Protocol of safe vaccination against COVID‐19 in patients with high risk of allergic reactions

Abstract Background Sars‐CoV‐2 infections are hazardous, especially to the elderly and patients with comorbidities. With no efficient treatment available, newly developed vaccines are the only way to change the course of the pandemic. However, reports of allergic reactions resulted in some patients and practicing physicians being concerned about the safety of vaccine administration, particularly in people with severe anaphylactic reactions to multiple or unknown factors in their medical history. This study aimed to develop an allergic work‐up protocol based on skin prick tests (SPT), intradermal testing (IDT) and intramuscular provocations, and desensitisation which may contribute to diagnosis and management of anti‐COVID‐19 vaccine allergy. Methods Two hundred and eighty‐five patients were enrolled. Two hundred and five of them entered the study based on severe anaphylactic reaction to unknown or multiple factors in their medical history which disqualified them for standard treatment. Another 80 patients were enrolled after developing an allergic reaction to the first dose of one such vaccine. In all subjects, SPT and IDT were performed. Serum tryptase was assessed in 79 patients randomly chosen from the study group. Results Two hundred and seventy‐seven patients with negative tests were given a vaccine without complications. Seven patients had positive skin tests. In two cases, tests confirmed Comirnaty allergy, while the other five confirmed solely skin sensitisation with no exposure prior to the study. Six patients with positive tests received titrated challenge using desensitisation protocol with a reasonable tolerance. One patient did not consent to desensitisation and one patient resigned despite negative tests. Overall, 283 (99%) patients were vaccinated using this newly developed protocol. Patients with adverse reactions to the first dose of the vaccine before the study had a significantly lower basal serum tryptase concentration (p = 0.001). Conclusion Skin tests with anti‐COVID‐19 vaccines are a useful tool in the vaccination protocol. This protocol enables safe immunisation of high‐allergy‐risk patients even in cases of positive skin tests.

before the study had a significantly lower basal serum tryptase concentration (p = 0.001).
Conclusion: Skin tests with anti-COVID-19 vaccines are a useful tool in the vaccination protocol. This protocol enables safe immunisation of high-allergy-risk patients even in cases of positive skin tests. Kingdom, two reports of severe allergic reactions that required epinephrine treatment were published. 6 Shortly after that, the Centers for Disease Control and Prevention (CDC) in the United States advised that all patients should be observed for 15 min after Sars-CoV-2 vaccination and that vaccination staff must be trained to manage anaphylaxis. 7 The CDC provided further recommendations 'that persons who have had an immediate allergic reaction of any severity to any vaccine or injectable therapy (intramuscular, intravenous, or subcutaneous) should discuss the risk of receiving the vaccine with their doctors and be monitored for 30 min afterwards'.
In addition, patients who have an immediate (within 4 h) or severe allergic reaction to an mRNA Sars-CoV-2 vaccine should not receive a second dose. 8 Similar precautions were taken with every authorised vaccine. This approach was met with reluctance in societies, especially after a few descriptions of severe post-vaccination allergic and adverse reactions. [9][10][11] Given the importance of the vaccination programmes in fighting the pandemic, understanding the allergic reactions and developing proper protocols for all allergic patients is crucial to balance a high vaccination rate with safety.
The most widely used approach to allergy work-up protocols was to perform polyethylene glycol (PEG) or polysorbate skin testing, which are considered to be the most allergenic exipients of anti-COVID-19 vaccines. 12,13 Skin prick tests (SPT), intradermal tests (IDT) and to some extend basophil-oriented in vitro tests were found reliable in detecting PEG and polysorbate allergy. [14][15][16] However, less data is available on IDT, and some suggest false positive results. 17 Both SPT and IDT may also become negative over time, especially when the patient is not exposed to the particular excipient frequently. 14,16 Also, some studies suggest that even PEG-allergenic patients can safely receive anti-COVID-19 vaccines containing PEG. 15   All patients were evaluated medically, including severe COVID-19 risk factors (at least one of the following: age>59, hypertension, coronary heart disease, diabetes, obesity, active neoplastic disease). 22 Additionally, in a randomly chosen subgroup of 79 participants, the basal serum tryptase concentration was analysed.
SPT and IDT were performed with the chosen vaccine in every patient according to Nilsson et al. 18 For the SPT, the undiluted vaccine was used, and the positive criterion was set at 3 mm. The concentrations for IDT were 1:100 and 1:10 consecutively (volume 0.02 ml), and the positive criterion was an increase of the primary wheal by 3 mm. All tests were read after 15 min.
In the case of negative tests, the previously chosen vaccine was   Figure 2).
The choice of the vaccine was made according to Figure 1.
However, in 28 cases despite the reaction after the first dose, the decision was made to continue with the same vaccine administration as the allergology specialist evaluated that the initial reaction did not include shock and the patient's decision was to continue with the same regimen.
In 278 patients, skin tests were negative. One of these patients withdrew consent for vaccination. In seven patients, skin tests were positive (Table 2) Food allergy showed a significant difference in these groups in the U Mann-Whitney test (p = 0.016).
Each patient with a positive test was offered to undergo titrated challenge with the anti-COVID-19 vaccine. One of them did not consent. In six cases, the procedure was performed. After completing the desensitisation, one of those patients received the same vaccine as initially, confirming that desensitisation functions in anti-COVID-19 vaccine allergy. In five cases, no adverse effects were observed,

F I G U R E 2
Comparison of basal serum tryptase concentration in patients' reaction after the first dose of a vaccine and those enrolled based on anaphylaxis history. X mean, -median; □ max; □ min; box quartile 25%-75%; □ outlier values. Five patients with tryptase above 20 ng/ml had mastocytosis diagnosed and in two cases mild adverse reaction (transient dyspnea with no impact on vital signs or physical examination) was noted that resolved quickly and did not require any treatment or hospitalisation (Table 2 and Figure 3).
Eventually, 283 people were vaccinated. In this group, 144 (50%) patients had risk factors for comorbidities of severe COVID-19, however, the management according to protocol enabled safe vaccination of all of those who had given informed consent. The results of the allergy work-up protocol and the outcome of the study for all patients is presented in Figure 3.
In the control group, SPT and IDT were performed with Comirnaty and Janssen. All results were negative and no skin irritation was observed.

| DISCUSSION
The main finding in our study was to establish a safe anti-COVID-19 vaccination protocol in the high-risk population of patients with prior anaphylactic reactions and with adverse reactions after the first dose of anti-COVID-19 vaccines. This is in line with the clinical trials of Comirnaty®, Spikevax®, Vaxzevria® and COVID-19 Janssen®. [2][3][4][5] According to the available data from the clinical trials, hypersensitivity or allergy to these vaccines is extremely rare-for Comirnaty® was assessed as 0.6%, for Spikevax ®-1.5%, for Vaxzevria® and COVID-19 Janssen®-<0.1%. [2][3][4][5] The numbers differ mostly due to the different reporting methodologies between the trials and in most cases were similar to the placebo. Although these rates are small compared to most allergenic drug groups such as penicillins, they are still notably higher than other vaccines introduced much earlier such as anti-Influenza or anti-Hepatitis B, as shown by Nilsson et al. 18 We are aware that this might be due to the different methodologies in these studies.
Real-life survey studies show that allergic reactions are reported four times more frequently by people with allergy histories (0.2%). 23 However, according to our experience, many patients consider common side effects to be an allergic reaction, 24,25 and it is difficult to distinguish those especially if no documentation is available.
Patients who have a history of anaphylactic reactions frequently present increased anxiety on receiving any drug. 26 34 However, it must be noted that ECNM did not take into account vaccines. These are extremely difficult to evaluate in such a registry due to the low vaccine allergy rate and rare administration.
Nevertheless, the possibility of a relationship between low tryptase level and increased reaction to an anti-COVID-19 vaccine should be considered a risk factor in future trials.
Although our study shows a relationship between skin sensitisation and food allergy, the group with positive tests is still relatively small. Furthermore, a logistic regression model did not reveal any significant correlation that would predict positive skin tests. Larger groups are required to investigate this.