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We have never seen anything like the Covid-19 vaccine. Here are the numbers indicating uptake: 

• 61.9% of world population has had at least one dose​ 
• 10.42 billion doses (21 Feb 2022)​ 
• 30.92 million doses per day​. 

However: 

• Only 10.6% of people in low-to-middle-income-countries have been vaccinated 
• In terms of SA, 34% of the country has been vaccinated (lowest of BRICS nations)​. 

In parallel with this unprecedented effort to vaccinate the globe, so too has an antivax sentiment emerged. Bear in mind that there is a difference between an adverse event following immunisation and a vaccine allergy.  

Many things can happen in the immediate period post vaccination, and we require a differential diagnosis for anaphylaxis, which includes: 

• Vasovagal episode​ 
• Panic attacks​ 
• Vocal cord dysfunction​ 
• Cardiovascular process eg MI​ 
• Seizure (hypoglycaemia)​ 
• Flushing syndromes​ 
• Non-histaminergic angioedema. 

Case definitions have been developed by the Brighton group for new adverse events, and an established one for anaphylaxis (rapid onset involving more than one system, such as skin and cardiac). 

Vaccine-induced anaphylaxis​ 

• Serious adverse event known as adverse event following immunization (AEFI) – adults and children ​ 
• ~1 in 1 million doses (or lower – Korean data)​ 
• Brighton collaboration standardised case definition for anaphylaxis used (2007) ​ 
• Reported to most available vaccines (highest IV, Tdap)​. 

In terms of mRNA anaphylactic events in the US roll-out, ​Pfizer-BioNTech (9 943 247 doses)​ and Moderna (7 581 429 doses)​, the rate, as shown in meta-analysis data is 7.91 cases/million (95% CI: 4-15.6). 

There seems to be a group of patients more prone to anaphylaxis: Over-representation of females​ and rapid onset of reactions​. There have been no deaths ​due to anaphylaxis. 

JnJ vaccine healthcare workers – Sisonke​ study 

Data currently under quality control and review​: 47 7234 doses administered​ and four adjudicated anaphylaxis events. This is a prevalence of 8.4 million doses​. 

This showed a similar clinical picture in that these patients all were female​ and all had symptom resolution​. One did not need adrenaline​ and one mast cell tryptase was measured and it was not elevated​. 

Data supports Covid vaccineation in atopic patients.  

Reactions to mRNA in highly allergic ​patients 

All patients had the vaccine administered under observation for two hours​. Nine (2.1%) females had reactions​, there were three cases of anaphylaxis (0.7%) within 20 minutes (no cardiovascular symptoms) – all treated with full symptom resolution​. 

Appearance of skin eruption, itching, or urticaria in the days after the first dose was 14.7% (32 of 218)​. There were four mild reactions on the second dose​. 

Clonal mast cell disorders and the vaccine​ 

These patients have clonal mast disorders, eg mastocytosis. They have increased risk of venom and drug-related anaphylaxis​. 

Several cohorts with bone marrow-proven clonal mast cell disorder (>150 patients)​ with antihistamine pre-med​ in a hospital setting​ had no anaphylaxis cases and only a few mild urticarial reactions​. 

Far more commonly than anaphylaxis, we have seen non-anaphylaxis hypersensitivity to vaccines​. 

This is divided into immediate and delayed reactions. Immediate (<4, <6 hrs)​ had limited cutaneous reactions, commonly urticaria or angioedema​. The commonest rash is macular papular/urticarial​ with large local/persistent nodule. 

It is important to differentiate these allergic conditions from other immune-mediated adverse drug reactions such as thrombocytopenia​ and the immediate reactogenicity-related to adverse drug reactions. 

Chronic urticaria and COVID-19 vaccines​ 

Other vaccines are associated with relapse or trigger of new chronic spontaneous urticaria (CSU) cases. The Covid-19 vaccine cases series documented new onset CSU post vaccine. ​In UCARE, data show 1857 CSU patients with 20% exacerbation of symptoms post vaccine (80% mRNA vaccines)​. 

US healthcare rollout of mRNA vaccines​ 

Overall allergic reactions were about 2% (self-reported)​, predominantly itching or rash other than at the injection site (n=788)​, respiratory symptoms (n=342)​, hives (n=244) or swelling (n=191)​. This is the same profile of the 16 anaphylaxis patients as previously described​. 

When to consider an excipient hypersensitivity reaction?​ 

This is a recurrent immediate or delayed reaction consistent with hypersensitivity but no known defined cause​. Recurrent hypersensitivity reactions are associated with structurally disparate medications.  ​ 

We sometimes see tolerance of an alternative formulation of the active ingredient​. Consider any hypersensitivity reaction associated with a vaccine​. 

Testing 

The accuracy of epicutaneous testing is very limited.  

In vivo and in vitro excipient testing​ 

In a small study (Warren et al) of 22 anaphylaxis cases (mRNA vaccines) – 17 BCC anaphylaxis​ 

They did skin prick testing, PEG and polysorbate, BAT and IgG and IgE to PEG​ testing with the following results: 

• 0/11 SPT positive to PEG and P80  
• 1/10 positive to mRNA vaccine​ 
• 10/11 positive BAT to PEG  
• 11/11 positive BAT to mRNA vaccine​ 
• No PEG IgE (0/17)​ 
• Positive PEG IgG in 7/17​. 

Data supports non-IgE mediated mechanism (IgG/IC activation of complement)​. No recommendation for routine pre-dose testing. 

Covid-19 vaccines in PEG-allergic patients​ 

PEG-allergic patients tolerated polysorbate 80-containing vaccines – J&J and AstraZeneca​ - 31 patients with pegaspargase reactions tolerated mRNA vaccines (no reactions)​ while 12 confirmed PEG allergic patients tolerated mRNA vaccines​. 

Don’t give up on the second dose. 

A study showed that after anaphylaxis to the first dose of mRNA SARS-CoV-2 vaccines, who had a second dose, were in the mild to moderate category:  

• 47 patients were referred to specialist allergy clinics (US and Denmark)​ 
• 39 mild allergic reactions and eight anaphylaxis histories to Pfizer-BioNTech vaccine​ 
• All 8 had in-patient testing for PEG sensitisation (all negative)​ 
• All 8 had pre-med with antihistamine​. 

All eight had successful second dose one-step 0.3ml dose of Pfizer BioNTech​. 

More safety data for second dosing​ 

Of 189 first-dose reactions to mRNA COVID19 vaccines (32 were anaphylaxis)​. Of those 159 (84%) managed to have a second dose, and 32/159 had mild, self-limited immediate allergic reactions with second dose resolved with antihistamines (30% pre-dose AH)​. 

Another study with 61 first dose reactions (25 to AZ vaccine), nine anaphylaxis​. Successful second dose in 52 (including seven anaphylaxis)​. Twenty-five AZ vaccine recipients received mRNA second dosing (one with urticaria post mRNA vaccine)​. 

Take-home messages 

Vaccine-induced allergic reactions are not uncommon (~2% mRNA), but severe life-threatening anaphylaxis is still rare (~8/million)​. It is important to differentiate true allergy from other reactions. PEG/Polysorbate anaphylaxis/allergy is very rare​. Reactions to mRNA vaccines are likely to be complement activation-related pseudoallergy or non-IgE with implications for second dose and labels​. Every effort should be made to aid and encourage life-saving adult vaccination with full dosing​.