Allergic reactions to COVID-19 vaccines
Local and systemic reactions were reported in phase III clinical trial of the ChAdOx1 nCoV-19 vaccine, which were mostly mild and moderate in intensity209. Cutaneous adverse effects of the available COVID-19 vaccines include injection site reactions, urticaria, angioedema, exacerbation of atopic eczema and systemic allergic reactions including anaphylaxis210. Anaphylaxis to the BNT162b2 vaccine was reported several days after the initiation of public vaccinations211. Overall, the incidence of COVID-19 mRNA vaccine-associated anaphylaxis is very low212, with only was 4.8 per million doses for BNT162b2 and 5.1 per million doses for mRNA-1273 according to data from Vaccine Safety Datalink213. Moreover, the second dose of the BNT162b2 vaccine elicited a higher rate of systemic events191. Nevertheless, the incidence of anaphylaxis- associated with COVID-19 vaccines is comparable to that of other vaccines214 and the benefits may outweigh the potential risks of COVID-19 vaccinations215,216. Unfortunately, the fear of an allergic reaction has caused vaccine hesitancy in the general public, haltering global vaccination efforts217.
Polyethylene glycol (PEG) is an additive present in the Pfizer-BioNtech and Moderna mRNA vaccines used to prevent premature degradation of the nanoparticless218, and it has been suggested to be the major culprit for anaphylaxis to COVID-19 vaccines219. PEG and its derivatives are also widely used in household products including toothpaste, cosmetics, pharmaceuticals, and foods220. Many types of vaccines, therapeutic medications and diagnostic media contain PEG with different molecular weights and their risks of anaphylaxis has been previously reported220,221. Exposure to products containing PEG via intravenous and intramuscular injection is the major route causing HSR to PEG. There is evidence showing that lipid-conjugated PEG or PEGylated liposomes have a stronger immunogenicity than PEG alone and may contribute to the anaphylaxis elicited by COVID-19 mRNA vaccines222,223. Anti-PEG IgE-mediated HSR, complement activation-related pseudoallergy induced by anti-PEG IgM and IgG antibodies and potential interaction of PEG with mast cells and viral RNA have been suggested to underly COVID-19 vaccine anaphylaxis222,224. IgG and IgM antibodies against PEG were found in up to 25% of the population without known prior exposure to PEGylated products and in up to 89% of patients with known prior exposure to PEGylated products225. Other excipients than PEG present in authorized COVID-19 vaccines might also cause severe allergic reactions to COVID-19 vaccines and need appropriate allergological assessment226.
EAACI has reported recommendations to perform in vivo tests (skin prick test and intradermal test) and in vitro tests (basophil activation test, BAT) to the vaccines or their components in individuals with severe reactions to the first dose of COVID-19 vaccines227. The positive rate of skin test with PEG or mRNA vaccine in patients with reactions to COVID-19 mRNA vaccine or with previous PEG or polysorbate allergies was very low228,229. Thus, the clinical significance of skin testing with mRNA vaccine in those with negative skin testing results with PEG is still unknown. BAT performed in patients with PEG allergy demonstrated that BNT162b2 and AZD1222 vaccines and PEGylated lipids, but not unmodified PEG, can activate mast cells223. Thus, positive BAT results to mRNA vaccines may be a potential diagnostic tool for confirming HSR to PEG excipient.
Studies have shown that most individuals with allergic reactions to the first dose tolerated well the second dose irrespective of the skin test results230,231. Thus, the second dose vaccine may be administered after careful evaluation and under careful monitoring in an allergy clinic. In a position paper by EAACI, allergic patients without prior allergic reaction to any of the vaccine components and patients with mild and moderate allergies were recommended that they should not be excluded from COVID-19 vaccinations227. On the contrary, it would put population immunity with vaccination at risk due to the high prevalence of allergic diseases227 . However, anaphylaxis may occur after vaccination in the absence of a history of allergic disease. Therefore, strategies for the prevention, diagnosis and treatment of severe allergic reactions and a list of recommended medications and equipment for vaccine centers were provided in the EAACI statement to minimize the risk of allergic reactions to COVID-19 vaccines227. Anaphylaxis induced by COVID-19 vaccines is rare but may be more severe in older people due to comorbidities and polypharmacy232. Intramuscular injection of adrenaline remains the first-line therapy for anaphylaxis in older people232. Modified dosing or alternative vaccines were recommended by EAACI for those with confirmed reactions to COVID-19 vaccines227. Herein, we provide a flow chart for the treatment of allergic reactions to COVID-19 vaccines (Figure 4).
Perspectives and conclusions
Anthropogenic activities, climate change and global population movement set a perfect environment for new outbreaks of zoonotic pathogens. Using the knowledge and experience gained from the COVID-19 pandemic, there is an urgent need to develop novel strategies to predict and prevent the emergence and transmission of novel pathogens 233. Effective surveillance of new SARS-CoV-2 variants and reporting their transmissibility and rate of breakthrough infection is warranted to assist international policymaking234. The trajectory of COVID-19 needs to be closely monitored to further our understanding of the immunity waning, antigen drifting and re-entries from zoonotic reservoirs 235. As we deepen our knowledge on COVID-19, vaccination strategies should be updated and revised, such as frequent administration of booster doses. The continuously mutating virus warrants the development of novel vaccines targeting current variant sequences236. The impacts of COVID-19 on allergen sensitization and the incidence of allergic disease are still unknown and need to be investigated by the society of allergy and clinical immunology.
In conclusion, similarly to other respiratory viruses, full eradication of COVID-19 is not on the horizon. Novel strategies should be developed for the prevention and management of this disease, particularly for patients at high risk of severe disease and to prevent MIS-C and long COVID. The emergence of new variants of concerns and global vaccinations efforts have substantially changed the clinical and immunological profiles of COVID-19.