INTRODUCTIONSevere allergic reactions to vaccines are rare and difficult to predict, generally occurring at a rate of approximately one event per million administrations. This topic review focuses on 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 allergic reactions to other vaccines, as well as information about the different COVID-19 vaccines, are found separately. (See “Allergic reactions to vaccines” and “COVID-19: Vaccines”.)

PREVACCINATION ASSESSMENT OF PATIENTS WITH CONTRAINDICATIONS TO VACCINATIONThe Centers for Disease Control (CDC) and Emergency Use Authorization (EAU) prescribing information for the COVID-19 vaccines indicate that a severe allergic reaction/anaphylaxis to a prior dose of the vaccine or any component of the vaccine is a contraindication to vaccination. To date, severe allergic reactions have been reported with the two messenger ribonucleic acid (mRNA) vaccines, produced by Pfizer-BioNTech and Moderna, and much less frequently after the viral vector vaccine produced by Janssen (Johnson & Johnson) (table 1) [1-3]. For patients who have had such reactions to a COVID-19 vaccine, we recommend evaluation by an allergist prior to the administration of additional doses, as described below. (See ‘mRNA vaccines’ below.)

The mechanism of the apparently allergic/anaphylactic reactions to COVID-19 vaccines has yet to be determined, and any potential causative allergen(s) are yet to be identified. The mRNA vaccines contain polyethylene glycol (PEG), which has rarely been implicated as an allergen in anaphylactic reactions to other PEG-containing products and medications. The viral vector vaccine contains polysorbate, which is structurally related to PEG, and has also rarely been implicated as an allergen in anaphylactic reactions to polysorbate-containing products and medications. Therefore, past anaphylaxis to PEG or polysorbate could be considered a contraindication to the administration of an mRNA or viral vector COVID-19 vaccine, respectively. However, to date, there is no confirmation that PEG or polysorbate allergy increases the risk for a reaction to COVID-19 vaccines, and we do not recommend any investigation of possible PEG or polysorbate allergy prior to the administration of these vaccines [4].

Many of the individuals who experienced possible anaphylaxis to the mRNA vaccines had a history of allergy to a variety of other allergens [1,2,5]. This association may be due to a heightened anticipation or appreciation of possible allergic symptoms by the patient or vaccine provider. While a history of anaphylaxis to other substances (eg, foods, medications, insect stings) is not considered a contraindication to vaccination by the CDC, it is recommended that such individuals remain for 30 minutes of observation after receiving the injection rather than the 15 minutes recommended for all vaccine recipients, although this additional wait time may be unnecessary [4]. As with any vaccine, all vaccination sites should be prepared with the medications (ie, epinephrine), training, and staff required to treat possible anaphylactic reactions.

CLINICAL MANIFESTATIONS

Immediate-type hypersensitivity reactions — Immediate-type hypersensitivity reactions are the result of the release of mediators from mast cell granules (degranulation) into local tissues or the systemic circulation. Most such 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 2), which typically begin within minutes to an hour of vaccination but can rarely be delayed beyond this timeframe.

The most common symptoms and signs are:

●Cutaneous symptoms, including flushing, itching, urticaria, and angioedema.

●Respiratory symptoms, including nasal discharge, nasal congestion, change in voice quality, stridor, cough, wheeze, and dyspnea.

●Cardiovascular symptoms, including faintness, syncope, altered mental status, palpitations, and hypotension.

●Gastrointestinal symptoms including nausea, vomiting, abdominal pain, and diarrhea.

Possible anaphylaxis — The most severe form of a mast cell-mediated (usually IgE-mediated) reaction is anaphylaxis, which is rapid in onset and may cause death [6]. Diagnostic criteria for anaphylaxis have been proposed by the National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium (table 3) [6]. The diagnosis of anaphylaxis is discussed in more detail separately. (See “Anaphylaxis: Acute diagnosis”.)

Mimics of anaphylaxis — It is important to recognize and treat anaphylaxis promptly, and, if the clinician is unsure if a reaction is anaphylactic, it is prudent to assume it is and treat accordingly (ie, with intramuscular epinephrine) (see “Anaphylaxis: Emergency treatment”). However, it is also important to understand that there are other reactions to vaccines that can mimic anaphylaxis, including vasovagal reactions and anxiety-related symptoms [7]. 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) are essential, and photographs of skin findings are very helpful to those evaluating the patient after the reaction has resolved. If anaphylaxis is suspected, a blood sample should be obtained within four hours of the acute onset of an apparent anaphylactic episode for mast cell tryptase (table 4) [8]. Although the result will not be available immediately, it is very useful for later evaluation because an elevated level essentially confirms the diagnosis of anaphylaxis, although a normal level does not exclude it. (See “Laboratory tests to support the clinical diagnosis of anaphylaxis”, section on ‘Tryptase’.)

Vasovagal reactions — Vaccine administration may elicit vasovagal reactions (fainting), particularly in patients who are prone to this response [9]. Vasovagal reactions are characterized by hypotension, pallor, diaphoresis, weakness, nausea, vomiting, bradycardia, and if severe, by 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 [10]. Fainting is usually preceded by 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 [11].

Anxiety-related symptoms — Vocal cord spasm can cause stridor and dyspnea, and panic attacks can cause a globus sensation, hypertension, tachycardia, dyspnea, and other symptoms [7]. Patients 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 dissociation. Some develop flushing in patches on the neck or face, but frank urticaria and angioedema are absent.

REACTIONS TO SPECIFIC VACCINESSeveral vaccines are available around the world for prevention of SARS-CoV-2 infection (table 1). The different types of vaccines are reviewed in more detail separately. (See “COVID-19: Vaccines”.)

mRNA vaccines — The first two vaccines to become widely available were mRNA vaccines, which contain mRNA in lipid nanoparticles. Produced by Pfizer-BioNTech and Moderna, both were granted emergency use authorization (EUA) by the US Food and Drug Administration (FDA) [12,13].

Possible anaphylaxis — Reactions with features of anaphylaxis following administration of both mRNA COVID-19 vaccines have been reported in the United Kingdom, the United States, Japan, and elsewhere [1,2,4,14]. The incidence of these reactions may be higher with these vaccines than with other vaccines, but the events are still rare. Reported rates vary with the surveillance method: 2.5 to 4.7 events per million with passive reporting [5], 4.8 to 5.1 events per million with active surveillance [15] and 7.91 events per million in a meta-analysis of adjudicated cases with one markedly higher outlier [4].

Most patients developed symptoms within 30 minutes of vaccination [2]. Some cases are being investigated to determine if they were anaphylactic, if they were IgE-mediated, and what the particular allergenic component(s) may be. 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 such reactions require prior exposure for sensitization. Also, the vast majority of allergens causing IgE-mediated reactions are proteins, and the mRNA vaccines do not contain protein. To date, an IgE-mediated mechanism has not been conclusively demonstrated. Complement activation-related pseudoallergy (CARPA) has also been theorized as a possible mechanism but not demonstrated [16].

Some cases have been described with rapid onset of symptoms and need for endotracheal intubation that clearly appear anaphylactic, although no investigation of mechanism was described [5]. However, most cases characterized and treated as anaphylaxis have subsequently been determined not to have been, and the patients have gone on to receive second doses uneventfully [17-20]. Many such patients have had early-onset symptoms of itching or tingling, the sensation of throat or tongue swelling or shortness of breath without objective signs of urticaria, angioedema, or wheezing. These reactions are consistent with anxiety-related reactions, termed “immunization stress related responses” (ISRRs) [7]. A questionnaire was administered to hospital employees after receiving the Pfizer/BioNTech mRNA COVID-19 vaccine, and reactions described by 55 of 2073 (2.7 percent) and 33 of 1856 (1.8 percent) respondents after first and second doses respectively were characterized as ISRRs [21]. Strong prevaccination anxiety and history of allergy were found to be risk factors for ISRRs.

At this point, there are no specific in vitro tests that can definitively diagnose the cause of a severe allergic reaction (eg, anaphylaxis) following COVID-19 vaccination. Referral to an allergy specialist is recommended for such patients, and most can receive additional doses with appropriate precautions.

Uncertain role of polyethylene glycol — There is no conclusive evidence to date that polyethylene glycol (PEG), which is an excipient in both of the mRNA COVID-19 vaccines, is responsible for allergic reactions to these vaccines, although it was suspected as a culprit when reactions were first reported. No other vaccines contain PEG, and the COVID-19 mRNA vaccines contain very small amounts of PEG 2000, which has a lower molecular weight than most PEGs in use [12,13]. Medications, bowel preps, and laxatives containing PEGs of higher molecular weight have caused allergic reactions [22,23]. PEG is structurally related to polysorbates and PEG castor oil (Cremophor), which have also been reported to cause allergic reactions [22,23]. Of note, these products contain much larger amounts of PEG than do the COVID-19 vaccines, and higher-molecular-weight PEGs have been more allergenic historically. The issue is further complicated by a study of PEG-allergic patients (but not vaccine reactors) using skin tests and basophil activation tests (BATs), suggesting that patients may react to PEGylated nanoparticles but not to PEG alone and that an atypical mechanism could be involved [24-26].

In contrast, there is accumulating evidence that PEG is not the culprit in the form of case series of patients who were known to be allergic to PEG or had past reactions to PEG-containing medications who subsequently tolerated the mRNA COVID-19 vaccines:

●Reactions consistent with anaphylaxis can occur with infusion of PEG-asparaginase for acute lymphoblastic leukemia. A reassuring report described a series of 65 young adults who had experienced allergic reactions to PEG-asparaginase in the past, although they had not undergone evaluation to determine if their reactions were caused by PEG or asparaginase [27]. Patients were contacted by phone and asked if they had received a COVID-19 vaccine. Fifteen had already received the vaccine without incident. Thirty-two were invited to receive the Pfizer-BioNTech vaccine in a supervised setting and were observed for 30 minutes without premedication. All tolerated vaccination without event.

●Another report describes 19 children and young adults with a history of immediate hypersensitivity reactions to PEG-asparaginase [28]. Five of the 19 had tolerated oral PEG since their PEG-asparaginase reaction, and the remaining 14 underwent PEG skin testing, all with negative results. All 19 tolerated first and second doses of the Pfizer COVID-19 vaccine uneventfully.

●Twenty-five patients with a history of immediate hypersensitivity reactions to Cremophor-containing paclitaxel or docetaxel received PEG-containing COVID-19 mRNA vaccines without immediate or delayed hypersensitivity reactions [29].

●In a series of 12 patients with confirmed or very likely PEG allergy, all received PEG-containing mRNA COVID-19 vaccines uneventfully [30].

●In another report, 235 patients with PEG or polysorbate reactions documented in their electronic medical records or referred to Allergy with reported PEG or polysorbate reactions received both doses of an mRNA COVID-19 vaccine uneventfully, except for three reporting mild rashes [31].

These studies argue strongly that patients with past allergic reactions to PEG or polysorbate in other medications can safely receive COVID-19 vaccines, without prior PEG skin testing or other special precautions.

Complement activation-related pseudoallergy — Another mechanism proposed as a possible cause of apparent mast cell-mediated reactions to PEG in mRNA COVID-19 vaccines is CARPA, where preexisting immunoglobulin G (IgG) or immunoglobulin M (IgM) antibody to PEG would activate complement, generating anaphylatoxins (C3a, C4a, and C5a), causing mast cell degranulation [16]. In a report of 11 patients with suspected allergic reactions to mRNA COVID-19 vaccines, evaluations for possible IgE-mediated anaphylaxis and for CARPA were performed [32]. None of the patients had positive skin test results or detectable serum specific IgE to PEG, and only one had a positive skin test result to the vaccine. However, 10 had positive BAT results to PEG, and all 11 had positive BAT results to the vaccines and measurable serum specific IgG to PEG. The authors conclude that the reactions are likely due to IgG anti-PEG-induced CARPA but acknowledge that additional studies are needed. 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 [33]. BAT is discussed separately. (See “Overview of in vitro allergy tests”, section on ‘Basophil tests’.)

MANAGEMENT

Immediate reactions to an initial dose — Our approach to patients who have 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, potentially anaphylactic reactions as we manage these two groups of patients differently. Note that the approach outlined here is consistent with the recommendations of an international expert panel, which were released in October 2021 [4]. The panel was composed of physicians from allergy, infectious disease, and emergency medicine and clinicians involved in administering vaccinations, and recommendations were based upon a systematic review and meta-analysis.

Mild reactions — Most patients with mild immediate vaccine reactions to the first dose of an mRNA COVID-19 vaccine do not require evaluation by an allergist or skin testing. The vast majority will go on to tolerate the second dose uneventfully [18,19,34]. We consider limited urticaria, flushing, subjective symptoms, or mild and spontaneously resolving chest or throat symptoms to be examples of mild reactions. We advise such patients to receive the second dose of the same vaccine in a setting in which they can be observed for 30 minutes after administration. Although the impact of nonsedating antihistamines on second dose reactions is unknown, some patients with mild reactions to first doses were advised to take a dose prior to their second dose, and we also recommend this. Examples include cetirizine (10 mg), loratadine (10 mg), fexofenadine (180 mg), and others, given one hour before vaccination.

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. Examples of moderate to severe reactions would include those that involved objectively observed diffuse urticaria, tongue or laryngeal edema, wheezing, hypotension, or emesis.

Both the Centers for Disease Control and Prevention (CDC) and the World Allergy Organization (WAO) recommend against administration of a second dose of an mRNA COVID-19 vaccine to a patient who has suffered a severe allergic reaction after the first dose, instead considering the substitution of a non-mRNA COVID-19 vaccine for the second dose [35,36]. The safety and effectiveness of this approach relative to administration of a second dose of the same mRNA COVID-19 vaccine that caused a reaction to the first dose (perhaps by graded dosing based on vaccine skin testing, with antihistamine pretreatment and prolonged observation) is unknown. As above, most cases characterized and treated as anaphylaxis have subsequently been determined not to have been, and the patients have gone on to receive second doses uneventfully. Thus, the choice of how to proceed in this circumstance should be informed by the severity of the original reaction and the timely availability of evaluation by an allergist. If such a reaction occurred after the first dose, the individual should ideally be evaluated prior to or at the due date of their second dose.

●Administer a non-mRNA vaccine – Non-mRNA vaccines available in different parts of the world include Ad26.COV2.S (Janssen), ChAdOx1 nCoV-19/AZD1222 (AstraZeneca), and NVX-CoV2373 (Novavax) (table 1). If a patient has had a severe reaction to the first dose of a mRNA COVID-19 vaccine, a non-mRNA vaccine can be given as a substitute for the second dose, as long as there is not also a contraindication to the other vaccine. Use of Ad26.COV2.S (Janssen) to complete an mRNA vaccine series has not been directly studied. However, some evidence on use of two different vaccines to complete a series suggests robust immunogenicity but a higher rate of systemic symptoms (fever, fatigue, headaches, myalgias) compared with using the same vaccine for both doses [37-39].

●Skin testing – If an allergist is available and residual vaccine for skin testing can be obtained, skin testing with the suspect vaccine is appropriate. This approach is identical to that used for evaluating immediate reactions to other vaccines (see “Allergic reactions to vaccines”, section on ‘Approach to the patient with suspected vaccine allergy’). The stability of any potential allergens in the mRNA vaccines is not known, and therefore skin testing should be performed using vaccine within the same six-hour timeframe from reconstitution used for vaccine administration. Some residual volume remains in multidose vials from both vaccines that can be used for skin testing to avoid wasting doses. Vaccine nearing its expiration date that would otherwise be discarded can also be used for skin testing. For many other vaccines, prick (epicutaneous) testing using the undiluted vaccine solution and intradermal testing using the vaccine solution diluted 1:100 have proved to be nonirritating concentrations [40]. For the Pfizer mRNA COVID-19 vaccine, the use of undiluted vaccine solution for both prick and intradermal testing has been reported to be nonirritating [41]. Of note, in patients who have previously received one or more doses of the vaccine with or without a history of a reaction, the intradermal vaccine skin test, whether positive or negative when read at 15 minutes, is likely to produce a delayed-type hypersensitivity reaction with induration beginning hours later and persisting for a couple of days, likely representing evidence of cell-mediated immunity [42]. Patients should be counseled that this late reaction may occur and is not relevant to the diagnosis of vaccine allergy.

•Negative result – Negative skin test results would argue that the reaction was not IgE mediated, and consideration can be given to administering the second dose as a single dose in a facility prepared to treat anaphylaxis with 30 minutes of observation. Although the impact on second-dose reactions is unknown, we premedicate with a nonsedating antihistamine, administered after skin testing, 30 minutes prior to the second dose.

•Positive result – In patients with positive skin test results, consideration can be given to administering the second dose in graded doses under close observation [43]. Although vaccine administration in graded doses is not considered a desensitization, the approach to management of symptoms during graded dosing would be similar, where if symptoms that develop resolve spontaneously or are successfully treated, the protocol can be resumed. For a vaccine where usual dose is 0.5 mL, administer graded doses of vaccine at 15-minute intervals:

–0.05 mL of 1:10 dilution

–0.05 mL of full strength

–0.10 mL of full strength

–0.15 mL of full strength

–0.20 mL of full strength

Administering second doses in these circumstances requires shared decision making with the patient, weighing the risk of a vaccine reaction against the risk of remaining inadequately vaccinated against COVID-19, and the possibility of administering a second dose substituting the available non-mRNA (ie, viral vector) vaccine [35].

In those patients with positive vaccine skin test results, polyethylene glycol (PEG) skin testing could be considered to assess PEG as a potential culprit allergen. However, such skin testing has proven to be of limited clinical utility [19]. In a study of 65 patients who had had immediate reactions (within four hours) to a first dose of an mRNA COVID-19 vaccine, only four had positive skin test results to PEG, two of whom went on to receive a second dose of the same vaccine uneventfully (one tolerated a dose of the Janssen vaccine as a substitute, and one did not receive the second dose). Among the 61 patients with negative PEG skin test results, 43 went on to receive a second dose of the same vaccine uneventfully, and five did not receive a second dose. However, 13 went on to have immediate reactions to their second dose of the same mRNA COVID-19 vaccine; most were mild, cutaneous reactions treated with antihistamines, but two patients received epinephrine for itching/rash, cough, and throat tightness. Thus, in this and other studies, PEG skin testing has demonstrated limited specificity and sensitivity [22,23], and skin testing with the vaccine itself, although also of uncertain sensitivity and specificity, may yield the most clinically relevant information [24].

●Assess immune status – Another alternative to the administration of a second dose of an mRNA COVID-19 vaccine that provoked a possible allergic reaction to the first dose would be to assess for the presence of anti-SARS-CoV-2 IgG antibody as evidence of immune reactivity to the first dose. Note that this requires an assay that detects antibody to the spike protein specifically, rather than the nucleocapsid protein, because infection typically leads to the production of antibodies to both spike and nucleocapsid proteins while vaccination leads to the production of antibodies only to spike protein. Some assays for antibody to SARS-CoV-2 spike protein use immunoassays that measure all anti-spike protein antibodies and typically provide qualitative (positive or negative) results, while others assays measure “neutralizing” antibodies that inhibit the interaction of spike protein with its receptor and typically provide quantitative results (measured titer) (see “COVID-19: Diagnosis”, section on ‘Testing following COVID-19 vaccination’). The particular level of anti-spike protein antibodies that represents a surrogate for or correlate of protection is not known. If a test for antibody to SARS-CoV-2 spike protein was positive and the risk of a reaction to a second dose were judged sufficiently high, the second dose could be withheld. However, it is very unlikely that a single dose provides the same level or duration of protection from disease as two doses, although a single dose may be sufficient in patients with prior positive COVID-19 antigen tests, whether symptomatic or not [44].

Delayed reactions — Other types of reactions reported with the mRNA COVID-19 vaccines include delayed urticarial reactions, late local reactions, and swelling at the site of dermal fillers.

Delayed-onset urticarial reactions — Occasionally, patients develop a few hives and/or mild angioedema several hours or days after administration, as with other vaccines. In contrast, the vast majority of the reported potentially serious systemic allergic reactions to the mRNA COVID-19 vaccines have occurred within 30 minutes of vaccination (most within 15 minutes). Hives and/or angioedema that develop hours or days later are exceedingly unlikely to represent an allergic reaction to the vaccine. Rather, this time course corresponds to the beginning of the normal immune/inflammatory response to an immunization, which may include the generation of cytokines or other factors that lead to non-IgE-mediated mast cell degranulation. In a study of 10 patients with delayed urticarial reactions after their first dose of an mRNA COVID-19 vaccine, only four developed delayed urticaria after their second dose and had no other symptoms [45]. As such, we do not believe that patients who develop hives or other mild symptoms more than two hours after vaccination require additional evaluation. Rather, we recommend that they receive their second vaccine dose on time in the usual manner but take a nonsedating antihistamine one hour before and be observed for 30 minutes after vaccination. This approach is often used for allergen immunotherapy and is unlikely to mask or delay the recognition of a serious allergic reaction.

Persistent urticaria — Some patients develop urticaria and angioedema after receiving a COVID-19 mRNA vaccine or booster, and the outbreaks continue to occur. Urticaria or angioedema that has no obvious cause and occurs most days of the week for more than six weeks is classified as chronic spontaneous urticaria (CSU). CSU has been reported in association with the Moderna mRNA booster in particular, although not exclusively [46]. In a study of over 800 patients in two cohorts with newly diagnosed CSU referred from allergy practices, 81 and 90 percent occurred after the administration of a booster dose of a COVID-19 mRNA vaccine, with 92 and 94 percent of cases associated with the Moderna vaccine or booster. Onset of urticaria was between 8 and 13 days after vaccination, and, in those patients with subsequent resolution, the duration of symptoms varied from two to six months. Based on the number of vaccine doses administered, the incidence rate for CSU after a COVID-19 mRNA vaccine was calculated to be 24 per 100,000 (0.024 percent). No data were provided regarding the baseline incidence of CSU unrelated to COVID-19 vaccines. Thus, although it is possible that COVID-19 mRNA vaccines, particularly Moderna, can precipitate CSU, this would appear to be rare, and such causality cannot be stated with certainty from this observational study without an appropriate control group. The management of CSU is reviewed elsewhere. (See “Chronic spontaneous urticaria: Standard management and patient education”.)

Late local reactions — In addition to the common injection-site reactions that may involve some combination of pain, redness, and swelling and typically occur within a day or two of vaccination, late-onset injection-site reactions have also been observed, mostly after first doses of the Moderna vaccine but also after the ChAdOx1n CoV-19 (AstraZeneca/Oxford) vaccine [47]. In a series of 12 patients, late local reactions developed a median onset of day 8 after vaccination and resolved over a median of six days [48]. Features included a fairly well-demarcated area of erythema, often accompanied by swelling and tenderness (picture 1). Some reactions have an overlying dermatitis. A second series of 12 patients with such reactions describes similar nature, onset, and duration [49]. The timing coincides with what is likely a robust local humoral and cellular immune response to the spike protein being generated by the vaccine mRNA at the injection site. Systemic symptoms are variable. Although such reactions could mimic cellulitis, infection after vaccination is uncommon.

Late local reactions typically resolve without treatment other than ice or an analgesic if they are painful or an antihistamine if they are pruritic. Although systemic glucocorticoids would likely hasten their resolution, they might also interfere with the immune response. Topical corticosteroids might be helpful and are unlikely to interfere with immunologic responses. We have recommended that patients with such reactions receive their second dose in the usual manner on time but in the opposite arm. There have been no recurrences of late-onset local reactions, but a minority of patients report similar but early-onset local reactions to their second doses [48,49]. The timing of these possible recurrences makes them difficult to distinguish from the more common injection-site reactions that occur within a day or two of first or second vaccine doses. The mechanism of these reactions is unclear; biopsy of one such lesion was consistent with delayed-type hypersensitivity [48], although it is unclear why the reactions would tend not to recur if this were the mechanism [50].

Swelling at site of dermal fillers — Facial swelling in areas previously injected with cosmetic dermal fillers has been reported following receipt of the Moderna vaccine. The pathophysiology is not yet clear, but local inflammation and fluid retention are proposed to play a role. These reactions are discussed separately. (See “COVID-19: Cutaneous manifestations and issues related to dermatologic care”, section on ‘Soft tissue fillers’.)

OTHER VACCINESThere are other vaccines for the prevention of SARS-CoV-2 infection that use viral vector platforms or contain recombinant proteins (table 1). Among 13,725 reports submitted to the Vaccine Adverse Events Reporting System (VAERS) after receipt of the viral vector vaccine produced by Janssen (Johnson & Johnson), there were 79 reports of anaphylaxis, but only four were confirmed as anaphylaxis cases after review (<0.5 cases per 1 million doses administered) [3]. Clusters of anxiety-related adverse events have also been reported after receipt of the Janssen vaccine [51].

REPORTING OF REACTIONSOnline registries have been established for health care professionals to report potential cases of anaphylaxis and allergic reactions to any COVID-19 vaccine, which can be accessed at Global surveillance for anaphylaxis reactions to COVID vaccines (qualtrics.com) and COVID-19 Vaccine Allergy Case Registry (partners.org).

SOCIETY GUIDELINE LINKSLinks to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See “Society guideline links: COVID-19 – General guidelines for vaccination” and “Society guideline links: COVID-19 – Index of guideline topics”.)

SUMMARY AND RECOMMENDATIONS

●Evaluation prior to vaccination – Allergy evaluation prior to receipt of the first dose of any coronavirus disease 2019 (COVID-19) vaccine is not required, even for patients with a history of anaphylaxis and those with possible allergy to polyethylene glycol (PEG). (See ‘Prevaccination assessment of patients with contraindications to vaccination’ above.)

●Immediate reactions (usually within 30 minutes) – Immediate reactions with features of anaphylaxis have been reported after immunization with COVID-19 vaccines, particularly after the messenger ribonucleic acid (mRNA) vaccines.

The reported incidence of 2.5 to 4.7 events per million administrations is higher than reported rates of anaphylaxis (approximately 1 per million) with other vaccines. Although some of the reactions appear consistent with anaphylaxis, the majority are more consistent with stress-related responses upon careful evaluation. (See ‘mRNA vaccines’ above.)

The mechanism of severe immediate/anaphylactic reactions to COVID-19 vaccines has not been determined. Although initially presumed to be immunoglobulin E (IgE) mediated, investigations of potential allergens, including PEG, have been inconclusive. (See ‘Possible anaphylaxis’ above.)

●Management after an immediate reaction – The management of individuals who had reactions to the first dose of an mRNA vaccine depends upon the severity of the reaction. (See ‘Immediate reactions to an initial dose’ above.)

•Mild reactions – Mild reactions include limited urticaria, flushing, subjective symptoms, or mild and spontaneously resolving chest or throat symptoms. Most patients who have had mild immediate reactions to first doses of mRNA vaccines have received second doses uneventfully or with only mild repeat reactions.

For these patients, we suggest administration of the second dose of the same vaccine along with pretreatment with a nonsedating antihistamine (Grade 2C). Observation for 30 minutes post-administration is advised. (See ‘Mild reactions’ above.)

•More severe reactions – More severe symptoms include objectively observed diffuse urticaria, tongue or laryngeal edema, wheezing, hypotension, or emesis.

For these patients, advice may vary depending on vaccine availability and patient preference. Options include:

–Administration of a non-mRNA COVID-19 vaccine as a substitute for the second dose (table 1); the safety and effectiveness of this approach is unknown.

–Allergy evaluation that includes skin testing to the causative vaccine.

If results are negative, the second dose of the same vaccine can be administered after pretreatment with a nonsedating antihistamine and with 30 minutes of observation afterward.

If testing is positive, consideration can be given to administering the same vaccine in graded doses under observation, using shared decision making with the patient. (See ‘Moderate and severe reactions’ above.)

–Another option is measurement of anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein antibodies to see if the patient has already generated a response; however, the levels that correlate with protection from disease are unknown.

●Delayed reactions (>2 hours after administration) – Late-onset or delayed reactions after receipt of the COVID-19 vaccines include delayed urticarial reactions appearing hours to days after vaccination and late-onset local injection-site reactions beginning several days after vaccination (picture 1). These reactions are not contraindications to second doses of the same vaccine, as they are not anaphylactic in origin. (See ‘Delayed reactions’ above.)