To the Editor:
Thank you for the correspondence of Krantz et al
“COVID-19 vaccine anaphylaxis:
PEG or not?”.1
We totally agree with the authors that patients previously allergic to
polyethylene glycol (PEG) might react to PEGylated liposomes when
exposed to them later on.1 Since PEGs of different
molecular weights are widely distributed, exposure and absorption
depending on the size and mode of application can take place viathe skin, the gastrointestinal mucosa, or other mucosal tissues
including conjunctiva, while some substances containing PEG are
administered intravenously, subcutaneously, or
intramuscularly2. This broad range of likelihoods how
PEG can be delivered to the immune system opens a wide range of
possibilities, where and how to get sensitized to PEG. Interestingly,
sensitization to PEG and PEG analogous occurs only very rarely in view
of the extremely high rate of expositions to these
substances.2,3 (Figure 1A).
Since hypersensitivity reactions take place more frequently after
intravenous or intramuscular injection of PEGs ,2 both
concentration and molecular weight might play a role. PEGs with lower
molecular weights might require in some situations a higher
concentration to induce hypersensitivity reactions, while PEGs with
higher molecular weights could sometimes induce severe hypersensitivity
reactions even at low concentrations (Figure 1B).
The individual thresholds to react to PEGs of different molecular weight
and at different concentrations in vivo and even during
diagnostic skin prick testing varies,4 so that a
patient primarily sensitized to a PEG with lower molecular weight might
react also to a PEG or even pegylated substance of higher molecular
weight as described by Krantz et al.5 If patients
previously sensitized to PEGs of higher molecular weights may react with
PEGs of lower molecular weights such as PEG2000 contained in the
micellar delivery system of Pfizer/BioNTech or Moderna COVID-19
vaccines, should be further analyzed.
In this context, it might be also possible that the way how PEG is
delivered to the immune system is of importance. The PEGylated form as a
carrier for drugs injected for example intramuscularly as a “shot” as
it is the case for the Pfizer/BioNTech and Moderna COVID-19 vaccines,
might increase not only the bioavailability and stability of the active
agent that is delivered, but also of the carrier and enhance thereby its
resistance to degradation, size, and allergenicity.
In addition to IgE-mediated hypersensitivity reactions, complement
activation-related pseudoallergy, called CAPR and mediated by PEGyated
nanobodies, which induce anaphylatoxins (C3a and C5a) and anti-PEG IgM
and IgG antibodies has been described.6 The anti-drug
antibodies are responsible for an accelerated blood clearance (ABD) and
thereby loss of efficacy of the drug and severe anaphylaxis. If such a
complement activation might be induced by the PEGylated Pfizer/BioNtech
or Moderna vaccine as a cause of some of the anaphylactic cases, for
example in non-allergic individuals, remains to be elucidated (Figure
2A).
If excipients of the new Pfizer/BioNTech and Moderna vaccines including
PEG would not be the reason for the hypersensitivity reactions to the
vaccine, one immunologic possibility could be the direct interaction of
RNA applied with the vaccine with mast cells. In this regard, it has
been demonstrated that cytosolic RNA in mast cells during viral
infections can be detected by retinoic-acid-inducible gene-1 (RIG-1),
which in vitro leads to the transient expression of type I
interferons and TNF-alpha as well as anti-viral proteins by mast
cells.7 However, mast cell degranulation did not occur
after intracellular RNA recognition in different in vitro
studies,7 so that such a way of mast cells activation
and degranulation in response to the mRNA delivered with the vaccine is
very unlikely (Figure 2B). This goes along with the clinical observation
that the frequency of allergic adverse events in the vaccine and the
placebo group in the phase-III-trial of Pfizer/BioNTech BNT162b2 vaccine
was quite similar and relatively low in regard to both, frequency and
severity,8 which would supposedly not be the case if
mast cell activation via mRNA would be of relevance.
A general hyperreactivity of mast cells as it is the case in patients
with systemic mastocytosis might be another reason for hypersensitivity
reactions to this new vaccine observed in a few cases since patients
with severe allergic reactions in the medical history and supposedly
mastocytosis have not been included in the clinical trials. However,
according to the very rare data available in the literature on this
topic, vaccines are in general well tolerated by adult patients with
different forms of systemic mastocytosis, while mast cell release
induced by vaccines has been reported to occur sometimes in children
with cutaneous mastocytosis .9,10
Last but not least, we would like to thank Kantz et al. for the really
helpful table and overview of PEG and polysorbate containing drugs
provided. We would like to add one important group of substances, which
contain PEG and its analogous to this overview of substances: PEG-coated
antihistamine tablets or PEG containing corticosteroids are often part
of emergency kits or used as rescue mediation to treat anaphylactic
reactions but should not be used in patients with documented
hypersensitivity reactions to PEGs or its derivates.
Beatriz Cabanillas1
Cezmi A. Akdis2,3
Natalija Novak4*
1Department of Allergy, Research Institute Hospital
Doce de Octubre, Madrid, Spain
2Swiss Institute of Allergy and Asthma Research
(SIAF), University of Zurich, Davos, Switzerland.
3Christine Kühne-Center for Allergy Research and
Education, Davos, Switzerland
4Department of Dermatology and Allergy, University
Hospital Bonn, Bonn, Germany.
*Corresponding author: Univ.-Prof. Dr. Natalija Novak
Department of Dermatology and Allergy, University Hospital, Bonn,
Venusberg Campus 1, 53127 Bonn, Germany.
Email:
natalija.novak@ukbonn.de