To date, the development of mRNA vaccines for the prevention of infection with the
severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been a success story,
with no serious concerns identified in the ongoing phase 3 clinical trials.
1
Minor local side effects such as pain, redness, and swelling have been observed more
frequently with the vaccines than with placebo. Systemic symptoms such as fever, fatigue,
headache, and muscle and joint pain have also been somewhat more common with the vaccines
than with placebo, and most have occurred during the first 24 to 48 hours after vaccination.
1
In the phase 1–3 clinical trials of the Pfizer–BioNTech and Moderna mRNA vaccines,
potential participants with a history of an allergic reaction to any component of
the vaccine were excluded. The Pfizer–BioNTech studies also excluded participants
with a history of severe allergy associated with any vaccine (see the protocols of
the two trials, available with the full text of the articles at NEJM.org, for full
exclusion criteria).
1,2
Hypersensitivity adverse events were equally represented in the placebo (normal saline)
and vaccine groups in both trials.
1
The Medicines and Healthcare Products Regulatory Agency (MHRA) in the United Kingdom
was the first to authorize emergency use of the Pfizer–BioNTech mRNA vaccine. On December
8, 2020, within 24 hours after the start of the U.K. mass vaccination program for
health care workers and elderly adults, the program reported probable cases of anaphylaxis
in two women, 40 and 49 years of age, who had known food and drug allergies and were
carrying auto-injectable epinephrine. On December 11, the Food and Drug Administration
(FDA) issued an emergency use authorization (EUA) for the Pfizer–BioNTech mRNA vaccine,
and general vaccination of health care workers was started on Monday, December 14.
On December 15, a 32-year-old female health care worker in Alaska who had no known
allergies presented with an anaphylactic reaction within 10 minutes after receiving
the first dose of the vaccine. The participants who had these initial three reported
cases of anaphylaxis would not have been excluded on the basis of their histories
from the mRNA vaccine clinical trials.
1,2
Since the index case in Alaska, several more cases of anaphylaxis associated with
the Pfizer mRNA vaccine have been reported in the United States after vaccination
of almost 2 million health care workers, and the incidence of anaphylaxis associated
with the Pfizer SARS-CoV-2 mRNA vaccine appears to be approximately 10 times as high
as the incidence reported with all previous vaccines, at approximately 1 in 100,000,
as compared 1 in 1,000,000, the known and stable incidence of anaphylaxis associated
with other vaccines. The EUA for the Moderna mRNA vaccine was issued on December 18,
and it is currently too soon to know whether a similar signal for anaphylaxis will
be associated with that vaccine; however, at this time a small number of potential
cases of anaphylaxis have been reported, including one case on December 24 in Boston
in a health care worker with shellfish allergy who was carrying auto-injectable epinephrine.
In response to the two cases of anaphylaxis in the United Kingdom, the MHRA issued
a pause on vaccination with the Pfizer–BioNTech SARS-CoV-2 mRNA vaccine, to exclude
any person with a history of anaphylactic reaction to any food, drug, or vaccine.
The Centers for Disease Control and Prevention (CDC) has issued advice pertaining
to administration of either the first or the second dose of the Pfizer–BioNTech or
Moderna mRNA vaccine, recommending exclusion of any person who has a history of a
severe or immediate (within 4 hours) allergic reaction associated with any of the
vaccine components, including polyethylene glycol (PEG) and PEG derivatives such as
polysorbates.
3
Anaphylaxis is a serious multisystem reaction with rapid onset and can lead to death
by asphyxiation, cardiovascular collapse, and other complications.
4
It requires prompt recognition and treatment with epinephrine to halt the rapid progression
of life-threatening symptoms. The cause of anaphylactic reactions is the activation
of mast cells through antigen binding and cross-linking of IgE; the symptoms result
from the tissue response to the release of mediators such as histamine, proteases,
prostaglandins, and leukotrienes and typically include flushing, hives, laryngeal
edema, wheezing, nausea, vomiting, tachycardia, hypotension, and cardiovascular collapse.
Patients become IgE-sensitized by previous exposure to antigens. Reactions that resemble
the clinical signs and symptoms of anaphylaxis, previously known as anaphylactoid
reactions, are now referred to as non-IgE–mediated reactions because they do not involve
IgE. They manifest the same clinical features and response to epinephrine, but they
occur by direct activation of mast cells and basophils, complement activation, or
other pathways and can occur on first exposure. Tryptase is typically elevated in
blood in IgE-mediated anaphylaxis and, to a lesser extent, in non–IgE-mediated mast-cell
activation, a feature that identifies mast cells as the sources of inflammatory mediators.
Prick and intradermal skin testing and analysis of blood samples for serum IgE are
used to identify the specific drug culprit, although the tests lack 100% negative
predictive value.
5
The clinical manifestations of the two U.K. cases and the one U.S. case fit the description
of anaphylaxis: they occurred within minutes after the injections, symptoms were typical,
and all responded to epinephrine. The occurrence on first exposure is not typical
of IgE-mediated reactions; however, preexisting sensitization to a component of the
vaccine could account for this observation.
4
Anaphylaxis is a treatable condition with no permanent effects. Nevertheless, news
of these reactions has raised fear about the risks of a new vaccine in a community.
These cases of anaphylaxis raise more questions than they answer; however, such safety
signals are almost inevitable as we embark on vaccination of millions of people, and
they highlight the need for a robust and proactive “safety roadmap” to define causal
mechanisms, identify populations at risk for such reactions, and implement strategies
that will facilitate management and prevention (Figure 1).
6
We can be reassured that vaccine-associated anaphylaxis has been a rare event, at
one case per million injections, for most known vaccines.
6
Acute allergic reactions after vaccination might be caused by the vaccine antigen,
residual nonhuman protein, or preservatives and stabilizers in the vaccine formulation,
also known as excipients.
6
Although local reactions may be commonly associated with the active antigen in the
vaccine, IgE-mediated reactions or anaphylaxis have historically been more typically
associated with the inactive components or products of the vaccine manufacturing process,
such as egg, gelatin, or latex.
6
The mRNA vaccines developed by Pfizer–BioNtech and Moderna use a lipid-based nanoparticle
carrier system that prevents the rapid enzymatic degradation of mRNA and facilitates
in vivo delivery.
1,2,7
This lipid-based nanoparticle carrier system is further stabilized by a polyethylene
glycol (PEG) 2000 lipid conjugate that provides a hydrophilic layer, prolonging half-life.
Although the technology behind mRNA vaccines is not new, there are no licensed mRNA
vaccines, and the Pfizer–BioNtech and Moderna vaccines are the first to receive an
EUA. There is therefore no prior experience that informs the likelihood or explains
the mechanism of allergic reactions associated with mRNA vaccines. It is possible
that some populations are at higher risk for non–IgE-mediated mast-cell activation
or complement activation related to either the lipid or the PEG-lipid component of
the vaccine. By comparison, formulations such as pegylated liposomal doxorubicin are
associated with infusion reactions in up to 40% of recipients; the reactions are presumed
to be caused by complement activation that occurs on first infusion, without previous
exposure to the drug, and they are attenuated with second and subsequent injections.
8
PEG is a compound used as an excipient in medications and has been implicated as a
rare, “hidden danger” cause of IgE-mediated reactions and recurrent anaphylaxis.
9
The presence of lipid PEG 2000 in the mRNA vaccines has led to concern about the possibility
that this component could be implicated in anaphylaxis. To date, no other vaccine
that has PEG as an excipient has been in widespread use. The risk of sensitization
appears to be higher with injectable drugs with higher-molecular-weight PEG; anaphylaxis
associated with bowel preparations containing PEG 3350 to PEG 4000 has been noted
in case reports.
9,10
The reports include anaphylaxis after a patient was exposed to a PEG 3350 bowel preparation;
anaphylaxis subsequently developed on the patient’s first exposure to a pegylated
liposome microbubble, PEGLip 5000 perflutren echocardiography contrast (Definity),
which is labeled with a warning about immediate hypersensitivity reactions.
11
For drugs such as methylprednisolone acetate and injectable medroxyprogesterone that
contain PEG 3350, it now appears that the PEG component is more likely than the active
drug to be the cause of anaphylaxis.
9,12
For patients with a history of an anaphylactic reaction to the SARS-CoV-2 Pfizer–BioNTech
mRNA vaccine, the risk of anaphylaxis with the Moderna SARS-CoV-2 mRNA vaccine — whose
delivery system is also based on PEG 2000, but with different respective lipid mixtures
(see Table 1) — is unknown. The implications for future use of SARS-CoV-2 vaccines
with an adenovirus carrier and protein subunit, which are commonly formulated with
polysorbate 80, a nonionic surfactant and emulsifier that has a structure similar
to PEG, are also currently unknown.
6,13
According to the current CDC recommendations, all persons with a history of an anaphylactic
reaction to any component of the mRNA SARS-Cov-2 vaccines should avoid these vaccines,
and this recommendation would currently exclude patients with a history of immediate
reactions associated with PEG. It would also currently exclude patients with a history
of anaphylaxis after receiving either the BioNTech–Pfizer or the Moderna vaccine,
who should avoid all PEG 2000–formulated mRNA vaccines, and all PEG and injectable
polysorbate 80 products, until further investigations are performed and more information
is available.
We are now entering a critical period during which we will move rapidly through phased
vaccination of various priority subgroups of the population. In response to the cases
of anaphylaxis associated with the Pfizer–BioNTech vaccine in the United Kingdom and
now several cases of anaphylaxis in the United States, the CDC has recommended that
only persons with a known allergy to any component of the vaccine be excluded from
vaccination. A systematic approach to the existing hypersensitivity cases and any
new ones will ensure that our strategy will maintain safety not only for this vaccine
but for future mRNA and SARS-CoV-2 vaccines with shared or similar components (Figure
1 and Table 1).
6
The next few months alone are likely to see at least five new vaccines on the U.S.
market, with several more in development (Table 1).
13
Maintaining public confidence to minimize vaccine hesitancy will be crucial.
14,15
As in any post-EUA program, adverse events that were not identified in clinical trials
are to be expected. In addition, populations that have been studied in clinical trials
may not reflect a predisposition to adverse events that may exist in other populations.
16
Regardless of the speed of development, some adverse events are to be expected with
all drugs, vaccines, and medicinal products. Fortunately, immune-mediated adverse
events are rare. Because we are now entering a period during which millions if not
billions of people globally will be exposed to new vaccines over the next several
months, we must be prepared to develop strategies to maximize effectiveness and safety
at an individual and a population level. The development of systematic and evidence-based
approaches to vaccination safety will also be crucial, and the approaches will intersect
with our knowledge of vaccine effectiveness and the need for revaccination. When uncommon
side effects that are prevalent in the general population are observed (e.g., the
four cases of Bell’s palsy reported in the Pfizer–BioNTech vaccine trial group), the
question whether they were truly vaccine-related remains to be determined.
1
If a person has a reaction to one SARS-CoV-2 vaccine, what are the implications for
the safety of vaccination with a different SARS-CoV-2 vaccine? Furthermore, what safety
issues may preclude future vaccination altogether? Indeed, mRNA vaccines are a promising
new technology, and demonstration of their safety is relevant to the development of
vaccines against several other viruses of global importance and many cancers.
7
For the immediate future, during a pandemic that is still increasing, it is critical
that we focus on safe and efficient approaches to implementing mass vaccination. In
the future, however, these new vaccines may mark the beginning of an era of personalized
vaccinology in which we can tailor the safest and most effective vaccine on an individual
and a population level.
17
Moreover, postvaccination surveillance and documentation may present a challenge.
On a public health level, the Vaccine Adverse Event Reporting System (VAERS; https://vaers.hhs.gov)
is a national reporting system designed to detect early safety problems for licensed
vaccines, but in the case of Covid-19 vaccines, the system will serve the same function
after an EUA has been issued. On an individual level, a system that will keep track
of the specific SARS-CoV-2 vaccine received and will provide a means to monitor potential
long-term vaccine-related adverse events will be critical to individual safety and
efficacy. V-safe (https://cdc.gov/coronavirus/2019-ncov/vaccines/safety/vsafe.html)
is a smartphone application designed to remind patients to obtain a second dose as
needed and to track and manage Covid-19 vaccine–related side effects.
In the world of Covid-19 and vaccines, many questions remain. What are the correlates
of protective immunity after natural infection or vaccination? How long will immunity
last? Will widespread immunity limit the spread of the virus in the population? Which
component of the vaccine is responsible for allergic reactions? Are some vaccines
less likely than others to cause IgE- and non-IgE–mediated reactions? Careful vaccine-safety
surveillance over time, paired with elucidation of mechanisms of adverse events across
different SARS-CoV-2 vaccine platforms, will be needed to inform a strategic and systematic
approach to vaccine safety.