Version July 2025
INTRODUCTION —
Severe hypersensitivity reactions to vaccines (of all types) are rare and difficult to predict, generally occurring at a rate of approximately one event per million administrations. This topic review focuses on immediate allergic reactions to vaccines to prevent infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the disease it causes (coronavirus disease 2019 [COVID-19]). A detailed discussion of immediate allergic reactions to other vaccines is found separately. (See "Allergic reactions to vaccines".)
Immediate hypersensitivity reactions typically begin within minutes to an hour of vaccination, and they are the focus of this topic review. Late-onset or delayed reactions may also occur. For the COVID-19 vaccines, delayed reactions include injection-site reactions, large local reactions (also known as "COVID arm"), morbilliform eruptions, delayed urticarial reactions appearing hours to days after vaccination, and the new onset of chronic spontaneous urticaria. These reactions are discussed in more detail separately. (See "COVID-19: Cutaneous manifestations and issues related to dermatologic care", section on 'Cutaneous adverse events' and "New-onset urticaria (hives)".)
IMMEDIATE HYPERSENSITIVITY REACTIONS
Classic immunologic mechanisms — Immediate-type hypersensitivity reactions typically begin within minutes to an hour of vaccination but can rarely be delayed beyond this timeframe. Immediate reactions to the COVID-19 vaccines have been defined in an international consensus document as "a generalized, systemic allergic reaction with acute onset occurring within four hours of vaccine administration" [1,2].
Immediate allergic reactions are the result of the release of mediators from mast cell granules (degranulation) into local tissues or the systemic circulation. Classic immunologic immediate reactions are immunoglobulin E (IgE) mediated (ie, due to an allergen cross-linking IgE antibody molecules bound to IgE receptors on mast cells). However, mast cell degranulation can occur due to the direct engagement of other receptors on mast cells by other exogenous or endogenous factors. Mast cell-mediated reactions may involve various combinations of up to 40 potential symptoms and signs (table 1). Of note, there is scant evidence that immediate reactions to COVID-19 vaccines are immunologic in nature [1].
The most severe form of a mast cell-mediated (usually IgE-mediated) reaction is anaphylaxis, which is rapid in onset and may cause death [3]. Diagnostic criteria for anaphylaxis have been proposed by the National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium (table 2) [3]. The diagnosis of anaphylaxis is discussed in more detail separately. (See "Anaphylaxis: Acute diagnosis".)
The utility of serum tryptase — If anaphylaxis is suspected, a blood sample should be obtained within four hours of the acute onset of an apparent anaphylactic episode for serum tryptase (table 3) because an elevated level essentially confirms the diagnosis of anaphylaxis [4]. Although the result will not be available immediately, it is very useful for later evaluation. (See "Laboratory tests to support the clinical diagnosis of anaphylaxis", section on 'Tryptase'.)
Mimics of anaphylaxis — It is important to recognize and treat anaphylaxis promptly. If the clinician is unsure if a reaction is anaphylaxis, it is prudent to assume it is and treat it accordingly with intramuscular or intranasal epinephrine (see "Anaphylaxis: Emergency treatment"). However, there are other, more common reactions to vaccines that can mimic anaphylaxis, including anxiety-related symptoms and vasovagal reactions [5].
Anxiety-related symptoms — Anxiety-related reactions were so consistently observed during the years of the COVID-19 pandemic that the syndrome was assigned a new term: immunization stress-related response (ISRR) [6].
Anxiety-related symptoms often lack objective findings, such as urticaria or reductions in blood pressure. Thus, careful recording of vital signs and physical exam findings (including skin, oropharynx, and lungs) is essential during an immediate reaction, and photographs of skin findings (taken with the patient's cellphone so they are available for future review) are very helpful to those evaluating the patient after the reaction has resolved.
Patients with ISRRs may report a variety of subjective symptoms, such as feelings of warmth without objective flushing; tingling of the mouth, face, or hands; dizziness; and sensations of dissociative neurologic symptoms. Some develop flushing in patches on the neck or face, but frank urticaria and angioedema are absent.
More severe ISRRs may involve vocal cord spasm causing stridor and dyspnea or a globus sensation, hypertension, tachycardia, dyspnea, and other symptoms [5]. Vocal cord dysfunction (inducible laryngeal obstruction) and vasovagal responses can develop as distinct reactions or as part of an ISRR [6].
Risk factors for ISRRs include a previous negative experience with injections or vaccines, expressed fear of injections, a history of vasovagal syncope, and preexisting anxiety [6]. Studies of apparent allergic reactions, most of which turned out to be ISRRs, report a large female preponderance [7].
Vasovagal reactions — Vaccine administration may elicit vasovagal reactions (fainting), particularly in patients who are prone to this response [8]. Vasovagal reactions are characterized by hypotension, pallor, diaphoresis, weakness, nausea, vomiting, bradycardia, and, if severe, loss of consciousness. Vasovagal reactions can mimic anaphylaxis because both may involve hypotension and collapse. However, the cutaneous signs and symptoms are usually quite different [9]. Vasovagal syncope is usually preceded by bradycardia and pallor, whereas anaphylaxis often begins with flushing and may also include itching, urticaria, and angioedema. In anaphylaxis, (reflex) tachycardia is more common than bradycardia.
In patients who report past fainting in response to vaccinations, it is prudent to administer future vaccines while the patient is lying supine [10].
IMMEDIATE REACTIONS TO COVID-19 VACCINES —
Vaccines of different types are available worldwide for prevention of SARS-CoV-2 infection (table 4), as reviewed in detail separately. (See "COVID-19: Vaccines".)
mRNA vaccines — The messenger ribonucleic acid (mRNA) vaccines, which contain mRNA in lipid nanoparticles, are produced by Pfizer-BioNTech and Moderna [11,12]. Most cases characterized and treated as anaphylaxis have subsequently been determined to be immunization stress-related responses (ISRRs) [1]. To our knowledge, no fatalities due to allergic reactions to any COVID-19 vaccine have been reported [1].
Incidence — Immediate reactions with features of anaphylaxis following administration of both mRNA COVID-19 vaccines have been reported worldwide [2,13-15]. The incidence of immediate reactions may be higher with the mRNA COVID-19 vaccines than with other vaccines, although they are still rare.
Rates vary with the surveillance method but are estimated at approximately 5 events per million:
●2.5 to 4.7 events per million with passive reporting [16]
●4.8 to 5.1 events per million with active surveillance [17]
●7.91 events per million in a meta-analysis of adjudicated cases, with one markedly higher outlier [2]
Signs and symptoms — Most patients developed symptoms within 30 minutes of vaccination [1,2,14]. The majority of immediate reactions to COVID-19 vaccines are consistent with ISRRs. (See 'Anxiety-related symptoms' above.)
Frequently reported symptoms included (table 5) [1,6]:
●Itching, tingling, or transient numbness, especially of the face
●A sensation of throat or tongue swelling
●Shortness of breath without repetitive cough or wheezing to suggest bronchospasm
●Tachycardia, increase in systolic blood pressure
●Deep, rapid breathing
●Lightheadedness, dizziness without hypotension
●Nausea
●Dissociative symptoms
●Lack of objective signs, such as urticaria, angioedema, hypotension, or wheezing
In a 2022 study, a questionnaire was completed by hospital employees after administration of the Pfizer/BioNTech mRNA COVID-19 vaccine, and reactions were described by 55 of 2073 (2.7 percent) and 33 of 1856 (1.8 percent) respondents after first and second doses, respectively [18]. These reactions were consistent with ISRRs. A high level of prevaccination anxiety and a history of allergy were found to be risk factors, consistent with what is known about predisposing factors for ISRRs [5]. (See 'Anxiety-related symptoms' above.)
Very rare cases have been described with rapid onset of symptoms and need for endotracheal intubation that seem more likely to have been anaphylactic [16], although no investigation of mechanism was described, and the episodes may have been vocal cord spasm.
Unclear mechanism(s) — No clear mechanism of hypersensitivity has been identified to explain immediate reactions resembling anaphylaxis to the mRNA vaccines. Most are believed to be ISRRs. Many patients have gone on to receive second doses of the same vaccine uneventfully [1,7,19-22].
●IgE mediated – An IgE-mediated mechanism has not been conclusively demonstrated. Most reactions developed after first doses, raising the question of how prior sensitization could have occurred if the reactions were, in fact, IgE mediated since sensitization requires prior exposure. Also, the vast majority of allergens that cause IgE-mediated reactions are proteins, and the mRNA vaccines do not contain any protein. An excipient in the mRNA vaccines, polyethylene glycol (PEG), was initially suspected to be allergenic.
PEG is commonly found in medications, laxatives, bowel preps, and personal products and rarely implicated in allergic reactions. PEG is structurally related to polysorbates and PEG castor oil (Cremophor), which have also been reported to cause rare allergic reactions [23,24]. However, the medications where PEG has been implicated as the culprit allergen contain much larger amounts and are of higher molecular weights than the PEGs in the mRNA vaccines [25,26]. Further, hundreds of patients with known or suspected PEG allergy have received PEG-containing mRNA COVID-19 vaccines uneventfully [27-31].
●Complement activation-related pseudoallergy – Complement activation-related pseudoallergy (CARPA) has also been theorized as a possible mechanism but not conclusively demonstrated [32]. It is proposed that preexisting immunoglobulin G (IgG) or immunoglobulin M (IgM) antibody to PEG could activate complement, generating anaphylatoxins (C3a, C4a, and C5a) and causing mast cell degranulation [32]. In one report of 11 patients with immediate reactions to mRNA COVID-19 vaccines, investigators did find some evidence to support this hypothesis [33]. All 11 patients had positive basophil activation test (BAT) results to the vaccines, and 10 had positive BAT results to PEG and measurable serum IgG specific to PEG. The authors concluded that immediate reactions to mRNA vaccines could be due to IgG anti-PEG-induced CARPA. However, among the factors complicating this interpretation are that some of the reported reactions may not have been mast cell mediated, only three control subjects were evaluated, and a substantial portion of the general population may have anti-PEG IgG or IgM [34]. BAT is discussed separately. (See "Overview of in vitro allergy tests", section on 'Basophil tests'.)
●Other possible mechanisms – Another proposed mechanism posits that the mRNA in these vaccines could be recognized through Toll-like receptors 3, 7, and 8 and cause mast cell degranulation [35,36]. However, there is no direct evidence that this is responsible for immediate reactions to COVID-19 vaccines.
Protein vaccines — Protein-based COVID-19 vaccines are available worldwide (table 4). In the United States, the only vaccine of this type available is the Novavax vaccine, which uses a recombinant protein platform, also called a protein subunit vaccine (table 6). Severe immediate hypersensitivity reactions have been reported less frequently after these vaccines [1,37]. The excipient in several protein vaccines is polysorbate 80 [2]; however, like PEG, it has not been shown to be responsible for immediate reactions to COVID-19 vaccines.
REPORTING OF REACTIONS —
As with all vaccines, serious reactions should be reported to the Vaccine Adverse Event Reporting System (VAERS) in the US or to vaccine surveillance programs in other countries. In addition, an online registry has been established to report potential cases of anaphylaxis and allergic reactions to any COVID-19 vaccine, which can be accessed at COVID-19 Vaccine Allergy Case Registry (VACR).
RECOMMENDATIONS FOR SPECIFIC SCENARIOS —
The recommendations presented in this section are consistent with those from the United States Centers for Disease Control (CDC) and a systematic review, meta-analysis, and consensus statement from an international group of experts in anaphylaxis composed of allergy, infectious disease, emergency medicine, and other clinicians, which was published initially in 2021 and updated in 2023 [1,2,38].
Contraindications to COVID-19 vaccines — The CDC states that a severe allergic reaction/anaphylaxis to a prior dose of a COVID-19 vaccine or any component of the vaccine is a contraindication to vaccination with the same vaccine [38]. The CDC states that individuals can receive a different type of COVID-19 vaccine. However, evidence that these reactions are allergic in nature is lacking, and there are data that patients with past immediate reactions to a given vaccine can safely receive the same vaccine [1,39]. (See 'Moderate and severe reactions' below.)
Initial vaccination of people with various allergies — Many of the individuals who experienced immediate reactions to the mRNA vaccines had a history of allergy to a variety of other allergens [13,14,16]. This association may be due to a heightened anticipation or appreciation of possible allergic symptoms by the patient or vaccine provider. A history of anaphylaxis to other substances (eg, foods, medications, insect stings) is not considered a contraindication or precaution to vaccination.
Patients with suspected or known allergies to PEG or polysorbates — For patients with suspected or proven allergy to polyethylene glycol (PEG) or polysorbates, no special precautions are needed for administration of a COVID-19 vaccine. Specifically, we do not advocate any investigation of possible PEG or polysorbate allergy, either prior to initial vaccination or after an immediate reaction [1,2,40]. The reasoning behind this approach is that PEG and polysorbates are ubiquitous, allergic reactions to them are rare, and it is not clear that these excipients are responsible for immediate reactions to the COVID-19 vaccines. In addition, anticipatory allergy testing to PEG and polysorbates is not useful, because it has unknown sensitivity and specificity for predicting immediate reactions to COVID-19 vaccines [1,2]. (See 'Unclear mechanism(s)' above.)
Revaccination of patients with past immediate reactions — The CDC recommends that everyone ages six months and older should get the current COVID-19 vaccine, including people who have received a COVID-19 vaccine before and people who have had COVID-19. However, for patients who are not at high risk for severe illness with COVID-19, vaccination may be less critical than it was earlier in the pandemic. Vaccines reduce the risk of severe COVID-19 and death, although the baseline risk of those outcomes in the context of preexisting immunity from prior infection and/or vaccination is uncertain and likely already low for those without risk factors. Thus, there may be rare circumstances where patients who have had a prior reaction would choose, through shared decision making, to forgo additional vaccine doses. Indications for vaccination are summarized elsewhere. (See "COVID-19: Vaccines", section on 'Indications and vaccine selection'.)
Our approach to repeat vaccination of patients who experienced immediate symptoms to the first dose of an mRNA COVID-19 vaccine is to distinguish those with mild reactions from those with more severe immediate reactions as we manage these two groups of patients differently.
Premedications are not necessary — For patients with past immediate reactions to COVID-19 vaccines, premedication with antihistamines or glucocorticoids is not necessary, and the use of glucocorticoids could theoretically alter the immune response to the vaccine. However, patients who take these medications daily for other reasons can continue their normal doses [1].
Mild reactions — Most patients with mild immediate reactions to the first dose of an mRNA COVID-19 vaccine do not require evaluation by an allergist or testing of any type prior to revaccination. The vast majority will go on to tolerate the second dose or the same or a different vaccine uneventfully [7,20,21]. As with any vaccine, all vaccination sites should be prepared with the medications (ie, epinephrine), training, and staff required to treat possible anaphylactic reactions.
Examples of mild immediate reactions include subjective symptoms, limited urticaria, flushing, or mild and spontaneously resolving chest or throat symptoms occurring within the first four hours after vaccination. We reassure such patients these mild reactions are well recognized with the COVID-19 vaccinations, not believed to represent potentially serious allergy, and that professional societies and the United States CDC provide options of receiving additional doses of a different vaccine type in the usual vaccination setting or additional doses of the same vaccine type and consider observation for 30 minutes after administration [38].
Moderate and severe reactions — Patients who have experienced moderate or severe, potentially anaphylactic immediate reactions to the first dose of an mRNA COVID-19 vaccine should be referred to an allergist for evaluation, if possible, prior to the administration of additional doses. Examples of moderate-to-severe reactions would include those that involved objectively observed diffuse urticaria within one hour of the vaccine, observed tongue or laryngeal edema, wheezing, or hypotension. If referral is not available, a different vaccine type can be administered in the usual vaccination setting [38].
Referral — Most cases characterized and treated as anaphylaxis have subsequently been determined not to have been allergic in nature, and many patients have gone on to receive second doses uneventfully [1,2,39]. Thus, the decision to refer should be informed by the severity of the original reaction and the timely availability of an allergy specialist. The allergy specialist will review the patient's past reaction in detail but likely do no skin or in vitro testing to excipients or to the vaccines. Instead, they can review options for future vaccination with the patient and, in some cases, administer additional doses under observation.
Studies of patients with immediate reactions to mRNA COVID-19 vaccines have shown vaccine skin testing to have limited diagnostic accuracy in predicting subsequent reactions [1]. Similarly, when subsequent doses are delivered by graded dosing, the rates of reaction are similar to when the subsequent doses are delivered as a single dose [1]. Thus, vaccine skin testing and graded dosing are generally not recommended [1].
If true anaphylaxis is suspected — In an individual patient who has had a moderate-to-severe immediate reaction that is more consistent with true anaphylaxis than an immunization stress-related response (ISRR), skin testing with the suspect vaccine (prick full strength and, if negative, intradermal 1:100) may be considered [41]. If skin test results are negative, the vaccine can be administered in a single dose under observation. If skin testing is positive, consideration could be given to administering the vaccine in graded doses (0.05 mL of 1:10 dilution, 0.05 mL of full strength, 0.1 mL of full strength, 0.15 mL of full strength, 0.2 mL of full strength at 15-minute intervals) under observation [42]. This is a general approach used for immediate reactions to conventional vaccines. (See "Allergic reactions to vaccines", section on 'Skin testing-based strategy'.)
SUMMARY AND RECOMMENDATIONS
●Immediate reactions – Immediate reactions with features of anaphylaxis have been reported after immunization with coronavirus disease 2019 (COVID-19) vaccines, particularly after the messenger ribonucleic acid (mRNA) vaccines. The reported incidence (5 events per million administrations) is higher than that for other vaccines (1 per million). However, despite extensive investigation, neither an allergen nor an allergic mechanism has been identified for these reactions, and the vast majority are believed to be immunization stress-related responses (ISRRs) and not true anaphylaxis. These reactions typically occur within 30 minutes of administration. Common symptoms include pruritus, tingling or transient numbness (especially of the face), a sensation of throat or tongue swelling, shortness of breath, tachycardia, hypertension, deep and rapid breathing, lightheadedness, and/or dissociative symptoms. Notably, objective signs, such as urticaria, angioedema, wheezing, or hypotension, are lacking. (See 'Immediate reactions to COVID-19 vaccines' above.)
●Contraindications to revaccination are evolving – The United States Centers for Disease Control (CDC) states that a severe allergic reaction/anaphylaxis to a prior dose of a COVID-19 vaccine or any component of the vaccine is a contraindication to vaccination with the same vaccine type and that such individuals can receive a different type of COVID-19 vaccine. However, evidence that these reactions are allergic in nature is lacking, and there are data that patients with past immediate reactions to a given vaccine can safely receive the same vaccine. Therefore, the decision of which vaccine to choose should be based on evaluation by an allergist and shared decision making with the patient. (See 'Contraindications to COVID-19 vaccines' above.)
●Evaluation prior to initial vaccination – For individuals with a history of anaphylaxis due to any cause (eg, foods, medications, or stinging insects) allergy evaluation prior to administration of any COVID-19 vaccine is not indicated or useful. This applies even to patients with a proven allergy to excipients in these vaccines (eg, polyethylene glycol [PEG] or polysorbates) since there are multiple case series of patients with known allergies to these excipients who tolerated the COVID-19 vaccines. (See 'Patients with suspected or known allergies to PEG or polysorbates' above.)
●Revaccination after a prior immediate reaction – Options for revaccination after a prior immediate reaction to a COVID-19 vaccine are either administration of a different type of COVID-19 vaccine from the one that caused the reaction (either an mRNA vaccine or a protein vaccine) or administration of the same vaccine (table 6). Our approach is determined by the severity of the previous reaction and shared decision making with the patient:
•Mild reactions – Mild reactions include limited urticaria, flushing, subjective symptoms, or mild and spontaneously resolving chest or throat symptoms. For patients with mild previous immediate reactions to an mRNA COVID-19 vaccine, any COVID-19 vaccine can be safely administered, including the same mRNA vaccine that was associated with the reaction. This can be given as a single dose, in a usual vaccination setting, and with an optional 30 minutes of observation. (See 'Mild reactions' above.)
•Moderate and severe reactions – Moderate-to-severe symptoms include objectively observed diffuse urticaria, tongue or laryngeal edema, wheezing, or hypotension. These patients should be referred to an allergist for evaluation, if possible, prior to receiving another dose of the same type of COVID-19 vaccine. Allergy evaluation will likely consist of revisiting the history of the reaction, patient reassurance, and administration of the same or a different vaccine under observation.
If referral is not possible, we suggest that patients with moderate or severe past immediate reactions to an mRNA vaccine receive a protein-based COVID-19 vaccine (Grade 2C). This can be given as a single dose, in a usual vaccination setting, and with an optional 30 minutes of observation. (See 'Moderate and severe reactions' above.)
●Patient preparation for revaccination – For patients with past reactions to COVID-19 vaccination, we suggest against any premedication prior to repeat vaccination (Grade 2C), although patients who chronically take antihistamines or glucocorticoids need not alter their normal regimens. (See 'Premedications are not necessary' above.)
