Editor—The day after the world watched the first person receiving the coronavirus
disease 2019 (COVID-19) vaccine on December 8, 2020, reports of three cases of suspected
allergic reactions in connection with the vaccine emerged from the UK. Two were reports
of anaphylaxis in healthcare workers, with onset within minutes of vaccination, responding
well to treatment with epinephrine. Both recovered fully and were reported to have
severe allergies to foods and drugs, respectively. The third case was less severe
and did not require epinephrine.
Immediate-type life-threatening reactions to vaccines are exceedingly rare; they are
reported to occur in 1.3 cases per million doses.
1
Therefore, two cases of anaphylaxis on the second day of a vaccination campaign with
a new vaccine require further scrutiny. The first important task is to confirm that
these cases were indeed anaphylaxis. If anaphylaxis is proved likely, the cause of
the reaction should be identified.
The active ingredient is rarely the cause, and the focus should be directed at the
many excipients usually present in vaccines.
2
A recent review of the literature showed that rare cases of immediate hypersensitivity
reactions to excipients have been described for adjuvants/preservatives; antimicrobials;
and a single case of a reaction to polysorbate 80, a polymer with structural similarities
to polyethylene glycol (PEG).
3
,
4
Hypersensitivity reactions to vaccines containing gelatin and egg had only been described
in patients with previous known hypersensitivity to gelatin and egg. In fact, large
studies have shown a very low risk of immediate reactions to ovalbumin in influenza
vaccines in patients with allergy to eggs,
5
and the recommendation to these patients is that the risk of anaphylaxis is no higher
than for non-allergics.
The COVID-19 vaccine from Pfizer–BioNTech recently introduced in the UK, USA, and
other countries is a messenger RNA (mRNA)-based vaccine (tozinameran, BNT-162b2) using
lipid nanoparticles to facilitate the transport of mRNA into cells.
6
The vaccine contains a number of excipients and lipids, one of them based on PEG-2000.
This is currently the only excipient in the vaccine with recognised allergenic potential.
The severity and rapid onset of the two reported reactions to the vaccine further
increase suspicion towards PEG.
Allergy to excipients is often overlooked because of a lack of knowledge about their
allergenic potential. However, allergy to PEG, also often called macrogol, has been
reported with increasing frequency over recent years,
7
,
8
Patients have usually had repeated systemic allergic reactions/anaphylaxis before
diagnosis. A typical history is of severe allergic reactions to several classes of
drugs, for example, penicillin, laxatives, injected corticosteroids, or antacids,
all containing PEG. Symptoms are of rapid onset, usually within minutes, and typically
result in severe generalised pruritus, urticaria, angioedema, hypotension, or difficulty
in breathing. Reactions are more severe with higher doses and with higher-molecular-weight
PEGs.
Polyethylene glycol is an ingredient in many laxatives, in about 30% of tablets and
is used as a surfactant in many injectable formulations, where a prolonged effect
is needed, such as in depot steroids. More recently, the technology of PEGylation
has been introduced to enhance drug delivery in many areas of medicine. No reactions
to PEG in vaccines have been reported, but PEG has not been a commonly used excipient
in vaccines until now.
The mechanism of sensitisation to PEGs is unknown, but from the cases described in
the literature
7
,
8
and our personal experience with a total of 18 patients with PEG allergy, there is
no reason to believe that existing inhalational or food allergies predispose to PEG
allergy. However, PEG allergy may be suspected in patients with very severe reactions
to drugs where the cause is unconfirmed, or patients with repeated immediate-type
reactions to several structurally unrelated drugs or other products containing PEG.
The potential benefit of an effective COVID-19 vaccine is far reaching and a potential
solution to a substantial threat to global health. The risk of hypersensitivity and
ultimately anaphylaxis is present for all drugs, including vaccines, although usually
low and is offset by the benefits of the drug. Randomised clinical trials of the Pfizer–BioNTech
COVID-19 vaccine in >22 000 individuals receiving the active treatment were independently
reviewed by the US Food and Drug Administration (FDA) and presented at an advisory
committee meeting for emergency approval of the vaccine on December 10, 2020. The
FDA found a small signal towards more hypersensitivity cases in the vaccine group,
but none of the reactions were immediate, severe, or requiring epinephrine. Exclusion
criteria for the clinical trials of the vaccine included individuals with known hypersensitivity
to vaccines, or with a history of allergy, hypersensitivity, or intolerance to the
COVID-19 vaccine or its excipients according to the registration of the trials on
ClinicalTrials.gov. At the FDA advisory committee meeting, the cases of anaphylaxis
in the UK were discussed at length. The advisory committee voted 17 to 4 in favour
of granting Pfizer emergency approval for the vaccine, which was granted on December
11, 2020. The FDA requested that a warning be added to the product information that
medication to treat immediate-type hypersensitivity reactions should be available
where vaccinations take place. Also, the FDA advised that the vaccine should be contraindicated
in patients with a severe allergic reaction to the first dose of vaccine, or with
known hypersensitivity to any ingredient/component of the vaccine. Finally, a stringent
surveillance system is to be initiated to monitor adverse effects of the vaccine with
monthly reporting.
In the UK, based on the anaphylactic reactions reported, the present advice from the
UK Medicines and Healthcare products Regulatory Agency (MHRA) is that ‘any person
with a history of anaphylaxis to a vaccine, medicine or food should not receive the
Pfizer/BioNTech COVID-19 vaccine’.
9
This is very likely to be overly cautious, but understandable, to maintain public
confidence in the vaccine until more detailed information about the reactions is available.
The individuals who have had allergic reactions to the vaccine in the UK should be
urgently investigated to determine the mechanisms behind the reactions and the potential
involvement of PEG. The reported history of previous severe allergies should be scrutinised
and their causes determined. Once details are available, it is very likely that more
specific recommendations about at-risk groups can be made to modify the rather broad
current MHRA recommendations. As a rule, allergy to foods, single drugs, or insect
venom does not predispose to allergy to other drugs or vaccines.
Tryptase measurement taken 0.5–2 h after the reaction should help determine if this
was indeed anaphylaxis.
10
As in all allergic reactions occurring in a hospital setting, other potential allergens,
such as disinfectants (e.g. chlorhexidine
11
) and latex, should be excluded. Investigations for allergy to PEG currently include
skin testing,
7
,
8
but in vitro tests may be in the pipeline.
12
As systemic allergic reactions have been reported in connection with skin prick testing
in PEG-allergic patients, the development of a reliable in vitro test is urgently
needed.
In conclusion, allergic reactions to vaccines are exceedingly rare, and there is no
reason to believe that this has changed. PEG has not been used previously as an excipient
in vaccines with this potential for wide dissemination, but even if PEG is concluded
to be the cause, allergy to this excipient is also very rare. As soon as a plausible
explanation for the suspected vaccine reactions has been found, clear recommendations
can be made for a safe vaccination strategy. At this stage, it is important that events
such as these do not lead to misinterpretations and detract from global implementation
of the vaccine.
The fact that these severe reactions have appeared early in the implementation of
the vaccine should remind us all that anaphylaxis is a rare risk of drug administration,
including vaccines. Anaphylaxis has a good prognosis when diagnosed and treated promptly
and correctly.
10
Vaccination centres should be made aware of the risk of anaphylaxis and have trained
staff and equipment immediately available to treat anaphylaxis. If such precautionary
measures are taken, combined with continued close surveillance of potential hypersensitivity
reactions, then the benefits of the COVID-19 vaccine clearly outweigh the risks, and
we can finally start hoping for an end to the COVID-19 pandemic.
Declarations of interest
The authors declare that they have no conflicts of interest.