EAACI statement on the diagnosis, management and prevention of severe allergic reactions to COVID‐19 vaccines

1.1. Prevention of the severe allergic reactions to vaccinations

Based on the experience with other vaccines, systemic allergic reactions to vaccine components are rare, within a range of 1–5 cases per million applications. ⁸ For the Pfizer/BioNTech BNT162B2 COVID‐19 vaccine, 11.1 cases of allergic reactions (including anaphylaxis) occurred per 1 million doses. ⁹ Other novel vaccine formulations, such as the recently approved vector‐based Ebola vaccine, may show a higher incidence of anaphylaxis. ¹⁰ , ¹¹ There are risk factors, which may aggravate allergic reactions that need to be identified while taking the patient's medical history. As shown in Table 1, these include previous severe anaphylactic episodes, uncontrolled asthma, mastocytosis and other mast cell disorders. ¹² , ¹³

Additionally, medications like beta‐blockers, commonly prescribed for cardiovascular diseases, can interfere with the treatment of anaphylaxis. Other known co‐factors for precipitating or worsening an anaphylactic reaction include recent physical exercise, alcohol consumption, non‐steroidal anti‐inflammatory drugs (NSAIDs), or menstruation. ¹⁴ It is currently not known whether these co‐factors are facilitating a severe allergic reaction after vaccine administration.

Importantly, anaphylaxis can happen to anyone, anywhere and anytime. ¹⁵ , ¹⁶ There is no correlation with age, sex, asthma, atopic status or previous non‐severe reactions. ¹⁷ Therefore, it is essential that each vaccination facility, regardless of whether it is located outside or inside a medical centre, is prepared to recognize and treat severe allergic reactions (Table 2). Even when severe, anaphylaxis can resolve with little or no sequelae with immediate and proper management. ¹⁸ , ¹⁹

Allergy to drugs, foods, insect venoms or inhalant allergens (house dust mites, pollens, animal dander, moulds) is in general not a contraindication for any vaccines, including those for SARS‐CoV‐2. Vaccination is contraindicated only when a proven diagnosis of hypersensitivity to a vaccine component is diagnosed by a qualified physician and supported by the appropriate allergy test. The specific safety recommendations released by the EU, US and UK regulatory agencies for administering COVID‐19 vaccines are overall consistent (Table 3). All agencies advise that the vaccines should be administered under close medical supervision with appropriate medical assistance available. The European Medicines Agency (EMA), US Food and Drug Administration (FDA), British Medicines Healthcare products Regulatory Agency (MHRA) as well as World Health Organization (WHO) advise that the vaccine should not be administered only i) when there is an allergy to one of the components of the vaccine and ii) when there was a severe allergic reaction to the first dose. ³ , ²⁰ , ²¹ , ²² Of note, at the beginning of the public vaccination campaign, MHRA issued more strict recommendations, ²³ but after reviewing the data from the ongoing mass vaccination programme and the publication of the report by the Joint Committee on Vaccination and Immunisation (JCVI), ²⁴ Public Health England and MHRA issued new recommendations, which are in line with those of FDA and EMA. ²⁵ Regarding the most recently approved AstraZeneca adenoviral COVID‐19 vaccine, MHRA has already applied this revised view and has stated that a contraindication is only applicable in case of hypersensitivity to the active substance or any of the excipients present in the vaccine. ²⁶ The COVID‐19 vaccines currently authorized in the EU, UK, and US, along with their dosing instructions, ingredients and common side effects are summarized in Table 4.

1.2. Diagnosis and treatment of a severe systemic allergic reaction

A systemic allergic reaction, often referred to as anaphylaxis, is currently defined as a serious reaction with rapid onset (minutes to hours) that is potentially life threatening. ¹⁹ , ²⁷ For the Pfizer/BioNTech BNT162B2 COVID‐19 vaccine, 71% of allergic reactions occurred within 15 min of vaccination. ⁹ Anaphylaxis usually manifests as a rapid, progressive reaction often involving (but not always) the skin or oral mucosa (such as lip or tongue swelling), the gastrointestinal system, the upper and lower respiratory tract, or cardiovascular system. ¹⁹ , ²⁸ The reaction can progress within minutes from the skin/oral mucosa to multiorgan involvement, abdominal cramps and vomiting, stridor, dyspnoea, wheezing, and circulatory collapse (due to massive volume loss into bodily tissues) (Figure 1).

The time elapsed from allergen exposure to cardiorespiratory failure can be within a few minutes. Therefore, upon first signs of anaphylaxis, it is necessary to immediately put the patient in recline position with legs up and administer intramuscular epinephrine ¹⁶ , ²⁸ , ²⁹ (Figure 1). There is no contraindication to epinephrine in treatment of anaphylaxis – it is life‐saving. ¹⁶ In some cases, the evolution of anaphylaxis may be delayed, and cardiorespiratory failure can occur up to 8 hours after the start of the symptoms. Therefore, the initial milder symptoms should not be ignored.

Once epinephrine has been administered, secure intravenous access and start volume replacement with intravenous 0.9% NaCl, assess vital signs, clear the airways, give oxygen via facial mask at least 10 litres/minute (Figure 1). If there is rapid volume loss/hypotension, the patient may require up to 2–3 litres of intravenous 0.9% NaCl administered in 10–20 minutes. If there is no improvement within 5–10 minutes, repeat the intramuscular epinephrine injection and call additional emergency assistance. If there is severe dyspnoea and or wheezing, administer short‐acting beta‐agonists such as salbutamol puffs via large‐volume spacer. Vaccination units within fully equipped medical centres may also consider nebulization with short‐acting beta‐agonists or if there are signs of severe upper airway obstruction (laryngeal/uvula/tongue oedema), nebulized epinephrine. ¹⁶ , ²⁸ However, due to the possibility of spreading the SARS‐CoV‐2 virus during nebulization, sublingual epinephrine (tablets or spray) may be a better option.

Other medications for the treatment of allergic reactions include oral or intravenous glucocorticoids and oral or intravenous antihistamines, usually administered to treat reactions isolated to the skin or mucosa (eg localized oedema without severity location, pruritus or hives). Glucagon is used when patients on beta‐blockers are unresponsive to epinephrine.

Patients without response to these initial steps should be immediately transferred to the nearest hospital's intensive care unit (ICU). ¹⁶ , ²⁸ At the ICU, within the first 2–3 hours after the beginning of the reaction, it is advised to draw blood for measuring mast cell tryptase (MCT), which can confirm anaphylaxis. ³⁰ A simplified algorithm for these initial treatment steps is shown in Figure 1.

1.3. Follow‐up

Patients whose symptoms fully resolve after the first dose of epinephrine can be discharged after 4–8 hours following full resolution of the symptoms. An extended observation period of 24 hours is recommended for patients who required repeated doses of epinephrine to monitor cardiac arrhythmias and late‐phase anaphylactic reactions. Upon discharge, patients should obtain written instruction to manage a late anaphylactic reaction (how to recognize and react to anaphylaxis), potentially a prescription for an epinephrine autoinjector as emergency medication, 50–100 mg oral prednisone or equivalent, oral antihistamines, and inhaled beta‐2 agonists. All patients with an anaphylactic reaction should be referred urgently to the allergy centre for a detailed assessment. Unless it is determined by an allergy specialist that the vaccine did not induce the allergic reaction, they should not receive the second dose of the vaccine.

2.1. Identification of the allergenic/immunogenic components

Currently, regulatory agencies, national research centres and academic institutions are investigating the pathogenesis of severe hypersensitivity reactions following the injection of mRNA‐based COVID‐19 vaccines to determine the culprit. The two first mRNA‐based COVID‐19 vaccines are packaged in multi‐dose vials and must be diluted before use. ⁷ While there are no added adjuvants or preservatives, the excipients that stabilize the active vaccine include several lipids, salts, sugars and buffers (Table 2). ³ , ²⁰ , ²¹ The main function of the lipids is to provide a nanoparticle carrier with a protective shield for the mRNA after injection and to facilitate its cellular uptake through the plasma membranes. The lipid nanoparticle (LNP) carrier consists of cationic lipids coating the polyanionic mRNA and zwitterionic lipids that mimic the phospholipids of the cell membrane. Cholesterol stabilizes the lipid bilayer of the LNP. Polyethylene glycol (PEG)‐modified lipids improve the aqueous solubility of the LNPs. PEG, also known as macrogol, is a polyether compound widely used as an additive in cosmetics, pharmaceuticals, and foods. In the case of the mRNA‐1273 and the BNT162b2 vaccine, a PEG with a molecular weight of 2000 g/mol is used (PEG 2000). ²⁰ , ²¹ While PEGs are considered generally safe for use in medical devices and drug formulations, ³¹ IgE‐mediated allergic reactions and anaphylaxis have been reported to PEGs of different molecular weights. ³² , ³³

The first recombinant viral vector‐based COVID‐19 vaccine, which uses a modified replication‐deficient chimpanzee adenovirus vector encoding the SARS‐CoV‐2 S glycoprotein, does not require freezing and can be stored at 2–8°C. ²⁶ , ³⁴ To stabilize the product, the ChAdOx1‐S vaccine includes as excipients polysorbate 80, the amino acid L‐histidine, ethanol, salts, sugars and buffers (Table 2). ²⁶ Polysorbate 80, also known as Tween 80, is a synthetic non‐ionic surfactant used as an excipient in various drug formulations. ³³ Polysorbate 80 is cross‐reactive to PEGs and may cause IgE‐mediated hypersensitivity reactions as well. ³²

2.2. Diagnostic and preventive allergy workup

Studies on the pathogenesis of the severe allergic reactions following mRNA‐based COVID‐19 vaccine components need to be prioritized. The allergenic components can be identified with in vitro approaches (eg in basophil activation test and or mast cell line assays) or in vivo skin testing before administration of the vaccine. Through potential collaboration with the vaccine producers and accessibility to vaccines or their components for allergy centres, novel procedures for in vivo and in vitro IgE testing and protocols for incremental dosing of the second (booster) injection in a subset of patients who may be at greater risk for anaphylaxis may become available. To further enhance safety in patients who experienced a severe allergic reaction after the primary vaccination, desensitization protocols with individual vaccine components can be envisaged. Molecular diagnostics may also be useful to develop a personalized approach to determine which vaccine platform is the most suitable one for an at‐risk patient (Box 2). ³⁵

2.3. Research needs

In addition to the urgent clinical needs in diagnosing and treating patients who have suffered severe allergic reactions after vaccination, multiple other research challenges and questions remain open (Box 3). To address these unmet needs, EAACI provides a concerted roadmap towards precision diagnosis and treatment of severe allergic reactions after COVID‐19 vaccination that includes besides clinical and scientific aspects, big‐data management, and legal, ethical and regulatory aspects (Figure 2). Data sets of state‐of‐the‐art multilayer omics approach (eg proteomics, single‐cell RNAseq transcriptomics, CyTOF mass cytometry of immune cells) from existing well characterized population cohorts can be combined with the ongoing vaccination campaign efforts in various countries. Such a multi‐layered approach promises to solve the unmet needs for the following reasons: 1) to analyse protective immune profiles to COVID‐19 vaccination; 2) to compare the individual COVID‐19 vaccination outcome with existing immune profiling data (eg SARS‐CoV‐2 serology, cellular immune responses to SARS‐CoV‐2); and 3) to combine clinical and research data with computational and big‐data approaches which guarantee rapid progress.

As the novel COVID‐19 vaccines are administered to millions of people over the next months and in the upcoming years, more data will become available to assess the incidence of hypersensitivity reactions and determine specific risk factors. As pharmacovigilance data are accumulated and analysed over the upcoming months, EAACI will revise and update these recommendations on the EAACI website. The current EAACI recommendations specifically target only those vaccines that have received conditional marketing authorization by EMA in the EU, and emergency use authorization by the FDA in the US and by MHRA in the UK.