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.