Allergic reactions to vaccines

INTRODUCTION — 

Severe allergic reactions to vaccines are rare and difficult to predict. An allergic reaction may be defined as an idiosyncratic reaction that is caused by an immunologic mechanism.

The World Allergy Organization (WAO) has recommended categorizing immunologic reactions to drugs (including vaccines) based upon the timing of the appearance of symptoms [1]. This system defines two general types of reactions: immediate and delayed. This approach is intended to distinguish immunoglobulin E (IgE) mediated (type I immunologic reactions), which account for many immediate reactions, from other types because these reactions carry the risk of life-threatening anaphylaxis if the patient is reexposed (table 1).

●Immediate reactions begin within one hour of administration and may begin within minutes. IgE-mediated reactions are most likely to present within this time period.

●Delayed reactions appear several hours to days after administration. These reactions may be caused by several different mechanisms, but they are rarely IgE mediated.

This topic review focuses on immediate-type allergic reactions to vaccines, although delayed reactions are also discussed briefly. Of note, reactions to coronavirus disease 2019 (COVID-19) vaccines, as well as the administration of influenza vaccine to egg-allergic patients, are discussed separately (see "COVID-19: Immediate hypersensitivity reactions to SARS-CoV-2 vaccines" and "Influenza vaccination in persons with egg allergy"). Additional information about other types of adverse reactions to immunization, including unsubstantiated concerns about autism, is found in reviews of specific vaccines elsewhere within UpToDate. (See "Autism spectrum disorder and chronic disease: No evidence for vaccines or thimerosal as a contributing factor".)

CLINICAL MANIFESTATIONS

Immediate reactions — Immediate IgE-mediated allergic reactions may involve various combinations of up to 40 potential symptoms and signs (table 2).

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, sensation of throat closure or choking, stridor, cough, wheeze, and dyspnea

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

Anaphylaxis — The most severe form of an IgE-mediated allergic reaction is anaphylaxis. Anaphylaxis is defined as a systemic allergic reaction that is rapid in onset and may cause death [2]. Diagnostic criteria for anaphylaxis have been proposed by the National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium (table 3) [2]. The diagnosis of anaphylaxis is discussed in more detail separately. (See "Anaphylaxis: Emergency treatment".)

In a patient with suspected anaphylaxis to a vaccine, it is extremely helpful to record vital signs and physical exam findings (including skin, oropharynx, and lungs) and photograph skin findings if possible.

A blood sample should be obtained within four hours of an apparent anaphylactic episode for mast cell tryptase [3]. Although the result will not be available immediately, it is very important for subsequent evaluation because an elevated level would confirm the diagnosis of anaphylaxis, although a normal level would not exclude it.

Incidence — Anaphylactic reactions to vaccines are rare, with rates from active surveillance studies ranging from 0.3 to 2.9 per million vaccine doses [4-7]. A review of reports to the Vaccine Adverse Event Reporting System (VAERS) over 26 years from 1990 to 2016 describes eight deaths possibly caused by anaphylactic reactions to vaccination [6].

Timing — When anaphylaxis occurs after administration of a vaccine, patients generally develop symptoms within 30 minutes [6,8,9], although the onset may rarely be delayed up to several hours [4,5]. The later-onset reactions tend to be less severe. Reactions that occur hours to days after vaccine administration could be due to delayed absorption of the allergenic component. Alternatively, some of these late reactions may not be causally related to vaccination but rather due to exposure to another allergen after vaccination.

Mimics of anaphylaxis — While it is important to recognize and treat anaphylaxis, it is equally important not to label these other conditions as anaphylaxis, particularly when there are no objective findings. There are other, more common reactions to vaccines that could mimic an anaphylactic reaction, including vasovagal reactions and anxiety-related symptoms, termed immunization stress-related response (ISRR) [10]. The term ISRR was introduced during the coronavirus disease 2019 (COVID-19) pandemic, when this type of reaction to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines was so common that an educational effort was begun to increase awareness among health care providers. The table summarizes the features of reactions that can resemble anaphylaxis (table 4).

Vasovagal reactions — Vaccine administration may elicit vasovagal reactions (fainting), particularly in patients who are prone to this response [11]. 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 [12]. With vasovagal reactions, 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 the bradycardia typical of vasovagal reactions.

In patients who report past fainting in response to vaccinations, it is prudent to administer future vaccines while the patient is lying supine and to counsel the patient to mention this going forward [13].

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 [10].

Delayed vaccine reactions — Several types of delayed reactions to vaccines have been noted, including common reactions like fever or local swelling and various rare reactions. These may be immunologic or nonimmunologic in nature.

●Fever – Fever, irritability, fatigue, myalgias, and/or headache are common after vaccination and should not preclude additional doses of the same vaccine in the future [14,15].

●Local reactions – Local reactions to vaccination, such as swelling and redness at the injection site, are common and self-limited. Symptoms usually develop a day or two after administration and may last for several days. They should not be considered reasons for avoiding administration of further doses of the vaccine [14,15]. Local reactions can be treated with cool compresses for the first hours after symptoms appear or with acetaminophen or nonsteroidal antiinflammatory drugs (NSAIDs) if pain or swelling is troublesome. However, antipyretics should not be administered empirically or prophylactically, as a few studies have found that these medications may reduce the immune response to vaccination. This issue is discussed separately. (See "Standard immunizations for children and adolescents: Overview", section on 'Prophylactic medications'.)

It was believed that shorter intervals between certain vaccine doses were associated with increased rates of local reactions, although studies have now shown that this is not the case. The recommended interval between doses of tetanus-containing vaccines had been 10 years. New vaccines were recommended in 2006 to provide not only booster doses for tetanus and diphtheria (Td) but also to pertussis (Tdap) [16-18]. Two subsequent studies reported rates of local reactions in patients given the new vaccine. In one, the rates of injection-site reactions to Tdap were no different among subjects who had received Td within the past two years compared with those vaccinated with Td more than two years before [19]. Another study found no higher rates of injection-site reactions whether a Tdap-containing vaccine was administered one month after a Td-containing vaccine or after placebo [20].

●Serum sickness and serum sickness-like reactions – Serum sickness and serum sickness-like reactions involve rash, fever, malaise, and polyarthralgias or polyarthritis, occurring one to two weeks after vaccination or sooner if the patient has received the vaccine more than once. (See "Serum sickness and serum sickness-like reactions".)

●Other rare reactions – Delayed immunologic reactions include rare cases of persistent, itchy injection-site nodules to aluminum-containing vaccines that may be related to delayed-type hypersensitivity to aluminum [21]. Another rare reaction is encephalopathy. Some of these more severe reactions may constitute contraindications to further doses of specific vaccines [14,15].

REACTIONS TO COVID-19 VACCINES — 

Reactions to vaccines to prevent infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease 2019 (COVID-19) are discussed in detail separately. (See "COVID-19: Immediate hypersensitivity reactions to SARS-CoV-2 vaccines".)

REACTIONS TO VACCINE CONSTITUENTS — 

Many different nonmicrobial constituents of vaccines could potentially result in systemic allergic reactions, including anaphylaxis. Possible sources of allergenic proteins in vaccines include gelatin, hen's egg, antimicrobial agents, yeast, and natural rubber latex (NRL).

Sources of information — The Institute for Vaccine Safety maintains online lists of potential allergens and excipients contained in vaccines. Package inserts for vaccines available in the United States are available online from the Institute for Vaccine Safety and the US Food and Drug Administration.

Gelatin — Gelatin, which is added to several vaccines as a stabilizer, is responsible for many anaphylactic reactions to measles, mumps, and rubella (MMR) and varicella vaccines (table 5) [22-25] (see 'Sources of information' above). Anaphylaxis from gelatin in an older gelatin-containing influenza vaccine has also been reported [26]. Anaphylaxis to gelatin-containing vaccines have been described in patients sensitized to alpha-gal, a carbohydrate allergen that also causes allergy to mammalian meats [27,28]. (See "Allergy to meats".)

A history of allergy to the ingestion of gelatin and gelatin-containing foods (eg, marshmallows and "gummi" candies) should be sought prior to the administration of any gelatin-containing vaccine (table 5). However, a negative history of an allergic reaction to the ingestion of gelatin does not exclude gelatin as being responsible for an allergic reaction when injected with the vaccine, and patients who have experienced a reaction to a vaccine may require testing for gelatin allergy [23]. (See 'Skin testing with vaccines and vaccine constituents' below.)

Persons who react to gelatin on ingestion should be evaluated by an allergist prior to receipt of gelatin-containing vaccines (table 5) [29,30]. If the history is consistent with an immediate-type allergic reaction to gelatin and this is confirmed by skin tests or serum-specific IgE antibody tests to gelatin, a non-gelatin-containing form of the vaccine should be administered if available (table 5), or skin tests with gelatin-containing vaccines should be performed prior to administration. If the vaccine skin tests are negative, the vaccine can be given in the usual manner but the patient observed for at least 30 minutes afterward. If the vaccine skin tests are positive, the vaccine can be administered in graded doses.

The incidence of allergic reactions to gelatin in vaccines was particularly high in Japan, a phenomenon that was subsequently attributed, in part, to genetic characteristics of the population [31,32]. Japanese manufacturers removed gelatin from some vaccines and switched to a more thoroughly hydrolyzed gelatin in others, with a dramatic reduction in the rate of reactions [33]. These strategies have been variably adopted in other countries, and reactions to gelatin in vaccines still occur.

Hen's egg — Hen's egg protein is present in yellow fever, MMR, and some influenza and rabies vaccines (table 6). However, the amount is not clinically significant, and all of these vaccines can be given normally to patients with hen's egg allergy without preceding evaluation or skin testing. (See 'Sources of information' above.)

●Influenza, MMR, and rabies vaccines may be safely administered in the usual manner to patients with egg allergy. It is not necessary to inquire about egg allergy prior to the administration of these vaccines, including on screening forms [34,35]. (See "Influenza vaccination in persons with egg allergy" and 'Measles, mumps, and rubella' below.)

●Yellow fever vaccine has also been shown to be safe for people with hen's egg allergy, although this was determined more recently, and, at the time of this update, some package inserts may still advise skin testing with the vaccine prior to administration. Studies demonstrating that skin testing is not necessary include the following:

•In the largest study, 171 children with egg allergy, including 24 percent with a history of anaphylaxis to egg ingestion, underwent skin testing with the vaccine [36]. Five had a positive skin prick test (SPT) result, and 21 had a positive intradermal skin test (IDT) result. Among the 26 with positive skin test results, 10 received the vaccine is a single dose and 11 in divided doses. All 171 tolerated the vaccine without reaction, irrespective of their vaccine skin test results or whether the vaccine was administered in single or divided doses.

•Two earlier studies of 24 and 71 patients with egg allergy, including some with anaphylaxis, reached the same conclusion [37,38].

Thus, yellow fever vaccine can be administered to egg-allergic recipients as a single dose without prior vaccine skin testing.

Cow's milk — Casein, an allergenic protein contained in cow's milk, has been implicated in causing anaphylaxis to diphtheria, tetanus, and pertussis vaccines (DTaP or Tdap) in a small number of severely milk-allergic children [39]. The vaccines are prepared in a medium derived from cow's milk protein, and nanogram quantities of residual casein have been demonstrated in these preparations. However, the vast majority of even severely milk-allergic patients have no allergic reactions to these vaccines. (See 'Tetanus' below.)

Thimerosal, aluminum, and phenoxyethanol — Thimerosal, aluminum, and phenoxyethanol are added to some vaccines as preservatives, although the use of thimerosal (which contains mercury) in vaccines has decreased dramatically due to theoretical concerns about cumulative mercury exposure in children. (See "Standard childhood vaccines: Caregiver hesitancy or refusal", section on 'Why caregivers refuse vaccines' and "Autism spectrum disorder and chronic disease: No evidence for vaccines or thimerosal as a contributing factor", section on 'Mercury toxicity'.)

These preservatives have not been documented to cause immediate-type allergic reactions to vaccines, and immediate-type skin testing is not indicated. They can cause delayed-type hypersensitivity reactions and contact dermatitis when applied topically to the skin, however:

●Contact sensitivity to them is not a contraindication to receiving vaccines containing them [14,15,40-42]. There is a case report of an adult who developed a generalized maculopapular rash to a thimerosal-containing influenza vaccine [43]. This was thought to be a T cell-mediated allergic response to thimerosal because of a positive patch test to this substance. This is a rare and unpredictable complication if indeed there is actually a causal relationship.

●The ability of these agents to cause delayed local reactions after vaccination is another concern for which some limited evidence exists. One study examined 125 patients with patch test-positive contact sensitivity to thimerosal or its derivatives who were challenged with intramuscular injections of thimerosal [44]. Only 4 percent (five patients) developed mild local reactions to the injection, indicating that local reactions are uncommon even in these contact-sensitized patients.

●Rarely, aluminum-containing vaccines cause persistent nodules at the injection site, possibly because of delayed hypersensitivity or other immune responses to aluminum [21].

Thus, patch testing or any specific testing for suspected sensitivity to these preservatives for the purpose of assessing a patient's ability to tolerate a vaccine containing it is not necessary. Patch testing can be performed for the diagnosis of allergic contact dermatitis, but this is not helpful in relation to vaccination. If a patient with documented contact dermatitis to one of these additives is concerned about receiving a vaccine containing the same agent, then it is prudent to administer a formulation that does not contain it, if available. Similarly, if a patient with known contact sensitivity has had a bothersome local reaction to a vaccine containing the preservative in the past and needs another, it would be prudent to give a product that is free of that preservative, if available. However, if a vaccine without the preservative is not available, the risk of any local reaction is minimal and should not preclude vaccination. (See 'Sources of information' above.)

Antimicrobials — Several antimicrobials may be added in trace amounts to vaccines, most commonly neomycin, polymyxin B, and streptomycin. Although there are no specific reports of vaccine-induced anaphylaxis in which these drugs were found to be the cause, the rare patients who have experienced anaphylactic reactions confirmed to be due to these antibiotics should not receive vaccines containing them without prior evaluation by an allergist. (See 'Sources of information' above.)

In contrast, contact dermatitis to these antimicrobials is not a contraindication to administration of vaccines containing trace amounts of them.

Latex — The "rubber" in vaccine vial stoppers or syringe plungers may be either dry natural rubber (DNR) latex or synthetic rubber. Patients with anaphylaxis to latex can safely receive vaccines from vials with synthetic rubber stoppers, obviously, but can likely also safely receive vaccines from vials with DNR stoppers.

It is exceedingly unlikely that latex-allergic patients would have a reaction to the DNR materials associated with vaccine administration. Although stoppers made with latex pose a theoretical risk, either as a result of liquid vaccine solution extracting latex allergens from the stopper by physical contact or by passing the needle through the stopper and retaining latex allergen in or on the needle, very few reports exist of this. One report of an anaphylactic reaction after hepatitis B vaccine administered to a latex-allergic patient was attributed to rubber in the stopper [45]. However, a review of >160,000 reports from the Vaccine Adverse Event Reporting System (VAERS) found only 28 cases of possible immediate-type allergic reactions after receiving a DNR-containing vaccine, and none were proven to have been caused by DNR [46]. In addition, a study of four different vaccine products contained in vials with DNR stoppers found undetectable levels of a major latex allergen [47].

In addition, patients with allergic contact dermatitis to latex products may receive vaccines from vials with latex stoppers [14,15].

Yeast — Some vaccines contain yeast protein, including hepatitis B vaccines (up to 50 mg per 1 mL dose) and human papillomavirus vaccines (<7 mcg per 0.5 mL dose), but adverse reactions to them, if any, appear to be rare [48]. Further, yeast allergy itself is very rare.

Dextran — Dextran has been implicated in allergic reactions to a particular brand of MMR vaccine previously used in Italy and Brazil [49]. The reactions were related to the presence of immunoglobulin G (IgG) antibodies to dextran, and the mechanism was hypothesized to be complement activation and anaphylatoxin release. This brand of vaccine has been withdrawn from the market, although dextran is found sporadically in other vaccines (eg, some rotavirus vaccines).

IgE-MEDIATED REACTIONS TO SPECIFIC VACCINES — 

The literature contains various reports of IgE-mediated reactions to specific vaccines, as summarized in this section. Rarely, these involve anaphylactic reactions to the microbial components of the vaccine.

Diphtheria — There is a report of anaphylaxis after a diphtheria (DT) booster with skin tests and radioallergosorbent tests (RAST) positive to both DT and tetanus toxoids [50]. Generalized hives attributed to IgE directed against the DT component of "Di-Te-Pol" (diphtheria-tetanus-polio) vaccine are also reported [51]. Children with reactions to DT vaccines sometimes lose the hypersensitivity with time, so a childhood reaction to this vaccine does not necessarily preclude its future use [52].

Hepatitis B vaccine — There are a few reports consistent with anaphylaxis to the hepatitis B vaccine, but none have been confirmed with skin tests or measurement of allergen-specific IgE in serum [53]. Reviews of the literature on adverse reactions to hepatitis B vaccination suggest that the rate of anaphylaxis is less than 1 in 100,000 vaccinations [54].

Haemophilus influenzae type b — There are a few reports consistent with anaphylaxis to Haemophilus influenzae type b (Hib) vaccine, but none have been confirmed with skin tests or measurement of allergen-specific IgE in serum [53]. There is a case of anaphylaxis after Hib-conjugate vaccine demonstrated to be due to the nontoxic diphtheria CRM197 conjugating protein [55]. This report demonstrates the importance of determining the specific culprit allergen since other vaccines contain the same conjugating protein.

Human papillomavirus vaccine — Anaphylaxis following administration of the human papillomavirus vaccine has been reported [11,56]. In most cases, this occurred after the initial dose of this vaccine, although a few patients developed symptoms after the second dose. Gardasil contains trace yeast proteins and the stabilizer polysorbate 80. However, four patients who had apparent anaphylactic reactions to it were skin test negative to the vaccine, baker's yeast, and polysorbate 80. Vaccination in adolescents is associated with a high rate of syncope, which may account for some of the events diagnosed as anaphylaxis [13].

Influenza — Some influenza vaccines contain hen's egg protein, although not in sufficient quantity to provoke reactions in egg-allergic recipients. Reactions to the influenza vaccine in egg-allergic patients are discussed in detail separately. (See "Influenza vaccination in persons with egg allergy", section on 'Risk of anaphylaxis to vaccines'.)

In Japan in 2011 and 2012, there was a three- to fivefold increase in influenza vaccine-associated anaphylaxis, which was reported in 36 children without egg allergy, of whom 19 were subsequently investigated [57]. These 19 had abnormally high levels of IgE directed against whole vaccine and against several hemagglutinin proteins, while they did not have egg-specific IgE or IgE directed against the various excipients in the vaccines. Skin testing with full-strength vaccine was performed in just 3 patients but was positive in all 3 and negative in 10 control patients, including some with egg allergy. The patients' basophils were activated when incubated with the vaccine. These findings suggest (but do not prove) that the allergen was some component (possibly hemagglutinin) of the vaccine. Interestingly, all reactions were caused by a vaccine from one specific manufacturer, and this preparation was unique in containing the preservative 2-phenoxyethanol (2-PE). IgE to 2-PE was not detected in the patients' sera, but the authors hypothesized that 2-PE may interact with vaccine components to enhance allergenicity in some way. The manufacturer replaced the 2-PE with thimerosal, and reaction rates returned to baseline.

In a subsequent Japanese study, whole vaccine-specific IgE and IgG were measured in 393 healthy children who had uneventfully received influenza vaccines [58]. Levels were assessed before and after one dose of vaccine or two doses of vaccine administered four weeks apart. Prior to vaccination, vaccine-specific IgE was present at baseline in 30 percent of those six months to two years of age and up to 70 percent of older children, presumably due to vaccination in prior years. Some additional increase in vaccine-specific IgE was observed after vaccination in the youngest age groups. Vaccine-specific IgG was also detected in most children and at higher levels in those who also had measurable vaccine-specific IgE. Vaccine-specific IgG/IgE ratios increased following vaccination in all age groups. The authors investigated the vaccine-specific IgG/IgE ratios in a separate group of five patients who had anaphylaxis after previous influenza vaccination, and this ratio was markedly lower compared with children who had tolerated the vaccine. Thus, it would appear that it is quite common to develop both vaccine-specific IgE and IgG after influenza vaccination, likely directed at hemagglutinin protein. In most vaccine recipients, the IgG, which may function as "blocking" antibody, is sufficient to protect from IgE-induced reactions. However, patients who develop higher amounts of IgE relative to IgG may be susceptible to allergic reactions.

Japanese encephalitis — Some immediate-type anaphylactic reactions have been reported with the Japanese encephalitis (JE) vaccine, including some reactions in which patients had IgE antibodies to gelatin [25]. With this vaccine in particular, there have been many reports of late-onset anaphylaxis (many hours to two weeks after vaccination) [59]. A new JE vaccine does not contain gelatin. Whether or not this vaccine will have a lower rate of adverse reactions has yet to be determined [60].

Measles, mumps, and rubella — Most anaphylactic reactions to measles, mumps, and rubella (MMR) are due to gelatin allergy [23,61]. There is no relation to hen's egg allergy since the vaccine contains no, or a minuscule amount of, egg protein. The safety of administering MMR vaccine to people with egg allergy was demonstrated in a study of 54 children who had never been vaccinated but had confirmed egg allergy [62]. Skin testing was performed with the vaccine in 17 children, and 3 were positive. All the children were given the MMR vaccine as a single full dose, and none had immediate or delayed adverse reactions.

Meningococcus — Anaphylactic reactions to meningococcal polysaccharide or polysaccharide-protein conjugate vaccines are very rare: one per million doses [63].

Pneumococcus — There are two reports of anaphylaxis in children who received 23-valent pneumococcal vaccine [64,65]. IgE antibody to the vaccine was demonstrated by skin tests or measurement of allergen-specific IgE in serum. A case of anaphylaxis after the 13-valent pneumococcal conjugate vaccine implicated the nontoxic diphtheria CRM197 conjugating protein as the allergen [66].

Rabies — There are several reports consistent with anaphylaxis to gelatin-containing rabies vaccines where gelatin has been determined to be the culprit allergen [67-70]. Some late-onset (several days after vaccination) serum sickness-like reactions and urticaria associated with IgE antibodies to betapropiolactone-altered human serum albumin in the vaccine have also been reported [71].

Tetanus — There are a few reports consistent with anaphylaxis (including fatalities) to tetanus vaccines, some of which were supported by positive skin tests and elevated levels of allergen-specific IgE directed against the tetanus and diphtheria (Td) toxoids [50,53,72,73]. However, children with reactions to DT vaccines sometimes lose the hypersensitivity with time, so a childhood reaction to this vaccine does not necessarily preclude its future use [52].

Diphtheria, tetanus, and pertussis vaccines (DTaP or Tdap) may also contain trace (nanogram) quantities of residual casein (an allergenic cow's milk protein) from the milk-based medium in which they are produced [39]. The possibility that this residual casein could be responsible for some anaphylactic reactions to the vaccines was raised by a case series of eight children who developed anaphylaxis within one hour (six within 20 minutes) of receiving DTaP or Tdap [39]. All had markedly elevated levels of milk-specific serum IgE (59 to >100 kIU/L) prior to vaccination. Six had histories of past allergic reactions to milk, and two had had milk removed from the diet in the setting of atopic dermatitis or proctocolitis (see "Milk allergy: Clinical features and diagnosis"). The results of this report require confirmation [74]. Most patients, even those with severe milk allergy, tolerate the vaccines as evidenced by the observations that milk allergy is common in infants and anaphylaxis to these vaccines is rare.

Typhoid — Rare anaphylactic reactions have been reported to both the injected Vi polysaccharide vaccine and the oral live-attenuated Ty21a vaccine [75]. Some of these reports involve the typhoid vaccines administered alone and others when the vaccines were coadministered with vaccines such as yellow fever. Although no tests for IgE antibody were reported, one patient appeared to have a reaction to rechallenge with the injected vaccine after a prior reaction to Ty21a, suggesting possible cross-reactivity.

Although there are several other reports of severe reactions to typhoid vaccine within one hour of vaccination, the reports are not consistent with anaphylaxis but rather involve high fever, vomiting, and headache [76].

Varicella — The rate of anaphylaxis is reported to be three reactions per million doses [77]. Most anaphylactic reactions to varicella vaccine are due to gelatin allergy [24].

Yellow fever — Anaphylaxis has been reported following the administration of yellow fever vaccine more often than following other vaccines [78,79]. The constituent responsible for these apparently IgE-mediated reactions has not been identified conclusively, but the vaccine contains hen's egg proteins and gelatin. The safety of the vaccine in people with hen's egg allergy has been studied and the risk shown to be negligible (see 'Hen's egg' above). Thus, gelatin may be the culprit, and anaphylactic reactions appear to be lower with a formulation of the vaccine that does not contain gelatin [80].

Zoster — Zoster vaccine is well tolerated [81]. Rare anaphylactic events have been reported in patients who reacted to gelatin in an older version of the vaccine, including one where alpha-gal appeared to be the allergen [27]; however, the current recombinant vaccine does not contain gelatin. (See 'Gelatin' above.)

APPROACH TO THE PATIENT WITH SUSPECTED VACCINE ALLERGY — 

The approach described in this section is consistent with published practice guidelines [82,83]. The algorithms distinguish between patients with a history of a suspected allergic reaction to a vaccine constituent (algorithm 1) and those with a history of a suspected allergic reaction to vaccine administration (algorithm 2).

Suspected allergic reaction to a vaccine constituent

●Gelatin – If the patient has a known or suspected immediate-type allergic reaction to gelatin, a non-gelatin-containing form of the vaccine should be administered if available (table 5), or skin tests with gelatin-containing vaccines should be performed prior to administration (prick skin test with undiluted vaccine and, if negative, intradermal skin test with vaccine diluted 1:100); if skin test results are negative, the vaccine can be administered as a single dose with 30-minute observation, and, if skin test results are positive, the vaccine can be administered in graded doses (algorithm 1).

●Other constituents – If a patient has known or suspected immediate-type allergic reaction to cow's milk, hen's egg, latex, or yeast, they can receive all vaccines in the usual manner (algorithm 1).

Suspected allergic reaction to vaccine administration — If the patient has a history of a suspected allergic reaction to vaccine administration, additional information should be sought (algorithm 2).

Are the nature and timing of reaction consistent with anaphylaxis? — The first step is to determine if the nature and timing of the reaction are consistent with an IgE-mediated reaction/anaphylaxis (table 2). If instead the reaction is more consistent with an immunization stress-related response (ISRR), subsequent doses can be administered in the usual manner but the patient observed for 30 minutes afterward.

Is there a history of a similar reaction? — It is also important to obtain a possible history of similar reactions to the same or other vaccines or to vaccine constituents. The various components of a vaccine are clearly listed in the package inserts supplied by the manufacturers. Package inserts for vaccines available in the United States are available online from the Institute for Vaccine Safety and the US Food and Drug Administration.

If the reaction occurred with the first dose of a vaccine, the chance that the immunizing agent itself is the allergen is greatly diminished. In this clinical situation, health care professionals should also inquire about allergic reactions to food, particularly gelatin (table 5).

Is there a need for future doses of this vaccine or other vaccines with common components? — Once a history has been obtained of a vaccine reaction occurring shortly after administration that is consistent with an IgE-mediated reaction, the clinician should determine if future doses of the suspect vaccine, or other vaccines with common components, are required. Given the potential for cross-reaction with common components in other vaccines and with foods, a thorough evaluation is appropriate, even if no further doses of the suspect vaccine are required.

Many vaccines are given as a series, yet some recipients generate an adequate response to fewer than the usual number of doses. Thus, if a prior possible reaction is concerning enough to consider withholding additional doses, it is reasonable to determine the antibody level achieved by the doses already received. Protective levels of specific antibody have been determined for many vaccines, and some are routinely available in commercial reference laboratories. If a patient has already generated a protective response, then it may not be necessary to give the remaining doses in the series. However, the level of protective antibody may not persist as long in persons vaccinated with fewer than the usual number of doses.

SKIN TESTING WITH VACCINES AND VACCINE CONSTITUENTS — 

If a patient with a suspected IgE-mediated reaction to a vaccine is to receive further doses, skin testing with the vaccine should be performed. Proper performance and interpretation of skin tests requires expertise in the procedure, including the use of appropriate positive and negative controls. Also, skin tests themselves can rarely cause anaphylactic reactions in highly allergic individuals. Thus, skin testing should only be performed by persons such as allergists with training in interpretation of and treatment of possible reactions to the tests and only in a setting where anaphylactic reactions can be recognized and treated quickly. (See "Overview of skin testing for IgE-mediated allergic disease".)

Methods — The vaccine should first be tested by the skin prick method. Full-strength (undiluted) vaccine can be used, unless the history of reaction was truly life threatening, in which case it is appropriate to dilute the vaccine before skin prick testing (SPT) [82].

If the full-strength prick test is negative, a more sensitive intradermal test (IDT) with the vaccine diluted 1:100 in 0.9% (isotonic) saline should be performed, again with appropriate positive and negative controls. (See 'Irritant reactions' below.)

Interpreting skin tests to vaccines — The history of the reaction is critically important in interpreting skin tests to vaccines. Clinically irrelevant positive skin tests are possible, as with skin testing to any allergen. The presence of a positive skin test to a vaccine is not necessarily predictive of a subsequent reaction, although it must be viewed as a significant risk factor. (See 'Administration of vaccines' below.)

Vaccines can induce IgE antibody production in the days to weeks after vaccination, although the clinical significance of this is unclear. Specific IgE to diphtheria (DT) and tetanus toxoids was induced by vaccination and found to persist for at least two years after immunization [84,85]. This specific IgE was not associated with allergic reactions with subsequent vaccination.

Irritant reactions — Irritant (false-positive) skin test reactions are also possible, particularly with IDT at concentrations of 1:10 or undiluted. One study of 20 adult volunteers without histories of vaccine reactions evaluated responses to SPT and IDT with 10 common vaccines [86]. Irritant reactions were not seen with SPT and were uncommon after IDT with a 1:100 concentration. However, they were common at higher intradermal concentrations (1:10 or undiluted). Thus, IDT to vaccines should only be performed at the 1:100 concentration.

Delayed reactions — Delayed-type hypersensitivity reactions at the site of skin testing (particularly intradermal) with a vaccine have been observed. These reactions are not relevant to the diagnosis of IgE-mediated vaccine allergy.

Testing for vaccine constituents — If the suspect vaccine contains cow's milk, hen's egg (yellow fever), gelatin (table 5), latex, or Saccharomyces cerevisiae yeast (hepatitis B and 4- and 9-valent human papillomavirus), the patient should also be skin tested to these constituents:

●Skin prick testing:

•Milk, egg, and Saccharomyces cerevisiae yeast extracts for skin testing are commercially available.

•Gelatin extract can be prepared by dissolving 1 teaspoon of sugared gelatin powder of any color or flavor (eg, Jell-O) in 5 mL of normal saline to create a prick skin test solution.

•Standardized extracts of natural rubber latex (NRL) for skin testing are commercially available in many countries, although not in the United States.

●Measurement of allergen-specific IgE in serum – Specific IgE to milk, egg, gelatin, latex, and yeast can be measured in serum by using commercially available immunoassays. The sensitivity of the latex ImmunoCAP and Immulite assays is approximately 80 percent, as discussed separately. (See "Latex allergy: Epidemiology, clinical manifestations, and diagnosis", section on 'Serology testing'.)

"Screening" skin tests — In patients who have had an apparent allergic reaction after a vaccine, skin testing with the vaccine in question is appropriate to assess whether or not the reaction was IgE mediated and to guide subsequent dosing and observation. In vitro tests (ie, specific IgE immunoassays) are not available to assess for allergy to whole vaccine solutions. In the case of a positive vaccine skin test result, additional evaluation for allergy to particular constituents is appropriate. In cases where an allergic reaction a specific vaccine is determined to be due to a particular constituent, skin testing with other vaccines that contain that constituent is appropriate prior to administration. However, vaccine skin testing should not be used to "screen" for possible allergy to other vaccines that do not contain the constituent.

In most circumstances, vaccine skin testing should also not be used to "screen" for possible allergy where a patient has a known allergy to a vaccine constituent but no history of vaccine reaction, because, for the vast majority of these constituents (eg, hen's egg, cow's milk, yeast, or latex), vaccine reactions are exceedingly rare even in patients with known constituent allergy. The exception is the rare patient who has a confirmed allergy to the ingestion of gelatin, where skin testing to gelatin-containing vaccines prior to administration would be appropriate.

ADMINISTRATION OF VACCINES

Skin testing-based strategy — Most patients with prior vaccine reactions can be safely vaccinated in the future with appropriate precautions [87]. Whatever risk this may pose needs to be balanced against the risk of leaving persons susceptible to vaccine-preventable diseases if they do not receive subsequent doses. The approach is based on the results of skin testing.

Negative skin test results — If the intradermal test (IDT) with the vaccine is negative, the chance that the patient has IgE antibody to any vaccine constituent is negligible, and the vaccine can be administered in the usual manner. Nonetheless, it is prudent to observe such patients for at least 30 minutes after administration with epinephrine and other treatment available. (See "Anaphylaxis: Emergency treatment".)

Positive skin testing results — If vaccine or vaccine component skin tests (to which the patient previously reacted) are positive and if a vaccine is deemed necessary, the vaccine may still be administered using a graded-dose protocol. A graded protocol is provided here. Administration of a vaccine to an allergic person, even by such a graded-dose protocol, still carries the risk of an anaphylactic reaction and should be undertaken only after obtaining written informed consent. In addition, administration should be undertaken in a setting with personnel and equipment to recognize and treat anaphylaxis. Successful administration of vaccines to patients with positive skin tests using graded protocols has been described for several different vaccines [72,88].

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. Administer graded doses of vaccine at 15-minute intervals:

●0.05 mL of 1:10 dilution

●10 percent of full dose full strength

●20 percent of full dose full strength

●30 percent of full dose full strength

●40 percent of full dose full strength

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient education" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Vaccines for children age 7 to 18 years (The Basics)" and "Patient education: Vaccines for babies and children age 0 to 6 years (The Basics)")

●Beyond the Basics topics (see "Patient education: Vaccines for children age 7 to 18 years (Beyond the Basics)" and "Patient education: Vaccines for infants and children age 0 to 6 years (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Anaphylaxis after vaccination is rare – Anaphylactic reactions to vaccines are rare, although potentially life-threatening. These immunoglobulin E (IgE)-mediated reactions are most often due to vaccine constituents rather than microbial components. Symptoms of anaphylactic reactions to vaccines are similar to those of anaphylaxis from other etiologies (table 2). Reactions usually begin within 30 minutes but may rarely be delayed up to several hours. Vaccine providers should be prepared to treat rare allergic reactions that may occur after any vaccine. (See 'Clinical manifestations' above.)

●Implicated vaccines – There have been reports of systemic allergic reactions to nearly every vaccine, although some vaccines are more commonly implicated, including the vaccines for yellow fever; measles, mumps, and rubella (MMR); and tetanus. (See 'IgE-mediated reactions to specific vaccines' above.)

●Mimics of allergic reactions – There are nonallergic reactions to vaccines that are far more common than true allergic reactions and have similar symptoms, such as vasovagal reactions and anxiety-related symptoms, termed immunization stress-related responses (ISRRs). The term ISRR was introduced during the coronavirus disease 2019 (COVID-19) pandemic, when this type of reaction to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines was so common that an educational effort was begun to increase awareness among health care providers. The table summarizes the features of nonallergic reactions that can resemble anaphylaxis (table 4). (See 'Mimics of anaphylaxis' above and 'Reactions to COVID-19 vaccines' above.)

●Evaluation and management – The two clinical scenarios that commonly arise are the need for initial vaccination of a patient who has a known or suspected allergy to some component of the desired vaccine and the need for vaccination in a person who reacted to a previous vaccine and needs it again. The approach differs for each scenario. (See 'Approach to the patient with suspected vaccine allergy' above.)

•Patients with known or suspected allergy to a vaccine component – For patients who have not yet received a vaccine because it contains a component to which they have a known or suspected allergy, the approach depends upon the specific component (algorithm 1):

-Gelatin – Gelatin has been implicated in allergic reactions to several vaccines (table 5). Gelatin-free preparations are available for most. If gelatin-free versions are not available, the patient can be referred to an allergy specialist for confirmation of the gelatin allergy and further evaluation. (See 'Gelatin' above.)

-Egg – Proteins from hen's egg are present in several vaccines (table 6). However, egg allergy (even severe) is not a contraindication to the administration of yellow fever vaccine or any other vaccine, including influenza, MMR, and rabies. It is not necessary to inquire about egg allergy prior to vaccination, and all egg-containing vaccines may be given normally. (See 'Hen's egg' above.)

-Other components – Most other allergens (eg, cow's milk, latex) and preservatives (eg, thimerosal, polysorbates, others) have either not been conclusively implicated in allergic vaccine reactions or have only been linked to delayed reactions that are usually not reproducible. Thus, no special precautions are needed for administration of vaccines containing these components. (See 'Reactions to vaccine constituents' above.)

•Patients with past anaphylaxis to a vaccine – For patients who developed apparent anaphylaxis to past administration of a vaccine and need the same vaccine in the future, we perform skin testing to the vaccine in question (algorithm 2). Skin testing to vaccines should be performed and interpreted by an allergy specialist. (See 'Skin testing with vaccines and vaccine constituents' above.)

-If skin test results are negative, the vaccine can be administered as a single dose followed by 30 minutes of observation. (See 'Negative skin test results' above.)

-If skin test results are positive, the vaccine can be administered in a graded fashion after a thorough assessment of the relative risks and benefits of proceeding (algorithm 2). (See 'Positive skin testing results' above.)