Prevalence of Allergic Reactions After Pfizer-BioNTech COVID-19 Vaccination Among Adults With High Allergy Risk

IMPORTANCE Allergic reactions among some individuals who received the Pfizer-BioNTech (BNT162b2) COVID-19 vaccine discourage patients with allergic conditions from receiving this vaccine and physicians from recommending the vaccine. OBJECTIVE To describe the assessment and immunization of highly allergic individuals with the BNT162b2 vaccine. DESIGN, SETTING, AND PARTICIPANTS In a prospective cohort study from December 27, 2020, to February 22, 2021, 8102 patients with allergies who applied to the COVID 19 vaccine referral center at the Sheba Medical Center underwent risk assessment using an algorithm that included a detailed questionnaire. High-risk patients (n = 429) were considered “highly allergic” and were immunized under medical supervision. EXPOSURES Pfizer-BioNTech (BNT162b2) COVID-19 vaccine. OUTCOMES MEASURES Allergic and anaphylactic reactions first second doses BNT162b2 among referral highly allergic, highly


Introduction
The COVID-19 pandemic has medical, economic, and many other global consequences. Immunization of most of the population seems to be the main tool to prevent morbidity and mortality and to facilitate a return to normalcy. In December 2020, the US Food and Drug Administration (FDA) issued an Emergency Use Authorization for the Pfizer-BioNTech (BNT162b2) COVID-19 vaccine and the Moderna COVID-19 vaccine (mRNA-1273), each administered as 2 doses separated by 21 and 28 days, respectively. 1,2 Both vaccines are composed of a nanoparticle-encapsulated lipid, nucleosidemodified messenger RNA (mRNA) that encodes the SARS-CoV-2 spike glycoprotein. Both vaccines were found to be approximately 95% effective in preventing COVID-19. Adverse events included mostly pain at the injection site, fatigue, and headache. 3,4 Nonetheless, several obstacles have occurred on the path of this global immunization program, one of which is the risk of allergic reactions to these vaccines. [5][6][7] In the clinical trials of the BNT162b2 and Moderna COVID-19 vaccines, participants with a history of an allergic reaction to any component of the vaccine or an allergy to other vaccines were excluded. Furthermore, in the BNT162b2 studies, individuals with other allergies were also excluded from participating. 3,8 After the FDA Emergency Use Authorization the BNT162b2 and Moderna COVID-19 vaccines for immunization of the general population, anaphylaxis, a severe, rapid-onset multisystem allergic reaction, was reported in 11.1 cases per 1 million injections with the BNT162b2 vaccine. 5,9 This resulted in an estimated higher risk of anaphylaxis with the BNT162b2 vaccine of up to 10-fold compared with commonly used vaccines. 10 Since these early estimates were generated, millions more doses of the COVID-19 vaccines were administered, with an updated reported anaphylaxis rate of 4.7 cases per 1 million doses. 7 Of note, 90% of anaphylactic reactions were among females and 81% reported prior allergies. Although the allergen within the vaccine is yet to be determined, it has been suggested that the polyethylene glycol (PEG) used to construct the nanoparticle-encapsulated lipid of this vaccine is a possible candidate. 10 The increasing concerns among patients and physicians about allergic reactions to the COVID-19 vaccines led the Centers for Disease Control and Prevention (CDC) and other authorities to publish different recommendations regarding the safety of these vaccines for patients with a history of allergic reactions. 11 Despite these recommendations, uncertainty remains, particularly among patients with a history of anaphylaxis and/or multiple allergies.
Israel was among the first countries to implement a national COVID-19 immunization program using the BNT162b2 vaccine, beginning December 19, 2020. At the same time, Sheba Medical Center in Ramat Gan, Israel, began receiving thousands of medical requests regarding vaccine safety. Moreover, many individuals had their vaccination deferred by their physicians and/or immunization teams because of "allergic concerns." Hence, a referral center was opened in the Sheba Medical Center to provide information and rapid assessment of risk of allergy to the BNT162b2 vaccine. We further offered an alternative for vaccination of high-risk individuals under special observation, with the aim to enable immunization for all. In this study, we describe our experience in the assessment and immunization of highly allergic individuals, as well as the rate of adverse reactions to the BNT162b2 vaccine in this population.

Methods
The COVID-19 vaccine referral center was created in Sheba Medical Center primarily as an information center for vaccine recipients and health care workers. In the vaccine center, a team of trained personnel from the infectious diseases unit and the infection prevention and control unit received applications for vaccination by phone or email. Among their assignments was to define patients as low risk vs high risk for allergies or with contraindication to be immunized according to the Israel Ministry of Health (MOH) and the CDC. 11,12 Patients could approach the center on their own behalf or via request of their general practitioner (GP). This cohort study followed the Strengthening JAMA Network Open | Allergy the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline for observational studies 13 and was performed in accordance with the Declaration of Helsinki 14 and in agreement with the institutional regulations and approval of the Sheba Medical Center institutional review board. Patient consent was waived as the data were deidentified.
Patients at low risk of allergic reactions included those with a history of sensitivity to aeroallergens or insect bite (including patients receiving immunotherapy for these allergens), food, latex, or contrast media or prior nonanaphylactic reaction to a single drug group or those who had chronic urticaria. Patients receiving immunotherapy or biologic therapy were instructed to delay that treatment for at least 1 week after immunization with the BNT162b2 vaccine. Patients at low risk of allergic reactions were recommended to be immunized in regular settings, with 30 minutes of observation after immunization. Patients and their GPs were instructed to inform our referral center of anaphylaxis or any adverse reaction to the vaccine. Moreover, any significant allergic reaction required notification to the MOH in Israel.
Patients who were not clearly at low risk of allergic reactions were instructed to complete a detailed questionnaire and were referred for further assessment at the clinical immunology and allergy department. The questionnaire included 5 questions about: (1) prior allergic or anaphylactic reactions to 1 or more oral or injectable drugs or vaccines, (2) other allergies (eg, insect bites, food, inhaled allergens, or asthma), (3) treatments used during prior allergic reactions (ie, antihistamines and/or glucocorticoids and/or adrenaline, or hospitalization), (4) current use of drugs (ie, adrenaline syringe carriage and/or antihistamine and/or asthma therapy used regularly), and (5) other immune comorbidities (eg, chronic urticaria, mast cell disorders).
Multiple drug allergy was identified if hypersensitivity to more than 1 drug group was reported (eg, penicillin and nonsteroidal anti-inflammatory drugs). Specifically, respiratory disease exacerbated by nonsteroidal anti-inflammatory drugs and aspirin was considered hypersensitivity to a single drug group. Multiple allergies were noted if patients had 2 or more of the following: (1) drug allergy regardless of the number of compounds, (2) insect sting allergy, (3) food allergy, and (4) allergic rhinitis and/or asthma.
Patients were considered to be at high risk for allergic reactions if one of the following was present: (1) prior anaphylactic reaction to any drug or vaccine, (2) multiple drug allergies, (3) multiple allergies, or (4) mast cell disorders, as were patients who were deferred by their GP or local allergist or the immunization team from vaccination in the regular setting because of concerns about allergic reactions. This high-risk group was referred to be immunized with 2 hours of observation by a dedicated allergy team after vaccination. Premedication was not recommended prior to receiving the first dose of the vaccine unless patients were regularly treated with these drugs (eg, antihistamines); in that case, they were instructed to continue their therapy. Patients with an allergy to PEG and/or 2 or more injectable drugs were rejected from vaccination according to the Israeli MOH recommendations at that time. 12 The second dose of the vaccine was provided in the same setting, and patients were asked to complete an adverse reactions form regarding the 21 days since receiving the first dose of the vaccine. Early adverse reactions were defined as those that occurred within minutes to 2 hours after vaccination and resolved within 24 hours, while late reactions were defined as those that lasted for more than 24 hours. Data were compared between younger recipients (aged 16-55 years) and older vaccine recipients (aged >55 years).
Statistical analysis was performed using SPSS statistics software for Windows, version 27 (IBM Corp). The Fisher exact test and/or χ 2 tests were used as appropriate. All P values were from 2-sided tests and results were deemed statistically significant at P < .05. recommended to receive immunization in the regular settings. The other 1219 individuals (15.0%) were required to complete a questionnaire and were referred for assessment by the clinical immunology and allergy team. After physician assessment of all questionnaires, an additional 785 individuals were defined as being at low risk and were referred to receive immunization in the regular settings. No serious allergic reactions were reported back to our referral center by patients or their GP after immunization in the regular settings.
Five patients (0.1%) were found to be ineligible for immunization by the clinical and immunology team according to the Israeli MOH instructions (2 patients owing to known sensitivity to PEG and 3 patients with multiple anaphylactic reactions to different injectable drugs). A relatively small group of 429 patients (5.3%) (304 women) were defined as highly allergic and recommended to receive immunization under special observation (Figure 1 and Table). Of these 429 patients, 304 (70.9%) were women, and they had a mean (SD) age of 52 (16)

Late Adverse Events After the First Dose of Vaccine
Local and systemic adverse events, either allergic or nonallergic, were documented prior to the second dose of immunization (ie, Յ21 days after the first dose) (Figure 2

Discussion
A nationwide immunization rollout with the BNT162b2 vaccine was initiated in Israel in December 2020. As of March 4, 2021, 4 847 286 people had received the first dose, and more than 3.5 million of these people had received 2 doses of the BNT162b2 vaccine. 15 Concerns regarding safety and, particularly, severe allergic reactions to this vaccine are a significant obstacle to implementation of this large immunization program. To our knowledge, this is the first study to report on a special immunization program with the BNT162b2 vaccine for highly allergic patients. In this study, we created an algorithm for rapid screening of individuals who were potentially at risk of immediate allergic reaction to the BNT162b2 vaccine. This simple method can be easily implemented in any country and allowed 95% of applicants to be immunized in the regular settings in Israel.
In our cohort, 429 patients (5.3%) were defined as being at high risk for an allergic reaction and were referred to receive immunization under medical observation. In this group, the mean age was 52 years, similar to the cohort in the Pfizer-BioNTech phase 3 clinical trial. 3 The Pfizer-BioNTech phase 3 trial comprised 49.4% women, whereas our cohort included 70.9% women. This finding could be expected, as the overall trend of allergic diseases, and particularly drug allergies, are seen more often in women than men. 16,17 Among our highly allergic adult patients, few risk factors may be suggested: history of multiple drug allergies, drug-related anaphylaxis, and/or multiple allergies. In our cohort, food allergy was reported by 68 patients (15.9%) and multiple drug allergies by were reported by 141 patients (32.9%), whereas in the general adult population less than 5% has a food allergy 18 and less than 1% has severe or multiple drug allergies. 19 Moreover, 95 patients (22.1%) in our cohort reported carrying an adrenaline syringe, which may explain why some were deferred by their GP or the immunization teams from vaccination in regular settings.
In this study, we vaccinated this highly allergic group in a special setting that provided reassurance to both patients and physicians and enabled immunization. Nonetheless, in this high-risk group, 2% of patients experienced an allergic reaction either to the first or second dose of the vaccine, of which 3 reactions (0.7%) were anaphylaxis to the first dose. Allergic reactions to vaccines are either acute or late in onset. 20 Acute-onset reactions are mediated by preformed IgE antibodies against a vaccine component or via other mechanisms that induce immediate mast cell activation.
These reactions occur within minutes to several hours after vaccination. 21 Vaccine-associated anaphylaxis is rare, with an estimated incidence of 1 reaction per 1 million injections for most known vaccines. 22 This rate was reported to be higher for the BNT162b2 vaccine in the CDC's reports, Furthermore, most high-risk patients who did not experience any adverse events from the first dose also did not exhibit a reaction to the second dose. This finding may suggest that a shortened observation period may be sufficient after the second dose of the vaccine for patients who did not experience a reaction to the first dose. Late adverse events in our cohort were relatively comparable with those previously reported (except for skin eruption and itching, which were present in 15% of this group of allergic patients and not otherwise reported).

Limitations
Our study has several limitations. The history of allergic reactions was provided by patients' reports and medical records, many of which were evaluated by allergists through the years. However, no assessment was performed prior to vaccination. In addition, it would have been useful to assess the time since the last allergic reaction or when adrenaline was last used. However, in a real-life setting, based on patient's recall, these data may be biased and therefore were not included in our analysis.
Data on most patients who were immunized in regular settings can only be estimated, as those patients were not actively followed up. Nonetheless, to our knowledge, among the group of patients defined as being at low risk, no severe allergic reactions were reported to our center or to the MOH in Israel. Although few low-risk patients reported minimal reactions, this lower rate could not be ascertained and thus was not included in our analysis. Owing to the relatively small number of total allergic reactions in our study, we could not assess links between factors that defined the entire highly allergic group and the actual reaction to the vaccine. More studies are needed to define the Statistically significant differences between the 2 age groups were found for pain at injection site (P < .001) and swelling (P = .02). Local reactions were pain at injection site and swelling; the rest are systemic reactions.