Florian KrammerDec 21, 2022

Here is a short commentary about the induction of anti-PEG antibodies by mRNA vaccines. A few studies (including one of ours) found that now. I do not think this is a safety problem but it should be monitored to make sure it does not impact on the half-life of PEGylated drugs in people who need them.

https://www.nature.com/articles/s41577-022-00825-x

Impact of anti-PEG antibodies induced by SARS-CoV-2 mRNA vaccines - Nature Reviews Immunology

The successful mRNA vaccines against COVID-19 contain polyethylene glycol (PEG) to stabilize the lipid nanoparticles. Recent data show that PEG-specific antibodies can be induced or boosted by mRNA vaccination. Further research is needed to study the potential links between PEG-specific antibodies, vaccine reactogenicity and enhanced clearance of other PEG-containing medicines.

Nature
Florian KrammerDec 22, 2022
Show threadEdward Nirenberg

@florian_krammer my secondary concern here is that this could functionally result in a reduction of the dose of mRNA-LNPs and limit antigen production in vivo in a manner similar to how memory cells outcompete naive ones for antigen in OAS, which would reduce one of the major advantages of mRNA over other approaches. Moderna did report this in 2019:

https://journals.aai.org/immunohorizons/article/3/7/282/4013/Accelerated-Blood-Clearance-of-Lipid-Nanoparticles

Accelerated Blood Clearance of Lipid Nanoparticles Entails a Biphasic Humoral Response of B-1 Followed by B-2 Lymphocytes to Distinct Antigenic Moieties

Abstract. Accelerated blood clearance (ABC) is a phenomenon in which certain pharmaceutical agents are rapidly cleared from the blood upon second and subsequent

American Association of Immunologists
Dec 21, 2022 at 5:18amWeb
Show threadBen PierceDec 22, 2022
@enirenberg @florian_krammer interesting! This 2019 study was i.v. administration : I wonder how the ABC phenomenon is affected upon i.m. administration
Show threadLZVolkDec 22, 2022
@BenFPiercePhD @enirenberg @florian_krammer Good point.
Show threadEdward NirenbergDec 22, 2022
@florian_krammer @BenFPiercePhD yeah that’s an important point and needs to be investigated
Show threadLZVolkDec 22, 2022
@enirenberg @florian_krammer Interesting paper. Especially 👉🏼 “Armstrong et al. have found that a significant fraction of the normal population actually possesses pre-existing anti-PEG Abs (i.e., the presence of PEG-specific Abs in the absence of treatment with PEGylated therapeutics), which may become even more prevalent in subsequent years. Both pre-existing and induced anti-PEG Abs should present significant challenges..”
PEG is almost ubiquitous.
Show threadLZVolkDec 22, 2022

@enirenberg @florian_krammer
This study found “detectable levels of anti-PEG antibodies in approximately 72% of the population, never treated with PEGylated drugs, based on plasma samples from 1990 to 1999.” Can dermal and/or orally administered PEG induce an immunological response?

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4515207/

Anti-PEG immunity: emergence, characteristics, and unaddressed questions

The modification of protein and nanoparticle therapeutics with polyethylene glycol (PEG), a flexible, uncharged and highly hydrophilic polymer, is a widely adopted approach to reduce RES clearance, extend circulation time, and improve drug efficacy. Nevertheless, ...

PubMed Central (PMC)
Show threadEdward NirenbergDec 22, 2022
@lzvolk @florian_krammer the irony is that one of the reasons PEG is often used as an excipient is because it’s relatively immunologically inert.
Show threadC. NiederstadtFeb 2, 2023
@enirenberg @lzvolk @florian_krammer
🤔 I'd really appreciate some endeavors of explanations here 😳
Show threadLZVolkFeb 2, 2023

@Niederstadt Some background on PEG and immunology.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4515207/

Anti-PEG immunity: emergence, characteristics, and unaddressed questions

The modification of protein and nanoparticle therapeutics with polyethylene glycol (PEG), a flexible, uncharged and highly hydrophilic polymer, is a widely adopted approach to reduce RES clearance, extend circulation time, and improve drug efficacy. Nevertheless, ...

PubMed Central (PMC)
Show threadC. NiederstadtFeb 2, 2023
@lzvolk
Thanks for pointing me to this article! That's quite embarrassing, I didn't have any idea...
The mechanism(s) of pre-existing α-PEG Abs pose fascinating questions, to be sure!