During the COVID-19 pandemic, following the FDA approval for COVID-19 vaccines and the USA Centres for Disease Control and Prevention (CDC) recommendations for vaccination, concerns about allergic reactions and vaccine safety have emerged among patients with pre-existing allergic conditions in the Middle East and worldwide, as well as concerns from other side effects (1). Allergic reactions to vaccines can be triggered by the vaccine, adjuvants, or excipients (2).

The incidence of severe allergic reactions secondary to the COVID-19 vaccines was low but somewhat higher than other vaccines. Reported reactions included anaphylaxis, acute urticaria, cutaneous, and delayed hypersensitivity reactions (3). The estimated incidence of anaphylaxis was approximately five cases per million doses of mRNA COVID-19 vaccines administered (2). Although reports were scarce in the Middle East, the incidence of allergic reactions secondary to the COVID-19 vaccine was low; symptoms ranged from skin rash to severe allergic reactions (4–7).

The exact mechanisms underlying these allergic responses and the role of allergy testing in managing such reactions are not yet fully understood. Excipients within the vaccine, such as polyethene glycol (PEG) and polysorbate 80, are suspected of playing a significant role in developing these reactions (8, 9).

PEG and polysorbate 80 are present in various medications and vaccines and have been associated with different types of allergic reactions, including anaphylaxis (10–12). In 2022, the ENDA/EAACI Position paper on COVID-19 vaccine allergy provided guidelines to help clinicians manage and offer safe recommendations to the public. The guideline recommended comprehensive clinical evaluation and allergy testing for patients with a history of immediate allergic reaction or anaphylaxis following COVID-19 vaccination, those with known allergies to vaccine components, and individuals with a history of recurrent drug-induced anaphylaxis. The recommended allergy testing includes skin prick tests (SPT), intradermal tests (ID), and patch tests for COVID-19 vaccine excipients, the vaccine itself, and potentially relevant allergens like latex and chlorhexidine (8). However, later, in 2023, an international consensus approach for evaluating and managing allergic reactions secondary to COVID-19 vaccines was published. The consensus recommended against allergy testing with the COVID-19 vaccine or its excipients to patients with or without a history of allergic reaction to the first dose of the vaccine (13). The USA CDC is still advising pre-vaccination screening to identify contraindications or a precaution to the immunisation and recommended consultation with an allergist when necessary (14).

There were several publications from different parts of the world about the allergic reactions to the COVID-19 vaccine, and researchers described their allergy evaluation approach (Supplementary Table E1), but, to our knowledge, no reports from the GULF region about this subject.

This report describes the frequency and type of allergic reactions following the mRNA COVID-19 vaccination, and it evaluates the use of allergy testing for PEG and polysorbate 80 excipients among patients who attended the adult allergy clinic at Hamad Medical Corporation (HMC), Doha, Qatar. Additionally, it offers valuable insights for healthcare providers to identify and manage potential allergic reactions, ultimately contributing to safer vaccination practices and reducing public concerns about vaccine safety.

This is a retrospective study that focused on patients who reported allergic reactions following COVID-19 vaccination at the adult Allergy and Immunology Division at HMC in Doha, Qatar, between April 2021 and August 2022 (population). These patients underwent supervised allergy skin testing for COVID-19 vaccine excipients (intervention). As this was a descriptive study, there was no comparison group. The outcome was the result of allergy testing and subsequent recommendations for future vaccinations.

Data collected included demographics, allergic comorbidities, allergic symptoms secondary to the mRNA COVID-19 vaccine, skin testing results, recommendations for further vaccinations, and the tolerability of subsequent COVID-19 vaccine doses in high-risk patients. The study received local ethical approval (MRC-04-24-589).

A total of 88 patients underwent skin prick testing (SPT) and intradermal (ID) testing for COVID-19 vaccine excipients during the study period. Thirty-eight patients with a documented history of allergic reactions to mRNA COVID-19 vaccines met the inclusion criteria and were included in the final analysis. All patients completed both SPT and ID testing. The study flowchart is outlined in Figure 1.

The reported allergic reactions, including severe cases, following the COVID-19 vaccination during the pandemic significantly contributed to vaccination hesitancy worldwide (17). The need for booster doses of the COVID-19 vaccine (14) prompted the development of a strategy to identify patients who can safely receive additional vaccinations and those who should avoid them despite the paucity of data on the outcome and validity of allergy testing. On the other hand, allergy consultation, with or without allergy testing, has helped to assure patients and reduce vaccination fear (18).

In addition, Banjri et al. proposed an algorithm to risk stratify patients based on their clinical history and allergist evaluation for the possibility of allergy testing (19). Therefore, utilizing available resources was crucial to address vaccine hesitancy during the pandemic.

Previous reports have shown that women are more likely than men to report adverse events following COVID-19 vaccination, with younger individuals experiencing a higher frequency of these reactions. At the same time, older adults are at greater risk for severe side effects (20). Our findings align with this, as most of our study population consisted of middle-aged females.

It has been proposed that individuals with food and drug allergies, along with a history of anaphylaxis, may have an elevated risk of developing cutaneous reactions to the COVID-19 vaccine; however, most of these reactions are generally mild (21). Our study observed a high prevalence of allergic comorbidities among our cohort, particularly food and drug allergies Furthermore, the majority of reported reactions in our cohort were mild.

Few studies have explored the procedure and outcome of allergy testing in individuals with a history of allergic reactions to COVID-19 vaccines or other allergic disorders from different populations (Supplementary Table E1). However, there were few reports from the Middle East and, to our knowledge, no reports from the Gulf region. Some researchers have also used COVID-19 vaccines for allergy testing. Most of the studies in Supplementary Table E1 concluded that the allergy skin testing for PEG and polysorbate 80 with or without the COVID-19 vaccine has limited predictive value in predicting tolerance to the second dose.

Few have concluded that the overall positivity rate of allergy skin testing has been low, but using the vaccine as part of the testing process may enhance sensitivity (22–24).

A 2023 systematic review and meta-analysis by Greenhawt, M. et al. analyzed 20 studies on skin testing (SPT) for BNT162b2, mRNA-1273, PEG, and Polysorbate 80. A total of 317 individuals underwent 578 skin tests. The overall sensitivity for predicting allergic reactions was 0.03 (95% CrI 0.01–0.08), with a specificity of 0.98 (95% CrI 0.95–1.00). Sensitivity for SPT with the mRNA vaccines was 0.2 (95% CrI 0.01–0.52) and specificity 0.97 (95% CrI 0.9–1). Sensitivity for PEG and Polysorbate 80 was lower, at 0.02 (95% CrI 0.00–0.07) and 0.03 (95% CrI 0.00–0.11), respectively, with specificity of 0.99 (95% CrI 0.96–1) for PEG and 0.97 (95% CrI 0.91–1) for Polysorbate 80 (25).

Due to limited resources and vaccine shortages during the early stages of the pandemic, our testing strategy focused on vaccine excipients rather than the vaccine itself. This approach was both resource-efficient and practical for addressing the challenges of that time. Also, to avoid false positive tests that were reported before with some medications due to local irritation effect (26), we performed the test on two healthy controls for each positive test. We calculated a negative predictive value of 71.4%, indicating that most patients with negative test results could safely receive the vaccine. However, this moderate predictive value highlights the need to remain cautious, as some risk of adverse reactions still exists.

Furthermore, the same meta-analysis reviewed three reports, revealing that most second-dose reactions occurred in non-sensitized individuals. Only a few patients had positive skin tests, with three reacting to the vaccine, one to PEG, and none to polysorbate 80. Among the six severe reactions following the second dose of an mRNA vaccine, four occurred in patients with no prior sensitisation to the vaccine or its excipients. The overall sensitivity of skin testing was notably low, identifying only around 3% of individuals who experienced immediate allergic reactions upon revaccination with the vaccine, PEG, or polysorbate 80 (25).

In our cohort study, 21.1% of the patients tested positive for vaccine excipients, and seven were advised to avoid further vaccination. However, one patient with mild initial symptoms could safely receive another dose of the same vaccine (Moderna) without complications despite having positive allergy ID testing for polysorbate 80 (Triamcinolone Acetonide). Of the 30 patients who tested negative, 10 (33.3%) patients only proceeded with further vaccinations. Seven (70%) received the same vaccine, while three patients opted for an alternative vaccine. Among these ten patients, three (30%) experienced a recurrence of the previous reaction (one developed anaphylaxis, and two had acute urticaria) and were advised against further doses, while the remaining patients reported no further reactions. No pre-medications or graded vaccine dosing were used for the subsequent vaccine doses. The remaining 20 patients who tested negative chose to abstain from receiving additional vaccine doses.

Interestingly, 50% of patients who reported anaphylaxis after receiving the first mRNA COVID-19 vaccine had positive test results, indicating that allergy testing might help to identify potential risks in patients with a history of immediate IgE-mediated reactions. However, the 50% rate also suggests that further studies are needed to refine these tests' predictive value and identify additional factors contributing to vaccine-related allergic reactions. Additionally, we could not revaccinate patients with positive test results due to safety and ethical considerations, limiting our ability to assess the test's positive predictive value.

Since August 2022, we have stopped performing allergy skin testing for the COVID-19 vaccine excipients. After allergy consultation, anxious patients or patients suspected to have an allergy to PEG or polysorbate 80 were referred to administer the vaccine under supervision at the HMC Center of Communicable Disease (i.e., in a hospital setting) or advised to receive a vaccine not containing PEG or polysorbate 80 based on availability and clinical suspicion.

To our knowledge, this is the first study from the Gulf region to report the frequency and type of allergic reactions to the COVID-19 vaccine and the use of COVID-19 vaccine excipients allergy testing. A limitation of this study was its retrospective nature, and the testing did not include the COVID-19 vaccine itself due to limited accessibility and resources of the COVID-19 vaccine during the pandemic. Another limitation was a possible underestimation of patients tolerating further vaccinations because most patients with negative allergy testing refused to receive further vaccine doses.

Most allergic reactions secondary to the mRNA COVID-19 vaccine reported in Qatar were mild. During the pandemic, a specific management protocol for patients with a history of allergic reactions to the COVID-19 vaccine was required to assure the public and reduce vaccine hesitancy. Our test showed a low positivity rate. Based on current evidence, we acknowledge that routine skin testing with PEG or polysorbate 80 may not help predict or risk-stratify patients for COVID-19 vaccination decisions. Further research is needed to explore and understand the exact mechanism of COVID-19 vaccine allergic reactions, hence developing an accurate allergy testing protocol.