Fear, facts, and the future: An update on coronavirus disease 2019 vaccine–induced anaphylaxis and vaccine hesitancy among those living with allergy

Abstract

Background

Despite the low incidence of coronavirus disease 2019 (COVID-19) vaccine–induced allergic reactions reported to date, concerns of such reactions have been reported in the literature among individuals with and without a history of allergic disease.

Objectives

Herein, we provide an update to a previous scoping review published by our group, focusing on COVID-19 vaccine hesitancy in relation to allergy and the incidence of anaphylactic reactions to COVID-19 vaccines.

Methods

The current review follows an a priori protocol drafted in accordance with Arksey and O’Malley’s framework for methodological reviews. A comprehensive search was conducted on 4 scientific databases (CINAHL, PsycINFO, MEDLINE, Embase) to identify eligible studies published since our initial review. Eligible articles included those published between February 12, 2022, and November 10, 2023, and were retrieved using an established search process developed by content and methodological experts. Among the 2,099 unique citations, 45 articles (2.1%) were included.

Results

Consistent with previously reviewed literature, COVID-19 vaccine–induced anaphylaxis remains rare among both those with allergies and the general population. Despite the rarity of anaphylaxis, hesitancy persists among individuals with and without allergies.

Conclusions

To prepare for future pandemics, it is evident that more efforts are needed to address concerns regarding the potential for allergic reactions following vaccination. As part of this process, it is important to ensure medical professionals are updated as new information becomes available and that evidence-based risk communication is accurate, accessible, and culturally appropriate.

Despite the success of vaccination in reducing the global burden of disease, many people remain vaccine hesitant.¹ The abundance of both valid and invalid information contributed to what has been described as the “infodemic” by the World Health Organization (WHO) and has played a pivotal role in amplifying doubts and fueling vaccine hesitancy, particularly in the context of coronavirus disease 2019 (COVID-19).^2,3 Concerns about vaccine hesitancy are not new, but the outbreak of the COVID-19 pandemic has arguably intensified these concerns by laying bare the impact of hesitancy on efforts to control the pandemic. While the causes of hesitancy are multifaceted, confidence in vaccine safety has been identified as a primary concern influencing vaccine uptake.⁴ In light of the important role played by safety in influencing vaccine confidence, it stands to reason that individuals with a history of allergy to food, drugs, or insects may be more hesitant to receive various vaccinations, including the COVID-19 vaccine, given that some vaccine excipients do contain allergens known to cause reactions in sensitive individuals.⁵ While reactions following vaccination are rare, extensive media coverage and misinformation surrounding vaccine-induced reactions hold the potential to undermine the confidence of some individuals with a history of allergic disease who may perceive themselves as vulnerable to such reactions.⁵ Furthermore, the emergence of anaphylaxis cases prompted cautionary advice discouraging individuals with allergies from getting vaccinated.6, 7, 8 The inconsistent communication from both governmental and nongovernmental entities regarding the suitability of COVID-19 vaccines for those with allergic conditions potentially exacerbated skepticism and uncertainty among individuals with a prior history of severe allergies.⁶

In light of this, we previously conducted a scoping review⁹ (published online in February 2023) aimed at better understanding the incidence of allergic reactions following COVID-19 vaccination and whether fear of allergic reactions contributes to vaccine hesitancy among both the general public and those with allergic disease. This review was based on literature published following the outbreak of the pandemic, but prior to February 11, 2022.⁹ Through this work, we found that rates of allergic reactions and anaphylaxis following vaccination for COVID-19 were relatively low (median incidence of anaphylaxis = 5 cases per million doses; median incidence of allergic reactions = 528 cases per million doses).⁹ Results also revealed that a history of allergic disease appeared to increase an individual’s risk of reaction; however, the incidence of adverse events following vaccination was low even among those with allergies.⁹ Despite the rarity of reactions, we found that fear of allergic reactions was a significant concern in both individuals living with allergy and those without a history of allergic disease. Not surprisingly, these concerns were also found to undermine vaccine confidence among those with a history of allergy.⁹

While these findings are important in demonstrating an initial link between fear of reactions and COVID-19 vaccine hesitancy, many studies have been published on the topic since our initial review of the literature that may help better establish the impact of reaction-related fears on vaccine hesitancy. The objective of this current study is to provide an updated synthesis of the recently published literature that investigates the incidence of anaphylaxis following COVID-19 vaccination and explores the relationship between such reactions and vaccine confidence. By critically examining the newly published studies, this review will contribute to closing the existing gaps and resolving inconsistencies, and serve as a valuable resource for informing and guiding future pandemic responses.

Methods

This review serves as an update to our original review ⁹ which was conducted in February 2022, and focuses on peer-reviewed literature published in the same 4 databases included in our previous review (ie, MEDLINE [Ovid], CINAHL [EBSCO], Embase [Ovid], and PsycINFO [Ovid]). Eligible articles included those published between February 12, 2022, and November 10, 2023 (the date of our final search), that provided original data on rates of anaphylaxis following vaccination for COVID-19. We also included articles that examined the relationship between allergic reactions or allergic disease and hesitancy surrounding the COVID-19 vaccine. For the purposes of the current study, hesitancy was defined as negative feelings toward the COVID-19 vaccine, delays in acceptance of the vaccine, or vaccine refusal. Any studies that were published in February 2022 and identified in both our original and updated search were included in the original scoping review only. The methodology, including search terms, study design, and data charting processes, closely mirrors that of our original review.9, 10, 11 The exclusion of gray literature further ensures that our synthesis is based on high-quality, peer-reviewed studies.

Shift in focus to anaphylaxis

In contrast to our original review, which encompassed both allergic reactions and anaphylaxis, the focus of this update is primarily on anaphylaxis. The initial review’s emphasis on both outcomes was prompted by limited data on anaphylaxis during the acute phase of the COVID-19 pandemic. Given the evolving COVID-19 landscape and the accumulation of more data on anaphylaxis, our current goal is to underscore the incidence of anaphylaxis. Given that there is no consensus definition of anaphylaxis, we did not restrict articles based on how anaphylaxis was defined as long as the definition did not differ markedly from commonly cited guidelines.

Of note, papers that investigated adverse reactions to the COVID-19 vaccine in individuals with mastocytosis were excluded from the review. It was believed that including these articles may unduly bias estimates of the incidence of allergic reactions following vaccination as the condition places individuals at higher risk of anaphylaxis.¹² However, papers examining postvaccination reactions and hesitancy in individuals with other chronic conditions were eligible for the current review.

Incidence calculation

To determine the incidence of anaphylaxis within the included studies, we employed an approach that involved calculating the proportion of reported anaphylaxis cases in relation to the total administered doses.

The formula used to calculate the incidence is as follows:

$$I=\left(\frac{A}{D}\right)\times 100\text{,}$$

where $I$ represents the incidence of anaphylaxis, $A$ represents the number of reported anaphylaxis cases, and $D$ represents the total number of administered COVID-19 doses.

Results

Literature search results

The academic literature search yielded 4768 articles (1429 from MEDLINE [Ovid], 3114 from Embase [Ovid], 28 from PsycINFO [Ovid], and 197 from CINAHL [EBSCO]). After removing duplicate papers, 2099 academic articles remained, which were then screened at the title and abstract level. Of these, 221 were assessed for eligibility at the full-text level, resulting in the inclusion of 45 academic articles (see Fig 1 for an overview of the screening process and Table I for an overview of the included papers).

Fig 1.

Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram demonstrating selection process of articles for the review update.

Table I.

Summary table of the included studies

First author	Year	Title	Country	Aim	Sample size	Methodology	Outcome measures	Key findings
Aberumand	2022	Understanding attitudes and obstacles to vaccination against COVID-19 in patients with primary immunodeficiency	Canada	To understand the perceptions regarding COVID-19 vaccination among patients with primary immunodeficiency and to identify factors related to vaccine hesitancy	449	Cross-sectional study	Ad hoc questionnaire on vaccine hesitancy	Reasons for vaccine hesitancy encompass concerns regarding potential long-term side effects (50.4%) and fear of reaction to the vaccine (32.2%)
Ahsanuddin	2024	Otolaryngologic side effects after COVID-19 vaccination	USA	To investigate otolaryngologic adverse events of COVID-19 vaccines reported to the VAERS and their clinical relevance	1,280,950	Retrospective study	Assessment of otolaryngologic adverse events following COVID-19 vaccination using the Food and Drug Administration's VAERS database	Anaphylaxis: n = 1,323 (PRR: 0.37 [95% CI: 0.26-0.54]), (ROR: 0.37 [95% CI: 0.26-0.53])
Al-Obaydi	2022	Hesitancy and reactogenicity to mRNA-based COVID-19 vaccines—early experience with vaccine rollout in a multi-site healthcare system	USA	To understand factors associated with mRNA-based COVID-19 vaccines hesitancy and reactogenicity	5,709	Cross-sectional study	Ad hoc questionnaire exploring factors for declining vaccination (nonvaccine receivers) and factors associated with occurrence and severity of local and systemic reactions after the first and second vaccine doses (vaccine receivers)	Anaphylaxis: n = 3 Allergy to other vaccines was associated with vaccine hesitancy
Amarasinghe	2023	COVID-19 vaccine-related adverse events following immunization in the WHO Western Pacific Region, 2021-2022	WHO Western Pacific Region Countries	To understand the landscape of COVID-19 vaccine-related adverse events following immunization in the Western Pacific Region	732,000,000	Retrospective observational study	Weekly reports provided by WHO Western Pacific Region country offices and countries	Anaphylaxis: n = 7,566
Cebeci Kahraman	2022	Cutaneous reactions after COVID-19 vaccination in Turkey: a multicenter study	Turkey	To investigate cutaneous and systemic adverse reactions following COVID-19 vaccination with Sinovac/CoronaVac (inactivated SARS-CoV-2) and Pfizer/BioNTech (BNT162b2) vaccines	2,290	Prospective cross-sectional study	Systemic, local injection site, and nonlocal cutaneous reactions after vaccination were identified, and their rates were determined	Anaphylaxis: n = 3, first dose (n = 1 for CoronaVac; n = 2 for BioNTech); second dose n = 1 for BioNTech
Connolly	2022	Disease flare and reactogenicity in patients with rheumatic and musculoskeletal diseases following two-dose SARS-CoV-2 messenger RNA vaccination	USA	To investigate disease flare and postvaccination reactions (reactogenicity) in patients with rheumatic and musculoskeletal diseases following 2-dose SARS-CoV-2 mRNA vaccination	1,377	Prospective observational study	Ad hoc questionnaire detailing local and systemic adverse events	Anaphylaxis: n = 0 Frequent reactions: injection site pain (87% after dose 1, 86% after dose 2) and fatigue (60% after dose 1, 80% after dose 2)
Crăciun	2022	mRNA COVID-19 vaccine reactogenicity among healthcare workers: results from an active survey in a pediatric hospital from Bucharest, January-February 2021	Romania	To investigate the adverse events following mRNA Pfizer-BioNTech vaccine immunization among health care workers at a Bucharest pediatric hospital, vaccinated during the first phase of the national vaccination campaign in Romania	574	Cross-sectional study	Ad hoc questionnaire on adverse events	Anaphylaxis: n = 0 Most frequent adverse event: injection site pain (80.3% after dose 1; 75.1% after dose 2)
Cserep	2022	The effect of a single dose of BNT162b2 vaccine on the incidence of severe COVID-19 infection in patients on chronic hemodialysis: a single-centre study	United Kingdom	To understand the 8-wk safety and efficiency of a single dose of the BNT162b2 vaccine in patients on chronic hemodialysis	83	Retrospective observational study	Local and systemic reactions in the 7-days following vaccination	Anaphylaxis: n = 0 No life-threatening allergic reactions or side effects observed
Du	2022	Safety of an inactivated COVID-19 vaccine in patients with wheat-dependent exercise-induced anaphylaxis	China	To investigate the comparison of adverse events associated with an inactivated COVID-19 vaccine between WDEIA patients and healthy controls	n = 72 WDEIA; n = 730 healthy matched controls	Cross-sectional study	Ad hoc questionnaire on adverse reactions after vaccination	Anaphylaxis: n = 0 Similar rates of adverse events in case and control groups
Filon	2022	Allergic reactions to COVID-19 vaccination in high-risk allergic patients: the experience of Trieste University Hospital (North-Eastern Italy)	Italy	To understand the risk of reactions in high-risk allergic patients vaccinated for COVID-19 at the University Health Agency Giuliano-Isontina of Trieste	269	Cross-sectional study	Structured survey questionnaire investigating the signs and symptoms developed after any COVID-19 vaccine dose	Anaphylaxis: n = 0 No anaphylactic events were observed
Gamez	2022	Safety of mRNA COVID-19 vaccines in patients with well-controlled myasthenia gravis	Spain	To investigate the safety of mRNA-based 2-dose vaccination in a cohort of patients with myasthenia gravis	91	Prospective observational study	Local and systemic reactogenicity after injection was monitored for each dose administered	Anaphylaxis: n = 0 No anaphylactic reactions reported
Goda	2022	Association between adverse reactions for the first and second doses of COVID-19 vaccine	Japan	To understand the frequency of adverse reactions to COVID-19 vaccines in Japan and the impact of first-dose adverse reactions on second-dose adverse reactions	671	Prospective cohort study	Ad hoc self-administered questionnaire on adverse vaccine events and general health	Anaphylaxis: n = 0 No anaphylaxis cases were reported
Guarnieri	2022	Adverse reactions to BNT162B2 vaccine in health care workers from an Italian Tertiary Care Hospital	Italy	To investigate adverse reactions and possible hypersensitivity reactions during the vaccination campaign of health care workers at Meyer Children's University Hospital in Florence (Italy), conducted with the mRNA Pfizer vaccine from January 1 to March 2, 2021	1,293	Prospective cohort study	Notifications by hospital pharmacy and face-to-face declarations with medical doctors	Anaphylaxis: n = 0 Following dose 1, individuals with a history of allergic disease were more likely to have had a suspected hypersensitivity reaction; after dose 2, this relationship did not reach statistical significance
Holzmann-Littig	2022	COVID-19 vaccines: fear of side effects among German health care workers	Germany	To investigate which side effects concern health care workers and how these are associated with vaccine hesitancy	4,500	Cross-sectional exploratory study	Ad hoc questionnaire about adverse reactions and fears of side effects	153 of 4,500 respondents (3.4%) feared an allergic reaction; concerns about serious side effects were associated with vaccination refusal
Ieven	2022	COVID-19 vaccination safety and tolerability in patients allegedly at high risk for immediate hypersensitivity reactions	Belgium	To investigate the allergist-observed safety and tolerability of COVID-19 vaccines in patients deemed at higher risk of COVID-19 vaccine-induced immediate hypersensitivity reactions, vaccinated in-hospital under medical supervision	196	Retrospective cohort study	On-site assessment by allergist and telephone interviews after 3-7 days	Anaphylaxis: n = 0 None fulfilled criteria for anaphylaxis
Imai	2022	Incidence and risk factors of immediate hypersensitivity reactions and immunization stress-related responses with COVID-19 mRNA vaccine	Japan	To investigate the incidence and risk factors for immediate hypersensitivity reactions and immunization stress-related responses with the Moderna COVID-19 vaccine	614,151	Nested case-control study	Relevant clinical findings of adverse events following immunization were collected via medical records in first-aid rooms and classified by trained physicians	Anaphylaxis: n = 2 Of the 318 immediate hypersensitivity reaction events, 2 were classified as anaphylaxis based on the Brighton criteria
Iwayama	2022	Early immunological responses to the mRNA SARS-CoV-2 vaccine in patients with neuromuscular disorders	Japan	To investigate the safety and efficacy of BNT16b2 in patients with NMDs with muscular atrophy compared to that in healthy subjects	11 patients with NMDs; 346 healthy patients	Observational cohort study	Ad hoc questionnaire on adverse reactions	Anaphylaxis: n = 0 No anaphylaxis occurred in any of the participants
Kara	2023	Self-reported allergic adverse events following inactivated SARS-CoV-2 vaccine (TURKOVAC) among general and high-risk population	Turkey	To investigate the distribution and severity of allergic adverse events following the administration of the TURKOVAC whole-virion inactivated COVID-19 vaccine as either the primary or the booster dose in 15 provinces in Turkey	29,584	Prospective cohort study	Ad hoc self-report structured questionnaire	Anaphylaxis: n = 0
Lewin	2023	COVID-19 vaccine concerns of health care providers and ancillary staff	USA	To understand COVID-19 concerns among a range of health care providers and ancillary staff, this study assessed reported vaccination of their adolescent children and intent to vaccinate younger children as part of an effort to improve pediatric COVID-19 vaccine uptake	1,437	Prospective cohort study	Ad hoc web-based survey to assess intent to vaccinate children against COVID-19 and concerns regarding vaccination	Nurses and other personnel had more vaccine concerns than physicians and pharmacists, especially about allergic reactions (concerns about allergic reactions: 15% of physicians vs 36% of nurses)
Lim	2022	Role of occupational health services in planning and implementing of staff COVID-19 vaccination clinic: a tertiary hospital experience in Singapore	Singapore	To investigate ways to address and overcome vaccine hesitancy among health care workers in a tertiary hospital in Singapore and ensure maximal uptake of the Pfizer-BioNTech COVID-19 vaccine	7,671	Interventional study	Patients were monitored for 30 min following vaccination, with adverse events recorded, and staff were also encouraged to report adverse events to their hospital’s occupational health clinic	Anaphylaxis: n = 0
Low	2022	Breastfeeding mother and child clinical outcomes after COVID-19 vaccination	Singapore	To investigate solicited adverse effects unique to lactating individuals, including axillary lymphadenopathy, mastitis, and breast engorgement, as well as to examine the systemic and local adverse effects of the Pfizer/BioNTech mRNA COVID-19 vaccine (BNT162b2) on lactating health care workers	88	Prospective cohort study	Ad hoc structured questionnaire	Anaphylaxis: n = 0
Lyons	2022	Risk stratification through allergy history: single-centre experience of specialized COVID-19 vaccine clinic	Ireland	To investigate the establishment of a specialized COVID-19 vaccine allergy clinic aimed at addressing the COVID-19 vaccination needs of individuals aged ≥16 y	n = 206	Observational study	Observations of adverse reactions	Anaphylaxis: n = 0 No cases of anaphylaxis
Matson	2023	Paediatric safety assessment of BNT162b2 vaccination in a multistate hospital-based electronic health record system in the USA: a retrospective analysis	USA	To investigate the adverse events associated with 2-dose BNT162b2 vaccination in the pediatric population (children aged 5-17 y)	56,436	Retrospective study	Multistate hospital-based electronic health records	Anaphylaxis: n = 6; n = 3 after first dose; n = 3 after second dose
Milito	2023	Safety of mRNA COVID-19 vaccines in patients with inborn errors of immunity: an Italian multicentric study	Italy	To investigate the reactogenicity and adverse event profile following 2, 3, and 4 doses of mRNA vaccines in patients with inborn errors of immunity	342	Observational study	Ad hoc self-report questionnaire	Anaphylaxis: n = 0
Najjar	2023	COVID-19 vaccination reported side effects and hesitancy among the Syrian population: a cross-sectional study	Syria	To investigate postvaccination side effects and identify factors associated with both general side effects and severe side effects	1,672	Cross-sectional study	Ad hoc questionnaire designed to collect specific and targeted information from participants regarding their experiences and perceptions related to COVID-19 vaccination	Anaphylaxis: n = 1
Niekrens	2022	Homologous COVID-19 BNT162b2 vaccination at a German tertiary care university hospital: a survey-based analysis of reactogenicity, safety, and inability to work among healthcare workers	Germany	To investigate the age- and sex-dependent reactogenicity and safety of BNT162b2 in a real-life setting	2,372	Retrospective study	Ad hoc questionnaire on adverse effects after first or second vaccine dose	Anaphylaxis: n = 4
Njoga	2022	COVID-19 vaccine hesitancy and determinants of acceptance among healthcare workers, academics and tertiary students in Nigeria	Nigeria	To investigate factors associated with COVID-19 vaccine hesitancy among Nigerian health care workers, academics, and tertiary students	1,525	Cross-sectional study	Ad hoc online questionnaire	24.6% (307 of 1,079) of participants expressed fear of an allergic reaction (307 of 1,079)
Odejinmi	2022	COVID-19 vaccine hesitancy: a midwifery survey into attitudes towards the COVID-19 vaccine	England	To understand midwifery uptake of and attitudes toward the COVID-19 vaccine in 2 ethnically diverse areas	378	Mixed methods	Ad hoc questionnaire on vaccine uptake and factors influencing vaccine hesitancy	22% of participants expressed fear of having an allergic reaction
Oka	2022	Awareness, barriers and concerns of adolescents toward the COVID-19 vaccine: a cross-sectional study in Singapore	Singapore	To investigate the awareness, concerns, and barriers of adolescents toward the COVID-19 vaccine	460	Cross-sectional study	Ad hoc web-based questionnaire on vaccine literacy and hesitancy	73.2% of participants had concerns about anaphylaxis
Ou	2021	Safety and reactogenicity of 2 doses of SARS-CoV-2 vaccination in solid organ transplant recipients	USA	To investigate the safety and reactogenicity of SARS-CoV-2 mRNA vaccines in solid organ transplant recipients	741	Prospective cohort study	Ad hoc questionnaire assessing local symptoms and systemic adverse reactions after each vaccine dose	Anaphylaxis: n = 0
Rayamajhi	2022	Adverse events following immunization with ChAdOx1 nCoV-19 and BBIBP-CorV vaccine: a comparative study among healthcare professionals of Nepal	Nepal	To investigate the local and systemic adverse events following vaccination with Vaxzevria (ie, ChAdOx1 nCoV-19) and BIBP (ie, BBIBP-CorV; Sinopharm, Beijing, China) among health care professionals of Nepal	606	Cross-sectional study	Ad hoc self-administered online survey tool on adverse events	Anaphylaxis: n = 0 No serious and life-threatening adverse events like anaphylaxis were reported
Rosada	2023	Safety of mRNA COVID-19 vaccinations in patients with allergic diseases	Poland	To investigate the degree of safety and assess the possible risk of acute allergic reactions following mRNA COVID-19 vaccination among a group of patients predisposed to allergic diseases	52	Prospective observational study	Ad hoc questionnaire aimed to gather information about participants' experiences of various symptoms after receiving the COVID-19 vaccine	Anaphylaxis: n = 0
Sa	2022	The safety of mRNA-1273, BNT162b2 and JNJ-7836735 COVID-19 vaccines: safety monitoring for adverse events using real-world data	USA	To understand the adverse effects and provide accurate postvaccination safety information	481,172	Retrospective study	VAERS database was searched from December 14, 2020 to September 30, 2021, to analyze and characterize postvaccination adverse events	Anaphylaxis: mRNA-1273 (ie, Moderna; n = 79), BNT162b2 (ie, Pfizer; n = 79), JNJ-78436735 (ie, Johnson & Johnson; n = 13) mRNA vaccines had lower risk for anaphylaxis in univariate analysis, but higher risk in multivariate analysis
Sarca Çevk	2022	Attitudes of family medicine residents in Ankara towards COVID-19 vaccines administered in Turkey: a descriptive, cross-sectional study	Turkey	To investigate the attitudes of family medicine residents in Ankara about the inactivated and mRNA COVID-19 vaccines being administered in Turkey	139	Cross-sectional study	Ad hoc survey on attitudes of residents toward COVID-19 vaccines	5% of residents said they would not recommend vaccination if the patient had a history of allergic reactions or anaphylaxis. Between 43.2% and 49.6% would not recommend a second dose of the COVID-19 vaccine after an anaphylactic reaction to the first
Sayaca	2023	The percentage of hesitation and factors associated with acceptance or refusal for COVID-19 vaccination: does education about vaccines by allergist affect personal decision?	Turkey	To investigate the vaccination perspective of patients and learn how many patients were persuaded to get vaccinated with the effect of the education provided by allergists	200	Cross-sectional study	Antivaccination scale form and questionnaire form developed by allergists	A similar proportion of patients with history of anaphylaxis (55.3%) indicated they planned to be vaccinated compared to those without such a history (61.7%); 88.2% of patients with allergies who indicated they were not interested in being vaccinated before the education session indicated that they ultimately received the vaccination after attending the educational talk
Sen	2022	COVID-19 vaccination-related adverse events among autoimmune disease patients: results from the COVAD study	United Kingdom; 94 countries	To investigate adverse events in patients with systemic autoimmune and inflammatory disorders and healthy controls 7 days postvaccination	10,900	Cross-sectional study	Ad hoc online survey of adverse events	Anaphylaxis: systemic autoimmune and inflammatory disorders group = 0.2% (11 of 5,867); healthy control = 0.4% (5 of 5,033)
Shivarev	2023	Adverse event reports of anaphylaxis after Comirnaty and Vaxzevria COVID-19 vaccinations, Western Australia, 22 February to 30 June 2021	Australia	To investigate anaphylaxis rates, characteristics, and outcomes of reported cases of anaphylaxis to COVID-19 vaccines in Western Australia	727,750	Retrospective observational study	Clinician reports of adverse events following immunization to the Western Australian vaccine safety surveillance system	Anaphylaxis: n = 12, with 8 cases associated with Vaxzevria and 4 cases with Comirnaty, resulting in rates of 15.9 and 17.7 per million doses administered for Vaxzevria and Comirnaty, respectively
Stehlin	2022	Intradermal testing with COVID-19 mRNA vaccines predicts tolerance	Switzerland	To investigate the management of individuals with a history of polyethylene glycol allergy or suspected allergic reactions after receiving the COVID-19 mRNA vaccine	604,267	Observational cohort study	A standardized evaluation involving people responding to questions either online or through a hotline	Anaphylaxis: n = 18
Sturkenboom	2022	Cohort monitoring of 29 adverse events of special interest prior to and after COVID-19 vaccination in four large European electronic healthcare data sources	Italy, The Netherlands, United Kingdom, Spain	To investigate the use of COVID-19 vaccines and monitor the incidence rates of prespecified adverse events of special interest prior to and after COVID-19 vaccination	25,720,158	Retrospective cohort study	PHARMO Database Network (The Netherlands), BIFAP database, ARS (Italian) database, Clinical Practice Research Datalink (United Kingdom)	Results revealed an anaphylaxis incidence rate of 11.7 per 100,000 person-years
Vanijcharoenkarn	2021	Immediate reactions after the first dose of SARS-CoV-2 mRNA vaccines do not preclude second-dose administration	USA	To investigate the institutional experience with immediate reactions to the COVID-19 vaccine, and to understand the protocol for graded or full-dose vaccine readministration for immediate reactors at low risk for true anaphylaxis	20,657	Retrospective study	Review of occupational health records, skin testing and observation	Likely anaphylactic episodes from dose 1 (Brighton level 2): 0.03% (n = 20657). Brighton level 3 reactions: 0.39%
Wang et al	2023	Characteristics of immune response profile in patients with immediate allergic and autoimmune urticarial reactions induced by SARS-CoV-2 vaccines	Taiwan	To investigate the risk factors and immune mechanisms associated with patients who develop immediate allergic reactions and chronic urticaria following SARS-COV-2 vaccination	129	Prospective observational study	Naranjo algorithm; Brighton Collaboration criteria	Of the 129 participants who reported immediate reactions, 5 experienced anaphylaxis (3.9%)
Wentrys	2021	COVID-19 vaccination including 198 patients with history of severe anaphylactic reaction—own observations	Poland	To understand the outcomes of patients with a history of severe anaphylactic reaction who were vaccinated against COVID-19	403	Prospective observational study	60-min observation; telephone interview after 1 wk to collect data about late allergic reaction	Incidence of anaphylaxis among participants with a history of anaphylaxis: n = 3 (1.5%); incidence of anaphylaxis among participants with no history of anaphylaxis: n = 6 (3%)
Wijesinghe	2021	Acceptance of COVID-19 vaccine in Sri Lanka: applying the health belief model to an online survey	Sri Lanka	To understand health and illness-related behaviors related to vaccines	895	Cross-sectional study	Questionnaire based on health belief model	Sample had concerns about vaccine brand, side effects, allergies, and protection duration, which influenced vaccine acceptance and beliefs about vaccine protection and future infection
Wong	2022	Adverse events of special interest and mortality following vaccination with mRNA (BNT162b2) and inactivated (CoronaVac) SARS-CoV-2 vaccines in Hong Kong: a retrospective study	China	To investigate and compare the incidence of various adverse events of special interest and all-cause mortality between CoronaVac (inactivated vaccine) and BNT162b2 (ie, the Pfizer mRNA-based vaccine)	1,938,237	Retrospective population-based cohort study	Electronic medical records of the Hong Kong Hospital Authority	Cumulative incidence of anaphylaxis after the first dose: BNT162b2, 27 per 100,000 person-years; CoronaVac, 7 per 100,000 person-years Crude incidence rate after the first dose: BNT162b2, 376 per 100,000 person-years, CoronaVac, 134 per 100,000 person-years Incidence rate ratio for first dose anaphylaxis: 0.34 (95% CI: 0.14–0.79, P = .01), indicating a lower risk with BNT162b2 Cumulative incidence of anaphylaxis after the second dose: BNT162b2, 13 per 100,000 person-years, CoronaVac, 3 per 100,000 person-years Crude incidence rate after the second dose: BNT162b2, 212 per 100,000 person-years, CoronaVac, 67 per 100,000 person-years
Yilmazbas	2023	Allergic children's parents' hesitancy about COVID-19 vaccination	Turkey	To investigate the COVID-19 vaccination rates in allergic children aged 12-19 y and evaluate contributing factors to vaccine hesitation	261	Cross-sectional study	Ad hoc questionnaire covering sociodemographic details of the child and parents, child's allergic disease type, COVID-19 vaccination status for both child and parents, reasons for vaccine acceptance or refusal, and the parent's perceived stress scale	4 of 124 individuals (3.22%) who were not vaccinated cited concerns about allergic reactions as a reason for the hesitancy; history of anaphylaxis did not significantly (P = .342) impact whether child received the vaccine or not

ARS, Agenzia regionale di sanità della Toscana; BIFAP, Base de Datos para la Investigación Farmacoepidemiológica en Atención Primaria; NMDs, neuromuscular disorders; PRR, proportional reporting ratio; ROR, reporting odds ratio; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; VAERS, Vaccine Adverse Event Reporting System; WDEIA, wheat-dependent exercise-induced anaphylaxis.

Evidence supporting findings from the original review

Incidence of anaphylaxis to COVID-19 vaccines

Our initial review of the literature from January 2020 to February 2022 found a low incidence of COVID-19 vaccine–induced anaphylaxis and allergic reactions (mean and median incidence for anaphylaxis = 12.4 cases per million doses and 5 cases per million doses, respectively; mean and median incidence for allergic reactions = 489.0 cases per million doses and 528.0 cases per million doses, respectively).⁹ In reviewing the literature published since that time, we have identified more support for this finding, as detailed below.

Among the included studies, 33 (73.3%) reported on the incidence of anaphylaxis following vaccination for COVID-19.13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45 Across these studies, anaphylaxis was found to range from 0.0% to 0.5% of doses. In 18 of these studies (54.5%), no cases of anaphylaxis were reported.16, 17, 18, 19, 20, 21, 22, 23, 24^,26, 27, 28, 29, 30^,32,35, 36, 37

In the United States, 5 studies investigated the frequency of postvaccination reactions, all of which consistently reported a low incidence of anaphylaxis.^{13,16,31,35,43} Al-Obaydi et al¹³ reported an incidence of 0.06% (3 of 5,340; 3 of 5,202) for anaphylaxis following both the first and second vaccine doses. Matson et al³¹ observed an incidence of 0.005% (6 of 106,872) for anaphylaxis among children aged 5-17 years old, with 3 cases occurring after the first dose and 3 following the second dose. Vanijcharoenkarn et al⁴³ noted that 0.4% (88 of 20,657) of doses resulted in allergic reactions, with 8% (0.032% of the total number of doses) likely representing anaphylaxis within this group. In their examination of adverse events following COVID-19 vaccination, Ahsanuddin et al⁴⁶ found 0.10% (1,323 of 1,280,950) of adverse events reported to the Vaccine Adverse Events Reporting System were coded as anaphylaxis. The remaining 2 American studies, by Connolly et al¹⁶ and Ou et al, ³⁵ reported no cases of anaphylaxis.

Thirteen European studies also reported on anaphylaxis incidence.^{17,18,20,21,23,24,30,32,34,37,41,42,44} In Germany, Niekrens et al³⁴ reported 4 cases of anaphylaxis, resulting in an incidence of 0.024% (4 of 16,704). In Switzerland, Stehlin et al⁴¹ reported an incidence of anaphylaxis at 0.003% (18 of 604,267). In a multinational study spanning Italy, The Netherlands, the United Kingdom, and Spain, Sturkenboom et al⁴² reported an incidence rate of 11.7 per 100,000 person-years for anaphylaxis. In Poland, Wentrys and Stopyra⁴⁴ reported an anaphylaxis incidence rate of 0.5% (4 of 800) among a mixed sample of adults with a history of severe anaphylactic reactions (57% of the sample) and those without a history of reactions (43% of the sample). Nine European studies documented no cases of anaphylaxis.^{17,18,20,21,23,24,30,32,37}

Thirteen studies conducted in Asia, primarily focused on exploring the safety profile and incidence of anaphylaxis, consistently reported low rates of anaphylaxis incidence.^14,15,19,22,25, 26, 27, 28, 29^,33,36,38,45 Three Chinese studies, which investigated various aspects of COVID-19 vaccine safety, reported a low incidence of anaphylaxis.^19,45,47 Wong et al⁴⁵ found that the incidence rate of anaphylaxis was 0.002% (27 of 1,308,820) for the first doses of the Pfizer-BioNTech Comirnaty vaccine (Pfizer, New York, NY; BioNTech, Mainz, Germany) and 0.0007% (7 of 955,859) for the Sinovac-CoronaVac vaccine (Sinovac Biotech, Beijing, China). After the second dose, the rates were 0.001% (13 of 1,116,677) and 0.0004% (3 of 821,560) for the Pfizer-BioNTech and Sinovac-CoronaVac vaccines, respectively. In a separate Chinese study involving patients with a history of wheat-dependent exercise-induced anaphylaxis, there were no reported cases of anaphylaxis.¹⁹ In a study of individuals who experienced allergic or urticarial reactions following vaccination for COVID-19, Wang et al⁴⁷ discovered that 3.9% (5 of 129) of patients who experienced reactions had symptoms consistent with anaphylaxis.

A Korean study reported an incidence of anaphylaxis to mRNA vaccines ranging from 0.03 to 0.05 cases per 100,000 doses, while for viral vaccines, the incidence rate was slightly higher at 0.09 cases per 100,000 doses.³⁸ In Japan, Imai et al²⁵ conducted a focused study on immediate hypersensitivity reactions following COVID-19 vaccination. Imai et al²⁵ reported an anaphylaxis incidence of 0.0002% (2 of 1,201,688). Two additional Japanese studies examining adverse reactions to the COVID-19 vaccine reported 0 cases of anaphylaxis.^22,26 In Turkey, 2 studies investigating adverse reactions found low anaphylaxis incidence.^15,27 Cebeci Kahraman et al¹⁵ reported an incidence of 0.13% (3 of 2290) for first-dose anaphylaxis and 0.05% (1 of 2189) for second-dose anaphylaxis, while Kara et al²⁷ reported no anaphylaxis cases. Similarly, 2 Singaporean studies by Lim et al²⁸ and Low et al²⁹ also reported no anaphylaxis cases. Furthermore, a Nepalese study investigating adverse events following immunization reported no cases of anaphylaxis.³⁶ In Syria, Najjar et al³³ reported an incidence of 0.06% (1 of 1,672).

A study conducted by Amarasinghe et al,¹⁴ which incorporated data from 31 countries in the WHO’s Western Pacific Region revealed varying reporting rates for anaphylaxis by vaccine type, ranging from 0.3 cases per 1 million doses administered for Sinopharm (Beijing, China) to 13.7 cases per 1 million doses for Pfizer-BioNTech. In Oceania, Shivarev et al⁴⁰ reported an incidence of 0.0016% (12 of 727,750), with 8 cases linked to Vaxzevria (AstraZeneca, Cambridge, UK) and 4 cases attributed to Comirnaty. This led to rates of 15.9 and 17.7 per million doses administered for Vaxzevria and Comirnaty, respectively.

Potential factors associated with anaphylaxis

Vaccine brand/type

In total, 5 of the 45 reviewed studies (11.1%) inferentially examined differences in the incidence of anaphylaxis across vaccine brands or types.^{15,38,40,42,45} The findings from this collection of studies were somewhat equivocal with 3 studies providing evidence of significant differences in anaphylaxis across various COVID-19 vaccines.^38,42,45 Results were also mixed in regard to whether the incidence of allergic reactions significantly differed across vaccine type (ie, mRNA, viral vector, inactivated). More specifically, 2 of the 3 studies that found significant differences across vaccines provided evidence that anaphylaxis was more common following vaccination with a mRNA-based vaccine,^38,45 while 1 study found higher rates of reactions with viral vector or inactivated vaccines.⁴² Notably, a WHO study in the Western Pacific region showed that the Pfizer-BioNTech vaccine exhibited the highest anaphylaxis reporting rate of the examined vaccines at 13.7 cases per 1 million doses, followed by AstraZeneca (9.9 cases per 1 million doses), Moderna (Cambridge, Mass; 8.9 per 1 million doses), Johnson & Johnson (New Brunswick, NJ; 5.6 cases per 1 million doses), Gamaleya (Moscow, Russia) (1.6 cases per 1 million doses), Sinovac (1.5 cases per 1 million doses), and Sinopharm (0.3 cases per 1 million doses).¹⁴ However, it is important to note that the study did not inferentially analyze these differences.

Hesitancy in relation to the COVID-19 vaccines

Review of the included studies revealed fear of allergic reactions to the COVID-19 vaccine was common. Although the proportion of participants expressing this concern varied considerably across papers (ie, 1.5%-73.2%), it was found to exceed 10% in 7 of the 9 reviewed studies that focused on vaccination-related concerns.48, 49, 50, 51, 52, 53, 54, 55, 56 A Singaporean study highlighted that 73.2% of respondents were concerned about anaphylaxis.⁵³ Not surprisingly, the majority of these papers also provided evidence linking fears of reactions to vaccine hesitancy.^48,49,51,54 For instance, Sayaca et al⁵⁴ found that 39% of individuals who did not consider getting vaccinated expressed concerns about the potential for allergic reactions, with similar findings reported by a Canadian study of patients with primary immunodeficiency.⁴⁸ Similarly, a Nigerian study on COVID-19 vaccine hesitancy reported that 28.5% of unvaccinated respondents cited allergic reactions as a reason preventing them from getting vaccinated.⁵¹ A German study assessing health care workers found that a significantly greater number of vaccine-hesitant participants reported concerns about allergic reactions, compared to individuals who accepted the vaccine.⁴⁹ In contrast to the previous findings, a Turkish study investigating vaccine hesitancy among the parents of children with allergic disease found that only 3% of parents whose children were not vaccinated expressed concerns about the potential for allergic reactions.⁵⁶ Taken as a whole, however, findings from the reviewed studies suggest that concerns about allergic reactions are often linked to vaccine hesitancy.

Emerging insights since the original review

COVID-19 vaccine hesitancy among health care professionals

Interestingly, results from the current review suggest that concerns regarding allergic reactions affect the vaccination decisions of not only the general population, but also health care professionals. A Turkish study that examined the attitudes of family medicine residents toward the COVID-19 vaccine found that 5% of residents would not recommend vaccination to patients with a history of allergic reaction/anaphylaxis.⁵⁷ Results also revealed that 43.2% of participants would not recommend further vaccination to patients who had a history of anaphylaxis after the first dose of the Pfizer-BioNTech vaccine. By comparison, 49.6% of the residents would not recommend further vaccination to patients who had anaphylaxis after the first dose of the Sinovac-CoronaVac vaccine.

In addition, some studies have demonstrated vaccine hesitancy among health care professionals and ancillary staff (ie, administrative personnel, laboratory scientists/technologists, and imaging personnel) due to fears of adverse reactions.49, 50, 51, 52 For instance, an American study discovered the proportion of nurses, advanced practice providers, and ancillary health care professionals who expressed concern (nurses: 36%; advanced care providers: 44%; ancillary staff: 39%) regarding allergic reactions was over double that of physicians (15%) and pharmacists (13%).⁵⁰ Similarly, 3 additional studies reported a notable proportion of health care professionals expressing hesitancy toward vaccination, citing concerns about postvaccination side effects and allergic reactions.^49,51,52

Discussion

Consistent with the original scoping review, the findings from the current review demonstrate anaphylaxis following COVID-19 vaccination continues to be rare. Despite the rarity of anaphylaxis, the literature indicates that a portion of the general population remains vaccine hesitant. Consistent with the literature included in the original review, many of the more recent studies have found that vaccine hesitancy associated with the potential for allergic reactions and anaphylaxis persists, which may indicate that risk communication surrounding such reactions to the COVID-19 vaccine has minimally, if at all, improved vaccine hesitancy.

Effective risk communication plays a crucial role in addressing vaccine hesitancy and promoting vaccine uptake. Qualitative research has provided valuable insights into the concerns and preferences of individuals living with allergy, enabling communicators to tailor their messages accordingly. One important finding from recent research is the need for tailored messages that directly address the concerns of individuals with allergy.⁵⁸ This suggests that a one-size-fits-all approach may not be effective in addressing vaccine hesitancy. Instead, communication efforts should be nuanced and customized to address the diverse range of concerns expressed by different individuals, patient populations, and communities.

Research also suggests that the source of the message plays a role in how well it is received.⁵⁸ Perhaps not surprisingly, health care providers, and public health agencies, have been cited as some of the most trusted sources of vaccine-related information.^59,60 In light of this, it appears as though allergists and immunologists have a particularly influential role to play in addressing the vaccination concerns of individuals with allergic disease and other immunological conditions. While addressing hesitancy is certainly no easy task, simply emphasizing the exceptionally rare nature of serious reactions following vaccination for COVID-19 may go some ways in reducing the concerns of patients.⁶¹ More generally, research has shown that adopting an assertive conversational style when discussing vaccinations, by using presumptive statements like: “Your son is due for his 4-month vaccines. We will give him these before you leave” is more effective in promoting acceptance than a participatory style (eg, “What do you want to do about your son’s vaccinations?”).⁶² For individuals who are especially entrenched in their hesitancy, follow-up visits reaffirming the importance of vaccination and motivational interviewing techniques have been shown to be effective in helping some individuals move toward acceptance.⁶²

A lack of access to health care professionals has also been reported to be a significant barrier to risk communication.⁵⁸ In such cases, alternative channels for information dissemination become essential. Pharmacists, community health workers, and designated personnel in administrative roles can serve as important intermediaries to deliver accurate vaccine information to individuals who may not have direct access to health care professionals. As we move past the acute phase of the pandemic, lessons like these should be considered and taken to heart well in advance of future outbreaks to ensure the necessary public health measures can be put into place as quickly as possible.

The current review expands on the previous findings by examining the attitudes and levels of vaccine acceptance among specific populations. By incorporating studies from different countries, exploring diverse ethnic groups, age groups, and occupational backgrounds, this review offers a broad perspective on the impact of anaphylaxis and vaccine hesitancy. For example, the current review has provided more insight into the attitudes of health care professionals toward allergic reactions, anaphylaxis, and vaccines. The concerns surrounding allergic reactions and anaphylaxis among health care providers underscore the critical role of timely, tailored, and evidence-based knowledge translation efforts. In the context of anaphylaxis, successful knowledge translation ensures that all members of the health care team are equipped with up-to-date information about anaphylaxis, minimizing knowledge gaps and ultimately promoting vaccine confidence.

Several limitations of the current review update warrant mention. This update, along with the original, used a narrative synthesis technique, as opposed to a meta-analysis. As a qualitative technique, narrative syntheses may be more likely to be affected by the biases of the reviewers, given that included studies are not synthesized quantitatively as they are in a meta-analysis. Also, it is important to highlight that although less severe reactions were frequently observed, the literature does not always explicitly specify whether these adverse events were allergic in nature. Defining severe allergic reactions, including anaphylaxis, can be challenging, which may introduce biases in the reported rates of such reactions. For instance, Hourihane et al⁶³ underscored the potential for ascertainment bias in reporting severe allergic reactions associated with COVID-19 vaccines. The study emphasized the importance of using appropriate diagnostic criteria and adequate clinical information when classifying postvaccination anaphylaxis to prevent overestimations of its incidence. Lastly, due to the brevity of this update, a comprehensive review of the gray literature was not included in the analysis.

Conclusion

As the severity of the COVID-19 pandemic continues to diminish, the literature describes the ways in which our response to the pandemic has been successful and provides suggestions for improvement in future outbreaks. The original review, along with the current update, highlight the rarity of anaphylaxis to all types of COVID-19 vaccines, including mRNA vaccines. Additionally, inconsistencies in defining anaphylaxis, may contribute to the overestimation of anaphylaxis risk and increased vaccine hesitancy. Despite the rarity of anaphylaxis, a sizeable proportion of individuals, both with and without allergic disease report being concerned about the potential for reactions. To prepare for future pandemics, it is evident that more efforts are needed to address these concerns. As part of this process, it is also important to ensure medical professionals are updated as new information becomes available and that evidence-based risk communication is accurate, accessible, and culturally appropriate for the patient population. Arguably, equipping health professionals with the tools to address hesitancy may provide one way to help ensure we are better prepared to face the next pandemic.

Disclosure statement

Funding for this study was provided by a COVID-19 Vaccine Confidence Operating Grant provided by the Canadian Institutes of Health Research, awarded to J.L.P. The funding body had no influence on the study design, data collection, analysis and interpretation, or manuscript writing.

Disclosure of potential conflict of interest: A. L. R. Batac serves on the Manitoba and Saskatchewan Steering Committee for ImmUnity Canada. P. Bégin is a member of Food Allergy Canada’s Healthcare Advisory Board and reports personal fees from ALK-Abelló, Aralez Pharmaceuticals, AstraZeneca, Bausch Health, Novartis, Pfizer, Sanofi-Genzyme, and Valeo Pharma; and has received grants from DBV Technologies, Novartis, Sanofi, and Regeneron Pharmaceuticals. M. Ben-Shoshan serves on several advisory boards, including Food Allergy Canada, Novartis, Sanofi, and Stallergenes Greer; reports personal fees from Bausch Health, Novartis, Sanofi, and Stallergenes Greer; has received grants from Stallergenes Greer; and has participated in clinical trials conducted by Aimmune Therapeutics, Novartis, and Sanofi. E. Ladouceur is the co-founder and director of Science for All Audiences; and reports consultancy for Novartis. J. L. Protudjer is the Section Head for Allied Health, Co-Lead of the Research Pillar for the Canadian Society of Allergy and Clinical Immunology; a member of the steering committee for Canada's National Food Allergy Action Plan; and reports consultancy work for Ajinomoto Cambrooke, ALK-Abelló, Novartis, and Nutricia. The rest of the authors declare that they have no relevant conflicts of interest.