Discussion
The tremendous global scale of COVID19 vaccination means that the
cumulative number of uncommon or rare AEFIs, such as anaphylaxis, can be
expected to occur in larger numbers than usual in the coming 12-18
months when compare to usual background rates In addition, . national
vaccine safety groups and clinicians need published data on registered
COVID19 vaccines to inform the public, create awareness of patients at
risk of AEFIs, and to correctly manage mild and severe AEFIs. No severe
(>grade 3) allergic AEFIs were noted in the phase I-III
studies of Janssen Ad26.COV2.S (7, 8), and only one post-marketing
surveillance study from Vaccine Adverse Events Reporting System (VAERS)
reported on “rash” as a non-anaphylactic allergic AEFI (9). Thus, this
study provides the largest cohort with detailed allergic AEFI reporting
following vaccination with the Janssen Ad26.COV2.S.
Allergic AEFI with the Ad26.COV2.S vaccine are uncommon in this large
cohort with an estimated prevalence for any allergic AEFI including
anaphylaxis of 1 in 2000 doses (0.052%) and 8.4 per million doses
(0.0008%), respectively.. This rate for anaphylaxis is higher than the
~1 case per million doses reported for most known
vaccines (3, 4), and the <0.5 per million dose rate reported
after investigation of 79 reports to the USA Vaccine Adverse Events
Reporting Systems (VAERS) following 7.98 million doses of Ad26.COV2.S
administered in the USA. However, when the data are disaggregated by
vaccine, the majority of post-marketing datasets reporting anaphylaxis
to mRNA COVID19 vaccines have an estimated prevalence of
>20 anaphylaxis cases per million doses (5), while
regulatory data for the ChadOx/AstraZeneca adenoviral vectored vaccine
estimate rates between 0.32 to 33.4 per million doses.Of note is that
there may be over-reporting in large pharmacovigilance reporting systems
with inclusion of non-allergic reactions as many reports do not
meetcriteria when reviewed and subjected to a more detailed allergy
work-up (5). Nevertheless, although overall rates for any allergic AEFI
and anaphylaxis are rare, rates of up to 1 in 50 for non-anaphylactic
reactions have been reported for mRNA COVID19 vaccines (2), so overall
the Ad26.COV2.S vaccine appears to to have a significantly lower risk of
inducing allergic reactions when compared to the mRNA vaccines.
Importantly, from an overall vaccine safety perspective, is that
although four cases met case definitions for anaphylaxis, no patients
died or suffered circulatory collapse requiring repeated dosing with
epinephrine. Several factors support non-IgE mechanisms including that
all cases were female; one recovered without epinephrine; and the single
mast cell tryptase measurement performed was not elevated (Table
1 ). Possible mechanisms include IgG against excipients (16) or
complement activation related pseudoallergy (CARPA), rather than
IgE-mediated anaphylaxis to a vaccine ingredient or excipient such as
polysorbate 80 (17).
The commonest allergic AEFI in this cohort was a delayed urticarial rash
and generalised pruritis with or without angioedema. , with onset
usually a day or up to 21 days following vaccination. Eight versus five
cases of urticaria were reported in active versus placebo arms of the
phase III ENSEMBLE study (7). Urticaria and angioedema have been
well-reported with several registered vaccines e.g. influenza and toxoid
vaccines (18, 19), as well as COVID19 vaccines (20). Catala A et
al. reported 405 cutaneous reactions following COVID vaccines in a
Spanish population with the commonest being urticarial, followed by
morbilliform and papulovesicular rashes. Interestingly, the only
adenoviral vectored vaccine included was the ChadOx/AstraZeneca vaccine
and urticaria accounted for a fifth of all cutaneous reactions reported
to this vaccine (20). Urticaria is also associated with several viral
infections, including adenovirus and more recently SARS-CoV-2 infections
(21, 22). Furthermore, unlike the immediate allergic AEFIs, patients
experiencing delayed urticarial AEFIs less commonly had a background of
atopic disease. This also suggests that the mechanisms underlying these
reactions relate to non-IgE pathways and the immune interaction – both
innate and adaptive - with viral vector expressed viral proteins,
vaccine ingredients or combinations of these.
The majority of reactions could be managed symptomatically with
antihistamines/corticosteroids and were self-limiting, not requiring
hospitalisation nor emergency treatment. However, in four patients
vaccine-induced urticaria has not resolved, now lasting > 6
weeks post vaccination. Vaccines can rarely trigger chronic spontaneous
urticaria (18) and induce urticarias such as cold urticaria (23). Some
infections, including SARS-CoV-2, have also been shown to exacerbate
chronic spontaneous urticaria (CSU) (24). Patients developing new or
exacerbated CSU following COVID19 vaccination should be reviewed by an
allergist with treatment focusing on the use of high doses of
antihistamines, rather than unnecessary corticosteroids which may
interfere with the development of a protective vaccine response (25).
Further research is now required to examine the effects of COVID19
vaccines on cohorts of chronic urticaria, which is not uncommon(24, 26).
The major strength of this study was the large cohort size and the
robust passive and active safety surveillance systems that allowed for
comprehensive AEFI reporting for allergic events. However, because not
all allergic AEFIs were followed up at pre-specified time points, and
events were managed at hospitals across the country by non-study staff,
a small amount of data could not be captured.
In conclusion, this study is the first to detail allergic AEFIs
following use of the novel Ad26.COV2.S vaccine. Reassuringly, allergic
AEFI were very rare with complete resolution of all cases of
anaphylaxis. Self-limiting delayed urticaria was the commonest allergic
AEFI and clinicians should be aware that these can occur several days
after vaccination. The majority of allergic reactions were self-limiting
and could be managed expectantly without ongoing problems.