COVID-19 vaccine provocation test outcome in high-risk allergic patients: A retrospective study from a tertiary hospital in Indonesia

Abstract

Background

High COVID-19 vaccine coverage is essential. Patients who are considered high risk for hypersensitivity reactions and have had an allergic reaction to the COVID-19 vaccine are usually referred to an allergist for assessment of vaccination. Administration of a vaccine graded challenge (also known as a provocation test) is an option that can be considered in this population. This primary objective of this study is to describe the outcome of the COVID-19 vaccine provocation test and to understand the predicting factors associated with hypersensitivity reaction after the provocation test as the secondary objective.

Methods

Adult patients with a history of hypersensitivity reaction to the first COVID-19 vaccine and high-allergic patients who underwent COVID-19 vaccine provocation test up until May 2022 were included. A protocol using skin prick test (SPT), intradermal test (IDT), followed by graded challenge was developed for the determined vaccine used.

Results

A total of 232 patients were included in the analysis. Twenty-eight had hypersensitivity to their first COVID-19 vaccine dose and 204 were high risk for allergic reaction. Hypersensitivity reactions occurred in 20 patients (8.6%, 95% CI: 5–12.2%), consisting of 4 reactions after SPT, 9 after IDT, 7 during or after titrated challenge. Half of the reactions were mild; however, 3 patients developed severe reactions. Patients with history of anaphylaxis were more likely to experience hypersensitivity reaction after provocation test (aRR = 2.79, 95% CI: 1.05–7.42).

Conclusion

Provocation test in COVID-19 vaccination has a high success rate in patients with a history of hypersensitivity to the first COVID-19 vaccine and in high allergic patients. History of anaphylaxis is associated with hypersensitivity reaction after a COVID-19 vaccine provocation test.

Introduction

Drug allergy is an unpredictable adverse drug reaction (ADR) covering the spectrum of immunologically mediated hypersensitivity reactions with various mechanisms and clinical presentations. Drug allergy accounts for approximately 5–10% of all ADRs.¹ Similar to drugs, vaccines also have the potential to cause allergic reactions. Allergy to vaccines, particularly to individual components of vaccines, is rarely known to cause serious complications. Even after an allergic reaction to vaccination, it is difficult to determine whether the allergic reaction was caused by that vaccine alone or other factors.²

During the coronavirus disease (COVID-19) pandemic, vaccination has been required to prevent the further spread of COVID-19, especially among people at higher risk of severe disease. Allergic reactions to COVID-19 vaccines vary from mild to severe, with the most common symptoms being urticaria, itching, redness of the skin, general discomfort, angioedema, shortness of breath, burning sensation, and fainting.³ The pooled prevalence of cutaneous adverse events (AE) after a COVID-19 vaccine dose is 3.8% (95% CI, 2.7%–5.3%).⁴ Estimated immediate hypersensitivity reactions to vaccines range from 1 in 50 000 to 1 in 1 000 000 doses. The most worrying allergic reaction, anaphylaxis, is estimated at 1 to 10 per 1 000 000 doses for most administered vaccines.^5,6 According to the Vaccine Adverse Event Reporting System and V-safe voluntary reporting data in the Center for Disease Control and Prevention (CDC), the rate of anaphylaxis after receiving an mRNA-based COVID-19 vaccine is 4.5 cases per million administered doses, with 89% occurring within an observation period of 15–30 min.^7,8 This is comparable to the rate of anaphylaxis with other vaccines, including inactivated influenza vaccine (1.4 per million), pneumococcal polysaccharide (2.5 per million), and live attenuated herpes zoster vaccine (9.6 per million).⁷ A recent meta-analysis showed that the prevalence of anaphylaxis as a reaction to COVID-19 vaccination is 0.05%.⁴

The mechanism of the observed anaphylactic events has yet to be established and it is necessary to consider an IgE-mediated route. Polyethylene glycol (PEG) in Pfizer and Moderna, polysorbate 80 in AstraZeneca, and aluminium hydroxide in Sinovac have been identified as the likely culprits, and their role in causing IgE-mediated anaphylaxis is well documented.9, 10, 11 In this manuscript, the term allergic or hypersensitivity reactions refers to the symptoms or reactions caused by the vaccine which are likely, but not confirmed, to be caused by IgE-mediated reactions.

It is generally accepted that patients with a suspected or confirmed allergic reaction to the SARS-CoV-2 vaccine or vaccine excipient be referred to an allergist-immunologist for risk-benefit assessment of vaccination. However, there is no specific explanation on how the allergist-immunologist should evaluate these high-risk patients. Administration of a graded challenge (also known as a vaccine provocation test) is an option that can be considered for patients with a history of severe allergies.¹² The test is given by administering the vaccine gradually, which is expected to reduce the risk of an allergic reaction to vaccination.¹³ However, data on COVID-19 vaccine provocation test is still scanty. The American College of Allergy, Asthma, and Immunology (ACAAI) COVID-19 Task Force has mentioned, but not endorsed, the consideration of graded vaccine challenges in certain individuals. Previous publications stated that graded challenge is both safe and convenient. However, further studies need to be done to assess the necessity of this method.14, 15, 16, 17, 18 This study aims to investigate the outcome of the COVID-19 vaccine provocation test in patients with a history of allergy to COVID-19 vaccine and high-risk allergic patients. Another objective of this study is to understand the predicting factors associated with hypersensitivity reaction after the provocation test.

Methods

Study population

This retrospective cohort study included all adult patients (18 years old and above) who underwent a COVID-19 vaccine provocation test up until May 2022 in a tertiary hospital in Indonesia. The vaccine provocation tests were done by trained allergists. The participants were patients that had been referred from other health facilities due to a history of COVID-19 vaccine allergy or high-risk allergic patients. The participants were divided into 2 groups: (1) patients with a history of hypersensitivity to the first COVID-19 vaccine dose; and (2) patients with a high risk of allergic reaction, including atopic, allergy, or anaphylaxis history.

Data collection

Data were collected from medical records, including age, gender, body mass index (BMI), atopic history (allergic rhinitis, atopic dermatitis, urticaria, asthma), known allergies (food allergy, drug allergy — multiple or single class of drugs), non-COVID-19 vaccine allergy, comorbidities (hypertension, diabetes mellitus, heart disease, autoimmune disease), and past allergic reaction (history of anaphylaxis, history of Stevens-Johnson syndrome [SJS]/toxic epidermal necrolysis [TEN]). Age was divided into 2 groups, less than 60 years old and more than or equal to 60 years old, with consideration of the risk of higher severity of COVID-19 in the latter group.¹⁹ The BMI category for obesity was defined as a BMI of 25 kg/m² or higher.²⁰ The outcome of COVID-19 vaccine provocation test was divided into 3 groups, namely: mild reaction (local reaction, such as redness, swelling, or pruritus), moderate reaction (skin and mucosal involvement, such as urticaria, angioedema, flush, or/and gastrointestinal involvement, such as abdominal pain, vomiting, diarrhea), and severe reaction/anaphylaxis (respiratory involvement, such as dyspnea or/and cardiovascular involvement, such as lowered blood pressure).²¹ The onset of positive hypersensitivity reaction was also noted as less than 4 h or more than 4 h after provocation in order to determine immediate or delayed type reaction.²

Statistical analysis

Categorical variables were expressed as frequencies and percentages, while continuous variables were expressed as means with standard deviation (SD). Bivariate analysis for gender, age, BMI, atopic history, comorbidities, vaccine allergy, drug allergy, history of anaphylaxis, and history of SJS/TEN was carried out using the Chi-Square test in order to compare factors associated with hypersensitivity reaction after COVID-19 vaccine provocation test. Variables with a p-value of less than 0.25 were then analyzed further with multivariate analysis using backward logistic regression, and the adjusted risk ratio (aRR) with 95% confidence interval (CI) was calculated. A p-value of less than 0.05 was considered significant.

Provocation test protocol

Skin prick test (SPT) and intradermal test (IDT) were done before the graded challenge. Both procedures were performed with the chosen vaccine according to Nilsson et al.²² The SPT used undiluted vaccine and normal saline as the control. The concentration used for IDT was 1:10, diluted in normal saline. Each test was evaluated after 15 min. The test was stopped if the patient showed a positive reaction defined by induration greater than 3 mm compared to the control or systemic symptoms.

Patients with negative SPT and IDT went through graded challenge with 3 doses administered depending on the vaccine: 0.1, 0.2, 0.2 mL for Sinovac, Moderna and AstraZeneca and 0.1, 0.1, 0.1 mL for Pfizer. There was a 15 min interval between the doses. All patients were then observed for 1 h. The complete protocol can be seen in Table 1. In the next 24 h after the test, patients were instructed to report any allergic reactions perceived.

Table 1.

Provocation protocol used for COVID-19 vaccine after skin prick test and intradermal test

Step	Dose (mL)	Cumulative dose (mL)	Cumulative time (minute)
Sinovac, Moderna, AstraZeneca
1	0.1	0.1	0
2	0.2	0.3	15
3	0.2	0.5	30
Observation			90
Pfizer
1	0.1	0.1	0
2	0.1	0.2	15
3	0.1	0.3	30
Observation			90

Results

Characteristics of the patients

A total of 232 adult patients were included in this study. Twenty-eight (12.1%) of them had hypersensitivity to their first COVID-19 vaccine dose, while 204 (87.9%) patients were high risk for allergic reaction. Most of the patients were female (82.3%) while the mean age was 42.2 (SD 14.4) years and the mean BMI was 25.0 (SD 4.6) kg/m². The most common atopic history was asthma (20.3%), followed by allergic rhinitis (13.8%), urticaria (6.5%), and atopic dermatitis (3.9%). Most patients were allergic to 1 or more classes of drugs (73.7%), but only 5.2% of patients had a history of previous non-COVID-19 vaccine allergy. Eighty-six patients (37.1%) had history of anaphylaxis and 23 patients (9.9%) had history of SJS/TEN.

The comparison between the 2 groups can be seen in Table 2 and Fig. 1. Of the 28 patients in group 1 (history of previous COVID-19 hypersensitivity), 7 (25%) patients had an anaphylactic reaction (dyspnea or unconsciousness) to their previous COVID-19 vaccine. The other 21 patients developed mild symptoms (local symptoms such as itchiness or erythema) and moderate symptoms (systemic symptoms such as nausea, vomiting, or urticaria). Of the 204 patients in group 2 (high risk patients), 79 patients had an any cause of anaphylaxis history, 3 patients had an any cause of anaphylaxis history and history of non-COVID-19 vaccine hypersensitivity, and 5 patients had a history of non-COVID-19 vaccine hypersensitivity.

Table 2.

Comparison of the two groups of patients enrolled in the study.

	High-risk patients (n = 204)	Hypersensitivity to first COVID-19 vaccine dose (n = 28)	Total (n = 232)
Socio-demographic characteristics
Female, n (%)	166 (81.4)	25 (89.3)	191 (82.3)
Age in years, mean (SD)	43.0 (14.8)	36.6 (10.1)	42.2 (14.4)
BMI in kg/m2, mean (SD)	25.0 (4.7)	25.8 (3.8)	25.0 (4.6)
Atopic history
Allergic rhinitis, n (%)	30 (14.5)	2 (7.1)	32 (13.8)
Atopic dermatitis, n (%)	9 (4.4)	0 (0)	9 (3.9)
Urticaria, n (%)	13 (6.4)	2 (7.1)	15 (6.5)
Asthma, n (%)	42 (20.6)	5 (17.9)	47 (20.3)
Known allergies
Food allergy, n (%)	57 (27.9)	9 (32.1)	66 (28.4)
Drug allergy, n (%)	159 (77.9)	12 (42.9)	171 (73.7)
Non-COVID-19 vaccine allergy, n (%)	10 (4.9)	2 (7.1)	12 (5.2)
Comorbidities
Hypertension, n (%)	32 (15.7)	1 (3.6)	33 (14.2)
Diabetes mellitus, n (%)	7 (3.4)	1 (3.6)	8 (3.4)
Heart disease, n (%)	6 (2.9)	0 (0)	6 (2.6)
Autoimmune disease, n (%)	31 (15.2)	3 (10.7)	34 (14.7)
Past severe allergic reaction
History of anaphylaxis, n (%)	79 (38.7)	7 (25)	86 (37.1)
History of SJS/TEN, n (%)	23 (11.3)	0 (0)	23 (9.9)

Abbreviations: SD, standard deviation; BMI, body mass index; SJS, Stevens-Johnson syndrome; TEN, toxic epidermal necrolysis

Fig. 1.

Results of the provocation test. ∗All patients who switched to second vaccine did not show any reaction.

COVID-19 vaccine provocation tests outcomes

Of the 232 patients, 156 patients started with the Sinovac provocation test (67.2%), while 49 started with Pfizer (21.1%), 18 with Moderna (7.8%), and 9 with AstraZeneca (3.9%). A total of 20 patients (8.6%, 95% CI: 5–12.2%) developed hypersensitivity reactions as a result of their first vaccine provocation tests: 12 in the Sinovac group, 4 in the Pfizer group, 2 in the Moderna group, and 2 in the AstraZeneca group. This meant that 7.7% of the patients receiving Sinovac, 8.2% of those receiving Pfizer, 11.1% of those receiving Moderna, and 22.2% of those receiving AstraZeneca had hypersensitivity reactions after provocation test. Most of the reactions (18 patients) occurred within 4 h after starting the provocation test. Four patients had positive reactions after SPT, 9 after IDT, and 7 during titrated challenge. A total of 9 patients developed mild symptoms (local induration, erythema, or itchiness), 3 patients developed moderate symptoms (urticaria, nausea, epigastric pain, mouth numbness, dizziness), and 1 patient developed severe symptoms (unconsciousness) during skin testing. Only 3 (15%) patients had delayed reactions, with symptoms appearing more than 4 h after provocation. Fifty percent of patients showed mild reactions (10 patients), 7 patients (35%) developed moderate reactions, and 3 patients (15%) developed severe reactions. Severe reaction or anaphylaxis was found in 1 patient receiving Sinovac, 1 receiving Moderna, and 1 receiving Pfizer. After failing their first COVID-19 vaccine provocation tests, 10 patients sequentially continued with different vaccine provocation tests, all with no hypersensitivity reactions. However, 10 patients decided not to continue with different vaccine provocation test. The complete summary of the provocation test can be seen in Table 3 and Fig. 1.

Table 3.

Summary of patients with positive provocation test.

Patient number	Gender	Age	COVID-19 vaccine causing hypersensitivity	Vaccine used for tests	Atopic history	Known allergies	Comorbidities	SPT result	IDT result	Graded challenge	Onset in hours	Type of reaction	Symptoms	Treatment	Replacement vaccine
Hypersensitivity to firstCOVID-19vaccine dose
1	F	41	Sinovac	AstraZeneca	–	Multiple drugs	–	–	–	+	<4	Moderate	Nausea, vomiting	Methylprednisolone	Pfizer
2	M	28	AstraZeneca	Pfizer	–	Other vaccine	–	–	+	ND	<4	Mild	Local induration, erythema	Methylprednisolone, antihistamine	Sinovac
3	F	31	AstraZeneca	Pfizer	Urticaria	Multiple drugs	Diabetes mellitus	+	ND	ND	<4	Severe	Urticaria, unconsciousness	Epinephrine, dexamethasone	ND
4a	F	33	Sinovac, Moderna, Pfizer	AstraZeneca	–	Multiple drugs	–	–	+	ND	<4	Mild	Local induration, itchiness	Methylprednisolone, antihistamine	ND
High-risk patients
1	F	47	–	Sinovac	–	Multiple drugs	–	–	–	+	>4	Severe	Angioedema, cheek rash, dyspnea	Patient was not at the clinic	AstraZeneca
2	F	34	–	Sinovac	Asthma	Multiple drugs	Hypertension	+	ND	ND	<4	Mild	Local induration, itchiness	Methylprednisolone, antihistamine	ND
3	F	42	–	Sinovac	–	Multiple drugs, food	–	–	+	ND	<4	Moderate	Dizziness	Methylprednisolone	ND
4	F	31	–	Sinovac	–	Multiple drugs	–	–	–	+	<4	Moderate	Nausea, vomiting, headache	Antihistamine	ND
5	F	57	–	Sinovac	–	Multiple drugs, food	–	+	ND	ND	<4	Moderate	Nausea, epigastric pain, itchy and red hand palm, mouth numbness	Methylprednisolone, antihistamine	ND
6	F	61	–	Sinovac	–	multiple drugs, food	Hypertension, diabetes mellitus	–	–	+	<4	Moderate	Angioedema	Methylprednisolone, antihistamine	Pfizer
7	F	26	–	Sinovac	–	Drug, food	Hereditary angioedema	+	ND	ND	<4	Mild	Local induration, erythema, itchiness	Methylprednisolone, antihistamine	Moderna
8	F	26	–	Sinovac	–	Multiple drugs	–	–	+	ND	<4	Mild	Local induration, itchiness	Methylprednisolone, antihistamine	AstraZeneca
9	F	38	–	Sinovac	Allergic rhinitis	Drug, food	–	–	–	+	>4	Moderate	Swollen lips	Methylprednisolone, antihistamine	Pfizer
10	F	61	–	Sinovac	Allergic rhinitis, urticaria, asthma,	Multiple drugs, food	Hypertension	–	+	ND	<4	Mild	Local induration, erythema	Methylprednisolone, antihistamine	Moderna
11	F	41	–	Sinovac	–	Drug, food	–	–	+	ND	<4	Mild	Local induration, erythema	Methylprednisolone, antihistamine	Pfizer
12	F	39	–	Sinovac	–	Multiple drugs, food	–	–	–	+	>4	Mild	Local itchiness	Methylprednisolone, antihistamine	ND
13	F	23	–	Pfizer	Allergic rhinitis, atopic dermatitis	Multiple drugs, food	–	–	+	ND	<4	Moderate	Urticaria	Methylprednisolone, antihistamine	ND
14	F	66	–	Pfizer	–	Multiple drugs	–	–	+	ND	<4	Mild	Local induration, erythema	Methylprednisolone, antihistamine	ND
15	M	27	–	Moderna	Allergic rhinitis	Drug	–	–	+	ND	<4	Mild	Local induration, erythema	Methylprednisolone, antihistamine	Sinovac
16	F	24	–	Moderna	–	Drug	SLE, SS	–	–	+	<4	Severe	Nausea, dizziness, rash, itchiness, dyspnea	Epinephrine, dexamethasone	ND

Abbreviations: F, female; M, male; SLE, systemic lupus erythematosus; SS, Sjögren syndrome; SPT, skin prick test; IDT, intradermal test; ND, not done; IV, intravenous; IM, intramuscular.

^aThis patient is allergic to previous COVID-19 vaccines (Sinovac, Moderna, Pfizer) with a history of anaphylaxis reaction to Moderna. Patient also had a history of allergy to antibiotics

Risk factors for hypersensitivity reaction after COVID-19 vaccine provocation test

The bivariate analysis in Table 4 showed that history of drug allergy and anaphylaxis was associated with hypersensitivity reactions after the provocation test. However, only history of anaphylaxis was found to be associated with the reaction after the provocation test in the adjusted model after multivariate analysis (aRR = 2.79, 95% CI: 1.05–7.42).

Table 4.

Comparison of the two groups of patients with and without hypersensitivity after first provocation test.

	Reaction post-provocation (n = 20)	No reaction post-provocation (n = 212)	Total (n = 232)	RR (95% CI)	p-value	B	S.E.	Adjusted RR (95% CI)	p-value
Gender, n (%)
Female	18 (90)	173 (81.6)	191 (82.3)	1.93 (0.47–8.00)	0.541
Male	2 (10)	39 (18.4)	41 (17.7)
Age, n (%)
≥ 60 years	3 (15)	24 (11.3)	27 (11.6)	1.34 (0.42–4.27)	0.712
< 60 years	17 (85)	188 (88.7)	205 (88.4)
BMI, n (%)
Obese	10 (52.6)	91 (48.1)	101 (48.6)	1.18 (0.50–2.78)	0.895
Non-obese	9 (47.4)	98 (51.9)	107 (51.4)
Atopic history, n (%)
Yes	6 (30)	72 (34)	78 (33.6)	0.85 (0.34–2.12)	0.912
No	14 (70)	140 (66)	154 (66.4)
Comorbidities, n (%)
Yes	6 (30)	68 (32.1)	74 (31.9)	0.92 (0.37–2.29)	1.000
No	14 (70)	144 (67.9)	158 (68.1)
Vaccine allergy, n (%)
Yes	4 (20)	34 (16)	38 (16.4)	1.28 (0.45–3.61)	0.751
No	16 (80)	178 (84)	194 (83.6)
Drug allergy, n (%)
Yes	19 (95)	152 (71.7)	171 (73.7)	6.78 (0.93–49.56)	0.046	1.71	1.05	5.53 (0.71–43.37)	0.103
No	1 (5)	60 (28.3)	61 (26.3)
History of anaphylaxis, n (%)
Yes	13 (65)	73 (34.4)	86 (37.1)	3.15 (1.31–7.60)	0.014	1.03	0.50	2.79 (1.05–7.42)	0.040
No	7 (35)	139 (65.6)	146 (62.9)
History of SJS/TEN, n (%)
Yes	3 (15)	20 (9.4)	23 (9.9)	1.60 (0.51–5.06)	0.429
No	17 (85)	192 (90.6)	209 (90.1)

Bold p-value means significant difference statistically. Abbreviations: BMI, body mass index; SJS, Stevens-Johnson syndrome; TEN, toxic epidermal necrolysis; RR, risk ratio

Discussion

Studies about the provocation test or graded challenge in COVID-19 vaccination are still rare and mostly limited to case reports or series, except for 1 study in Poland.14, 15, 16, 17 Other than safety, graded challenge also has some advantages compared to full vaccination challenge, such as improving patient's satisfaction and early detection of anaphylaxis for high-risk patients.^16,23,24

Participants enrolled in this study were mostly female (82.3%). The prevalence of allergies typically occurs in young and middle-aged adults and is more common in females than males.25, 26, 27 Immune cell functions are related to sex chromosome-encoded genes and estrogen and prolactine on T, B, and dendritic cells in women are involved in immune activation in the allergic reaction.^25,28 Because the activity and quantity of innate immune cells, such as macrophages, dendritic cells, and monocytes, are higher in females than in males, stronger responses to allergens may be expected in females.²⁹

The available studies used diverse vaccine platforms, mostly mRNA-based vaccines.14, 15, 16, 17 Only 1 case series in Turkey used inactivated virus vaccine.¹⁵ Most of the patients of this study (67.2%) used Sinovac (inactivated virus vaccine) for the provocation test. The view that mRNA-based vaccines cause more AE compared to inactivated virus vaccines predisposed patients to choose Sinovac during the shared decision-making.³⁰ Moreover, Sinovac was the first and most widely available vaccine in Indonesia (49%) as of September 2021 compared to AstraZeneca (31%), Moderna (13%), and Pfizer (7%).³¹ Both these factors contributed to the majority of patients using Sinovac for the provocation test.

This study showed a rate of hypersensitivity reaction after the provocation test of 8.6% (95% CI: 5–12.2%) with 7.7% for inactivated virus vaccine (Sinovac), 9% for mRNA-based vaccine (Pfizer and Moderna), and 22.2% for viral vector-based vaccine (AstraZeneca). Romantowski et al reported a 2.5% rate of hypersensitivity reaction after provocation test in 285 patients. The hypersensitivity reaction rate in this study was higher for mRNA-based vaccine compared to that study (9% vs. 2.2%). The discrepancy could be explained by the different brands of vaccine used, and protocols utilized for the provocation test. Romantowski et al used Spikevax and Comirnaty for mRNA-based vaccines.¹⁷ Furthermore, because only 9 patients of this study received a viral vector-based vaccine (AstraZeneca provocation test), the rate of hypersensitivity might be overestimated.

Allergic reactions are 4 times more likely to be reported by people with past allergies.³² However, a history of allergy and/or anaphylaxis are reliant on patient reporting, which may be biased. Therefore, the role of allergists in detecting the risk of these patients becomes crucial.^33,34 Patients with a history of anaphylaxis may also experience increased anxiety before receiving any drugs.¹⁷ A shared decision-making process is important in dealing with high-risk allergic patients in order to increase COVID-19 vaccine coverage.^18,35 The process favours vaccination through full or graded dosing (with or without additional observation time post-vaccination) or changing vaccine platforms to another agent over no vaccination, because there is currently no single best approach to assess and manage a patient with a suspected SARS-CoV-2 vaccine reaction or vaccine excipients.¹⁸

In this study, graded vaccine administration was discontinued after a positive SPT or IDT with 1 type of vaccine. We decided to use 1:10 dilution for the intradermal test due to its safety, according to previous report.³⁶ A consensus from a multidisciplinary group of international experts did not recommend allergy testing prior to vaccination due to its low sensitivity and specificity.¹⁸ However, this recommendation was based on limited case studies and case reports. Performing skin testing as part of the allergy-work up may reduce a patient's stress, thus affecting the patient's decision to continue with the vaccination.¹⁷ Moreover, anxious patients are more willing to receive a vaccine after the skin test shows a negative result. For this reason, a different vaccine was chosen for the provocation test in this study if the patient had experienced an allergic reaction to the first COVID-19 vaccine.⁸ Patients who have a history of vaccine allergy are more likely to be fearful of vaccination.¹⁷ However, a recent report suggested that patients who continue provocation testing with the same vaccine after a positive SPT or IDT may not necessarily develop a hypersensitivity reaction.¹⁷

In this study, not all patients agreed to change vaccine after a positive SPT, IDT, or graded challenge. Half of the participants who experienced an allergic reaction due to the test decided to stop rather than try another type of vaccine. As a result, these patients may miss the following dosage of COVID-19 vaccination or not be vaccinated at all. This may impact on the government's vaccination program. As of July 20, 2022, vaccination coverage in Indonesia for dose 1 reached 97.02%, dose 2 reached 81.47%, and dose 3 or the booster vaccine reached 25.75%.³⁷ This study only included dose 1 and 2 of the vaccination schedule, although the COVID-19 booster vaccine program has been carried out since January 12, 2022 in Indonesia. Vaccine hesitancy is also prevalent in Indonesia, reaching 68.6%, which also contributes to patient rejection for further testing.³⁸ Lastly, the COVID-19 vaccination program is the first obligatory mass vaccination for adults in Indonesia. All of these circumstances can contribute to the booster vaccine target not being attained. A new approach in vaccination is required to reassure high-risk allergic patients and make them feel safer.

The only significant risk factor for hypersensitivity reaction after COVID-19 vaccine provocation test in this study was a history of anaphylaxis. Previous studies reported that history of allergies (drugs, food), history of anaphylaxis, and atopic history are all possible risk factors for COVID-19 vaccine-related allergy.^8,28,39, 40, 41, 42, 43 Patients with a history of drug allergy are 9.4 times more likely to be allergic to other types of drugs than those without drug allergies. If a patient has an immediate allergic reaction, such as rash, anaphylaxis, or drug fever, then other drug allergic reactions tend to be also immediate.⁴⁴ However, this study found no association between past drug allergy and COVID-19 vaccine allergy after provocation test. Thus, anaphylaxis could be the predictor factor that needs to be assessed in patients prior to receiving vaccination with the graded method, and allergists need to be more careful when doing provocation tests in patients with a history of anaphylaxis. The graded-dose vaccination should be done in facilities that are capable in recognizing and treating signs of anaphylaxis.

This study has several limitations. First, the delayed reactions (>4 h) to the provocation test that were documented were not actively followed up for each participant and only relied on patient's self-reporting. Second, this study did not contain a control group in which the vaccinations might be provided in other types of challenge. Third, the types of vaccine utilized for the provocation test were too diverse. The decision of vaccine depended on availability of the vaccines and shared decision-making process. Fourth, logistical concerns, such as vaccine access or institutional limits on executing graded challenge due to emergency use authorisation, limited the generalizability of this study to other doctors. Furthermore, because Sinovac, Moderna, Pfizer, and AstraZeneca were the only vaccines available at the time, it was not possible to prescribe a similar graded-vaccine approach with the other vaccines. Fifth, atopic history, comorbidities, vaccine allergy, drug allergy, and history of anaphylaxis are all based on patient's acknowledgments and there was no method to confirm this information. Sixth, this study did not check antibodies to SARS-CoV-2 to establish the efficacy of graded-vaccine administration. It also was not known whether the immunity produced after graded challenge was as effective as full dose vaccination or not.

Conclusion

This study showed a high success rate of COVID-19 vaccine provocation test without hypersensitivity reaction in high-risk allergic patients. History of anaphylaxis was associated with hypersensitivity reaction after COVID-19 vaccine provocation test. Patients who had a hypersensitivity reaction to a previous COVID-19 vaccine or are considered high risk for hypersensitivity reaction may still receive COVID-19 vaccination using provocation test under supervision.

Abbreviation

ACAAI, The American College of Allergy, Asthma, and Immunology; ADR, adverse drug reaction; AE, adverse events; aRR, adjusted risk ratio; BMI, body mass index; CDC, The Center for Disease Control and Prevention; CI, confidence interval; COVID-19, coronavirus disease; IDT, intradermal test; SD, standard deviation; SJS, Stevens-Johnson syndrome; SPT, skin prick test; TEN, toxic epidermal necrolysis.

Acknowledgments

We would like to express our gratitude to Utami Susilawati and Salfia Dian Lastari who guided us with the statistical analysis in this study. We would also like to thank the patients for their cooperation during the procedures.

Funding information

There was no funding for the study or the preparation of this paper.

Availability of data and materials

The data used or analyzed during the study is available upon reasonable request from the corresponding author.

Author's contributions

SK, SM, AW, ASH, THK, SS, LDL, SD, and IR were in charge of patient care.

SK, DK, and MY were in charge of data entry, gathering, data management.

SK, SM, ASH, DK, MY, and EY were in charge of manuscript drafting.

SK and EY directed the project and was in charge of the manuscript's critical proofreading.

The final manuscript was read and approved by all writers.

Ethics approval and consent to participate

Ethical approval was provided by the Ethics Committee of the Faculty of Medicine Universitas Indonesia and Cipto Mangunkusumo Hospital for the use of routinely collected anonymous data in the Allergy-Immunology Clinic with a waiver for informed consent. All the methods employed in this study were performed in accordance with the Declaration of Helsinki. All participants' personal identifiers were anonymized before data processing was performed in order to maintain confidentiality.

Consent for publication

The manuscript's publishing is approved by all of the authors.

Declaration of competing interest

All authors declare no conflict of interest.