Results
From the 17th February to 17th May 2021 a total of 477234 [female n=357481 (74.9%)] SA HCWs received a single, open-label dose of the Ad26.COV2.S vaccine in the Sisonke phase 3B study. A total of 10,279 (2.2%) HCWs reported AEFI of which 139 (1.4%) AEFI. Searching of these AEFI identified 569 possible allergic reactions for screening, and 318 could be excluded as non-allergic AEFI (Figure 1 ), leaving 251 (0.052%)probable allergic AEFI for an overall prevalence of 1 in 2000 doses. Thereafter, more detailed review including telephonic contact was attempted for the 251 participants with probable allergic AEFI; of which 38/251 (15%) were uncontactable. Of the 251, 139 did not require / seek medical attention.The majority [92/251 (36%)] reported a localized, transient rash (morphology undocumented) or pruritis that was self-limiting (lasting less than 24 hours), responsive to over-the-counter medications, and not requiring contact with either a family physician or emergency medical services. Six patients (2%) noted isolated worsening of existing symptoms of allergic rhinoconjuncitivitis in the 24 hours following vaccination, necessitating use of existing allergic medications. Four participants (see exclusions Figure 1 ) reported delayed-onset of non-urticarial type rashes (one blistering, two purpuric and one eczematous) all of which were referred to specialist dermatologists. One of these cases had a confirmed cutaneous vasculitis (on the basis of skin biopsy) and was known with underlying systemic lupus erythematous.
Four cases of immediate allergic AEFI were adjudicated as anaphylaxis, accounting for an overall prevalence of 8.4 per million doses.Table 1 details the four adjudicated cases of anaphylaxis that met both Brighton Collaboration case definition (n=3/4 level 1, 1/4 level 3) of anaphylaxis and NIAID criteria. The median (IQR) age of patients with anaphylaxis was 50 (45-53) years, and all cases were female. The median (IQR) time to onset was 10 (9-52) minutes, with 3/4 cases having an onset of reaction within the 15 minute protocol recommended observation time. All patients had a background of atopic disease with all four giving a history of prior anaphylaxis to medication. One patient had a history of vaccine-associated anaphylaxis to a yellow fever vaccine. One of these patients had prior confirmed SARS-CoV-2 infection. All patients required emergency room treatment, with three being admitted to hospital. All patients except one received epinephrine, antihistamines, intravenous (IVI) corticosteroids and Beta-agonist therapies. All patients recovered completely. Unfortunately, only 1/4 patients had a post-reaction tryptase measurement; this single normal tryptase measurement was performed six hours post-vaccine in a 56 year old female, known with uncontrolled asthma, who presented with facial angioedema and bronchospasm 10 minutes after vaccination (Table 1 ).
Mild/moderate allergic AEFI that necessitated treatment and contact with the medical services occurred in 107/251 (43%). The commonest allergic AEFI were delayed (>6 hours) reactions (n=69/107, 64%), with isolated urticaria and/or angioedema (n=70/107, 65%) the most frequently reported individual allergic phenotype (Table 2 ).
Table 2 shows demographic details, past medical and allergy history, clinical features and management of non-anaphylactic allergy AEFI needing medical attention, comparing immediate with delayed reactions, and isolated urticaria and/or angioedema. Similar to anaphylaxis cases, the majority [91/107 (85%)] of non-anaphylactic allergy AEFI occurred in females with a median(IQR) age of 37 (27-43) years. Reactogenicity was common, occurring in 67/107(63%) participants. Overall 53/88 (60%) of participants with non-anaphylactic allergy AEFI, had a history of prior anaphylaxis or atopic disease Of the 24 immediate non-anaphylactic allergy AEFI, ten occurred within 15 minutes, seven between one and three hours, and five between 4-6 hours post dosing [median(IQR) 0.75(1-3) hours)]. Amongst delayed reactions, 24/69 (35%) started within 24 hours post dosing, with 29/69 (42%) starting between 3 and 21 days post vaccination.. Only eight cases of non-anaphylactic allergy AEFI required admission to hospital with the majority successfully treated with antihistamines 62/107 (58%) and oral corticosteroids 30/107 (28%) only. Five patients in this group received epinephrine treatment for either severe bronchospasm, or angioedema of the upper respiratory tract due to concern around airway swelling.
Isolated urticaria and/or angioedema was the commonest single allergic reaction phenotype. The majority (39/70, 56%) occurred 24 hours or more after dosing, with a median (IQR) of 48(11.5-120) hours. More than half of these patients had no history of atopy. Only one patient in this group needed hospitalisation, and only four needed to receive emergency treatment.
Data on number of days of symptoms was not available; however all patients, except four, reported complete resolution of their AEFI at the time of telephonic contact (five to seven months post vaccination), with the majority indicating that symptoms resolved within a week of onset. Four patients reported urticaria and/or angioedema that was ongoing at the time of contact and these patients have been referred for further allergy care and management as chronic urticaria.