environments. − PEGylation can avoid NP clearance by the mononuclear phagocytic system and therefore improve the blood circulation time and the accumulation of NPs at tumor sites. ,− However, the injection of PEGylated NPs can stimulate the production of anti-PEG antibodies, which in turn results in complement activation and recognition by the immune system. , Consequently, repeated injection of PEGylated NPs induces the accelerated blood clearance (ABC) phenomenon, which reduces the blood circulation time of PEGylated NPs and their therapeutic efficacy. − Recent work has shown that the mRNA NP vaccines used to combat the severe acute respiratory syndrome coronavirus 2 contain PEG-lipids that can also boost the levels of anti-PEG antibodies . This increase in anti-PEG antibody levels is associated with the increased association of PEGylated NPs to human blood immune cells and high reactogenicity.…”

Section: Introductionmentioning

confidence: 99%

Engineering Poly(ethylene glycol) Nanoparticles for Accelerated Blood Clearance Inhibition and Targeted Drug Delivery

et al. 2022

Self Cite

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Surface modification with poly(ethylene glycol) (PEGylation) is an effective strategy to improve the colloidal stability of nanoparticles (NPs) and is often used to minimize cellular uptake and clearance of NPs by the immune system. However, PEGylation can also trigger the accelerated blood clearance (ABC) phenomenon, which is known to reduce the circulation time of PEGylated NPs. Herein, we report the engineering of stealth PEG NPs that can avoid the ABC phenomenon and, when modified with hyaluronic acid (HA), show specific cancer cell targeting and drug delivery. PEG NPs cross-linked with disulfide bonds are prepared by using zeolitic imidazolate framework-8 NPs as templates. The reported templating strategy enables the simultaneous removal of the template and formation of PEG NPs under mild conditions (pH 5.5 buffer). Compared to PEGylated liposomes, PEG NPs avoid the secretion of anti-PEG antibodies and the presence of anti-PEG IgM and IgG did not significantly accelerate the blood clearance of PEG NPs, indicating the inhibition of the ABC effect for the PEG NPs. Functionalization of the PEG NPs with HA affords PEG NPs that retain their stealth properties against macrophages, target CD44-expressed cancer cells and, when loaded with the anticancer drug doxorubicin, effectively inhibit tumor growth. The innovation of this study lies in the engineering of PEG NPs that can circumvent the ABC phenomenon and that can be functionalized for the improved and targeted delivery of drugs.

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

Cited by 147 publications

References 42 publications

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

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

Lessons learned from immunological characterization of nanomaterials at the Nanotechnology Characterization Laboratory

Engineering Poly(ethylene glycol) Nanoparticles for Accelerated Blood Clearance Inhibition and Targeted Drug Delivery

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