Allergic reactions to COVID-19 vaccines
Local and systemic reactions were reported in phase III clinical trial
of the ChAdOx1 nCoV-19 vaccine, which were mostly mild and moderate in
intensity209. Cutaneous adverse effects of the
available COVID-19 vaccines include injection site reactions, urticaria,
angioedema, exacerbation of atopic eczema and systemic allergic
reactions including anaphylaxis210. Anaphylaxis to the
BNT162b2 vaccine was reported several days after the initiation of
public vaccinations211. Overall, the incidence of
COVID-19 mRNA vaccine-associated anaphylaxis is very
low212, with only was 4.8 per million doses for
BNT162b2 and 5.1 per million doses for mRNA-1273 according to data from
Vaccine Safety Datalink213. Moreover, the second dose
of the BNT162b2 vaccine elicited a higher rate of systemic
events191. Nevertheless, the incidence of anaphylaxis-
associated with COVID-19 vaccines is comparable to that of other
vaccines214 and the benefits may outweigh the
potential risks of COVID-19 vaccinations215,216.
Unfortunately, the fear of an allergic reaction has caused vaccine
hesitancy in the general public, haltering global vaccination
efforts217.
Polyethylene glycol (PEG) is an
additive present in the Pfizer-BioNtech and Moderna mRNA vaccines used
to prevent premature degradation of the
nanoparticless218, and it has been suggested to be the
major culprit for anaphylaxis to COVID-19 vaccines219.
PEG and its derivatives are also widely used in household products
including toothpaste, cosmetics, pharmaceuticals, and
foods220. Many types of vaccines, therapeutic
medications and diagnostic media contain PEG with different molecular
weights and their risks of anaphylaxis has been previously
reported220,221. Exposure to products containing PEG
via intravenous and intramuscular injection is the major route causing
HSR to PEG. There is evidence showing that lipid-conjugated PEG or
PEGylated liposomes have a stronger immunogenicity than PEG alone and
may contribute to the anaphylaxis elicited by COVID-19 mRNA
vaccines222,223. Anti-PEG IgE-mediated HSR, complement
activation-related pseudoallergy induced by anti-PEG IgM and IgG
antibodies and potential interaction of PEG with mast cells and viral
RNA have been suggested to underly COVID-19 vaccine
anaphylaxis222,224. IgG and IgM antibodies against PEG
were found in up to 25% of the population without known prior exposure
to PEGylated products and in up to 89% of patients with known prior
exposure to PEGylated products225. Other excipients
than PEG present in authorized COVID-19 vaccines might also cause severe
allergic reactions to COVID-19 vaccines and need appropriate
allergological assessment226.
EAACI has reported recommendations to perform in vivo tests (skin prick
test and intradermal test) and in vitro tests (basophil activation test,
BAT) to the vaccines or their components in individuals with severe
reactions to the first dose of COVID-19 vaccines227.
The positive rate of skin test with PEG or mRNA vaccine in patients with
reactions to COVID-19 mRNA vaccine or with previous PEG or polysorbate
allergies was very low228,229. Thus, the clinical
significance of skin testing with mRNA vaccine in those with negative
skin testing results with PEG is still unknown. BAT performed in
patients with PEG allergy demonstrated that BNT162b2 and AZD1222
vaccines and PEGylated lipids, but not unmodified PEG, can activate mast
cells223. Thus, positive BAT results to mRNA vaccines
may be a potential diagnostic tool for confirming HSR to PEG excipient.
Studies have shown that most individuals with allergic reactions to the
first dose tolerated well the second dose irrespective of the skin test
results230,231. Thus, the second dose vaccine may be
administered after careful evaluation and under careful monitoring in an
allergy clinic. In a position paper by EAACI, allergic patients without
prior allergic reaction to any of the vaccine components and patients
with mild and moderate allergies were recommended that they should not
be excluded from COVID-19 vaccinations227. On the
contrary, it would put population immunity with vaccination at risk due
to the high prevalence of allergic diseases227 .
However, anaphylaxis may occur after vaccination in the absence of a
history of allergic disease. Therefore, strategies for the prevention,
diagnosis and treatment of severe allergic reactions and a list of
recommended medications and equipment for vaccine centers were provided
in the EAACI statement to minimize the risk of allergic reactions to
COVID-19 vaccines227. Anaphylaxis induced by COVID-19
vaccines is rare but may be more severe in older people due to
comorbidities and polypharmacy232. Intramuscular
injection of adrenaline remains the first-line therapy for anaphylaxis
in older people232. Modified dosing or alternative
vaccines were recommended by EAACI for those with confirmed reactions to
COVID-19 vaccines227. Herein, we provide a flow chart
for the treatment of allergic reactions to COVID-19 vaccines (Figure 4).
Perspectives and conclusions
Anthropogenic activities, climate change and global population movement
set a perfect environment for new outbreaks of zoonotic pathogens. Using
the knowledge and experience gained from the COVID-19 pandemic, there is
an urgent need to develop novel strategies to predict and prevent the
emergence and transmission of novel pathogens 233.
Effective surveillance of new SARS-CoV-2 variants and reporting their
transmissibility and rate of breakthrough infection is warranted to
assist international policymaking234. The trajectory
of COVID-19 needs to be closely monitored to further our understanding
of the immunity waning, antigen drifting and re-entries from zoonotic
reservoirs 235. As we deepen our knowledge on
COVID-19, vaccination strategies should be updated and revised, such as
frequent administration of booster doses. The continuously mutating
virus warrants the development of novel vaccines targeting current
variant sequences236. The impacts of COVID-19 on
allergen sensitization and the incidence of allergic disease are still
unknown and need to be investigated by the society of allergy and
clinical immunology.
In conclusion, similarly to other respiratory viruses, full eradication
of COVID-19 is not on the horizon. Novel strategies should be developed
for the prevention and management of this disease, particularly for
patients at high risk of severe disease and to prevent MIS-C and long
COVID. The emergence of new variants of concerns and global vaccinations
efforts have substantially changed the clinical and immunological
profiles of COVID-19.