Official reprint from UpToDate®

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Allergic reactions to vaccines

Author: John M Kelso, MD

Section Editor: N Franklin Adkinson, Jr, MD
Deputy Editor: Anna M Feldweg, MD

All topics are updated as new evidence becomes available and our peer review process is
complete.
Literature review current through: Nov 2016. | This topic last updated: May 02, 2016.

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, the administration of influenza vaccine to egg-allergic
patients is discussed separately (see "Influenza vaccination in individuals 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 and chronic disease: No evidence for vaccines as a contributing factor".)

CLINICAL MANIFESTATIONS

Immediate reactions — Immediate, immunoglobulin E (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
 Definition of 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]. Anaphylactic reactions to vaccines are rare, with rates from active surveillance
studies ranging from 0.65 to 1.31 per million vaccine doses [3,4].

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".)

Timing — When anaphylaxis occurs after administration of a vaccine, patients generally

develop symptoms within 30 minutes [5,6], although the onset may occasionally be delayed up to
several hours [3,4]. 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.

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 and irritability are common after vaccination and should not preclude additional
doses of the same vaccine in the future [7].

● Local reactions – Local reactions to vaccination, such as swelling and redness at the
injection site, are common and self-limited. These should not be considered reasons for
avoiding administration of further doses of the vaccine [7]. 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", section on
'Prophylactic acetaminophen'.)

It was believed that shorter intervals between 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) [8,9]. 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 [10]. 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 [11]. It is now
recommended that Tdap be given to all adolescents and adults regardless of interval since
the last Td [12].

● 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 [13]. Another rare reaction is encephalopathy. Some of these
more severe reactions may constitute contraindications to further doses of specific vaccines
[7].
Vasovagal reactions — Vaccine administration may elicit vasovagal reactions (fainting),
particularly in patients who are prone to this response [14]. 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 [15]. Fainting is usually
preceded by pallor, whereas anaphylaxis often begins with flushing and may also include itching,
urticaria, and angioedema. In anaphylaxis, 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 [16].

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, egg, antimicrobial agents, yeast, and
natural rubber latex (NRL).

Sources of information — A list of potential allergens contained in vaccines is maintained by the

Institute for Vaccine Safety and is available on the internet [17].

In addition, the US Centers for Disease Control (CDC) and Prevention provides tables of
excipients contained in vaccines, categorized by vaccine [18].

Gelatin — Gelatin, which is added to many vaccines as a stabilizer, is responsible for many
anaphylactic reactions to measles, mumps, and rubella (MMR), varicella, and Japanese
encephalitis vaccines (a new Japanese encephalitis vaccine does not contain gelatin) [19-22] (see
'Sources of information' above). Anaphylaxis from gelatin in influenza vaccine has also been
reported [23].

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 4). 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 [20].
(See 'Skin testing with vaccines and vaccine constituents' below.)

Persons who react to gelatin on ingestion should be evaluated by an allergist prior to vaccine
administration. If the history is consistent with an immediate-type allergic reaction to gelatin and
this is confirmed by skin tests or serum-specific immunoglobulin E (IgE) antibody tests to gelatin, it
is prudent to skin test such patients with gelatin-containing vaccines 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
[24,25]. 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 [26].
These strategies have been variably adopted in other countries and reactions to gelatin in
vaccines still occur (table 4).
Egg — Egg protein is present in yellow fever, MMR, and some influenza and rabies vaccines.
However, the amount is potentially of clinical significance only in the yellow fever vaccine (table 5)
[27]. (See 'Sources of information' above.)

● The recommendations regarding the administration of influenza vaccines to persons allergic

to egg are reviewed elsewhere. (See "Influenza vaccination in individuals with egg allergy".)

● MMR and rabies vaccines may be safely administered in the usual manner to patients with
egg allergy. (See 'Measles, mumps, and rubella' below.)

● A history of allergy after the ingestion of egg, raw or cooked, should be sought prior to the
administration of yellow fever vaccine, and persons with positive histories should be evaluated
by an allergist [28]. Such patients should be skin tested with yellow fever vaccine 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. (See 'Skin testing with
vaccines and vaccine constituents' below.)

Cow's milk — Casein, an allergenic protein contained in cow's milk, has been preliminarily
implicated in causing anaphylaxis to diphtheria, tetanus, and pertussis vaccines (DTaP or Tdap) in
a small number of severely milk-allergic children [29]. 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 "Autism and chronic disease: Lack of evidence for thimerosal
as a contributing factor", section on 'Mercury toxicity' and "Standard childhood vaccines: Parental
hesitancy or refusal", section on 'Why parents refuse vaccines'.)

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

● Contact sensitivity to them is not a contraindication to receiving vaccines containing them

[7,30-32]. There is a case report of an adult who developed a generalized maculopapular rash
to a thimerosal-containing influenza vaccine [33]. 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 [34]. 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.
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. Those made with latex pose a theoretical risk to latex-
allergic patients, 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. One report of an anaphylactic reaction after hepatitis B vaccine
administered to a latex-allergic patient was attributed to rubber in the stopper [35]. 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
these may have been due to other components [36]. The latex content of vaccine packaging can
be found in a table provided by the US Centers for Disease Control (CDC) and Prevention [18].

Patients with anaphylaxis to latex can safely receive vaccines from vials with non-DNR stoppers. If
the only available preparation has a latex stopper, the stopper should be removed and the vaccine
drawn up directly from the vial without passing the needle through the stopper [37]. If the only
available vaccine contains latex in the packaging that cannot be avoided, such as in a prefilled
syringe, the vaccine can still be administered, but the patient should be observed for at least 30
minutes afterward.

In contrast to patients with latex-induced anaphylaxis, patients with contact allergy to latex, such
as hand dermatitis, may safely receive vaccines from vials with latex stoppers [7].

Yeast — Some vaccines contain yeast protein, including Hepatitis B vaccines (up to 25 mg per
dose) and 4- and 9-valent human papillomavirus vaccines (<7 mcg per dose), but adverse
reactions to these, if any, appear to be rare [38]. Yeast allergy itself is very rare but, if a patient has
a history of clinical reactivity to baker's or brewer's yeast and a positive skin test to
Saccharomyces cerevisiae, it would be appropriate to skin test with yeast-containing vaccines
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.
Dextran — Dextran has been implicated in allergic reactions to a particular brand of MMR vaccine
previously used in Italy and Brazil [39]. 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 immunoglobulin E (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 [40]. Generalized hives
attributed to IgE directed against the DT component of "Di-Te-Pol" (diphtheria-tetanus-polio)
vaccine are also reported [41]. 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 [42].

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 [43]. 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 [44].

Haemophilus influenza type b — There are a few reports consistent with anaphylaxis to
Haemophilus influenza type b (Hib) vaccine, but none have been confirmed with skin tests or
measurement of allergen-specific IgE in serum [43]. There is a case of anaphylaxis after Hib-
conjugate vaccine demonstrated to be due to the DT-conjugating protein [45]. 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 [14,46]. 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 [16].

Influenza — Some influenza vaccines contain egg protein, although allergic reactions may be due
to some other components as well. For example, 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 [47]. 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 three patients, but was positive in all
three 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.

Reactions to the influenza vaccine in egg allergic patients are discussed in detail separately. (See
"Influenza vaccination in individuals with egg allergy", section on 'Risk of anaphylaxis to vaccines'.)

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 [22]. With this vaccine in particular, there have been many reports of late-
onset anaphylaxis (many hours to two weeks after vaccination) [48]. 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.

Measles, mumps, and rubella — Most anaphylactic reactions to measles, mumps, and rubella
(MMR) are due to gelatin allergy [20]. There is no relation to 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 [49]. 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 [50].

Pneumococcus — There are two reports of anaphylaxis in children who received 23-valent
pneumococcal vaccine [51,52]. IgE antibody to the vaccine was demonstrated by skin tests or
measurement of allergen-specific IgE in serum.

Rabies — There are a few reports consistent with anaphylaxis, but none confirmed with skin tests
or measurement of allergen-specific IgE in serum [53]. 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 [54].

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 [40,43,55,56]. 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 [42].

Diphtheria, tetanus, and pertussis vaccines (DTaP or Tdap) may also contain trace (nanogram)
quantities of residual casein (an allergenic milk protein) from the milk-based medium in which they
are produced [29].

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 [29].

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 cow's 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 [57]. Most patients, even those with severe cow's
milk allergy, tolerate the vaccines as evidenced by the observations that milk allergy is common in
infants and anaphylaxis to these vaccines is rare. Until more information is available, we suggest
that infants with severe milk allergy be observed for at least 30 minutes after vaccination.

Typhoid — Rare anaphylactic reactions have been reported to both the injected Vi polysaccharide
vaccine and the oral live-attenuated Ty21a vaccine [58]. 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 [59].

Varicella — The rate of anaphylaxis is reported to be three reactions per million doses [60]. Most
anaphylactic reactions to varicella vaccine are due to gelatin allergy [21].

Yellow fever — There are many reports consistent with anaphylaxis to yellow fever vaccine [61].
The constituent responsible for these apparently IgE-mediated reactions has not been
investigated, but the vaccine contains gelatin as well as egg proteins.

APPROACH TO THE PATIENT WITH SUSPECTED VACCINE ALLERGY — The approach

described in this section is consistent with published practice guidelines (algorithm 1) [62]. Of note,
this algorithm applies to patients with a history of a suspected allergic reaction to a vaccine.

In contrast, the diagnostic approach is different for a patient who has reacted to a vaccine
constituent, such as gelatin, egg, latex, or yeast, but not to the vaccination itself. The most
commonly encountered example of this situation is influenza vaccination of a patient with egg
allergy, which is reviewed in detail separately. (See "Influenza vaccination in individuals with egg
allergy".)

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 immunoglobulin E (IgE)
-mediated reaction/anaphylaxis (table 2).

Is there a history of a similar reaction? — It 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.

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, healthcare professionals should also
inquire about allergic reactions to food, particularly gelatin (table 4).

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, 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 the patient is to receive
further doses of a vaccine, 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 allergic disease".)

Methods — The vaccine should first be tested by the skin prick method. Full-strength 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 [62].

If the full-strength prick test is negative, an intradermal test with the vaccine diluted 1:100 in 0.9
percent (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.

Vaccines can induce immunoglobulin E (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 [63,64]. 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 intradermal testing at concentrations of 1:10 or undiluted. One study of 20 adult volunteers
without histories of vaccine reactions evaluated responses to skin prick testing and intradermal
testing with 10 common vaccines [65]. Irritant reactions were not seen with skin prick testing and
were uncommon after intradermal testing with a 1:100 concentration. However, they were common
at higher intradermal concentrations (1:10 or undiluted). Thus, intradermal testing 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 egg (yellow fever and
influenza) (table 5), gelatin (table 4), 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:

● 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 (for example 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 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'.)

ADMINISTRATION OF VACCINES — Most patients with prior vaccine reactions can be safely
vaccinated in the future with appropriate precautions.

General strategy — If the intradermal test with the vaccine is negative, the chance that the patient
has immunoglobulin E (IgE) antibody to any vaccine constituent is negligible, and the vaccine can
be administered in the usual manner [66,67]. 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".)

If vaccine or vaccine component skin tests 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 in
the footnote of the algorithm (algorithm 1). Successful administration of vaccines to patients with
positive skin tests using graded protocols has been described for several different vaccines
[55,68].

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.

Giving influenza vaccine to an egg-allergic patient — The administration of influenza

vaccine to an egg-allergic patient is a relatively common clinical dilemma. This issue is discussed
in detail separately. (See "Influenza vaccination in individuals with egg allergy", section on 'Our
approach'.)

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e-mail these topics to your patients. (You can also locate patient education articles on a variety of
subjects by searching on "patient info" 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

● 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 products.

● Symptoms of anaphylactic reactions to vaccines are similar to those of anaphylaxis from other
etiologies (table 2). They usually appear within 30 minutes but may rarely be delayed up to
several hours. (See 'Clinical manifestations' above.)

● There have been rare 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.)

● Evaluation of a possible vaccine allergy begins with determining if symptoms and timing are
consistent with an anaphylactic reaction (algorithm 1 and table 2). The next step is discerning
if the patient had previous exposure to the vaccine or needs further doses of the vaccine in
question, or vaccines with common constituents, in the future. (See 'Approach to the patient
with suspected vaccine allergy' above.)

● Skin testing to vaccines should be performed and interpreted by an allergy specialist. The skin
prick test may be performed with an undiluted solution of the vaccine in question, or with a
diluted solution in patients whose reactions were truly life-threatening. If negative, this is
followed by intradermal testing with a 1:100 dilution of the vaccine. (See 'Skin testing with
vaccines and vaccine constituents' above.)

● If the suspect vaccine contains egg (yellow fever and some influenza), gelatin (table 4), latex,
or Saccharomyces cerevisiae yeast (hepatitis B and 4- and 9-valent human papillomavirus),
skin testing to these constituents should also be performed. (See 'Skin testing with vaccines
and vaccine constituents' above.)

● If skin testing with the vaccine is negative, it is recommended that the patient receive the
vaccine in the usual manner. For safety, such patients are usually given the vaccine under the
supervision of the allergy specialist. (See 'Administration of vaccines' above.)

● If skin testing to a constituent (gelatin, egg, etc) or the vaccine is positive, it may still be
possible for the patient to receive the vaccine in a graded manner (algorithm 1). However, this
should only be undertaken after a thorough assessment of the relative risks and benefits of
vaccination. (See 'Administration of vaccines' above.)
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Topic 2074 Version 21.0

GRAPHICS

Gell and Coombs classification of immunologic drug reactions

Clinical
Type Description Mechanism
features

I IgE-mediated, Antigen exposure causes IgE-mediated Anaphylaxis

Immediate immediate-type activation of mast cells and basophils, Angioedema
reaction (within hypersensitivity with release of vasoactive substances,
Bronchospasm
one hour) such as histamine, prostaglandins, and
leukotrienes. Urticaria (hives)
Hypotension

II Antibody- An antigen or hapten that is intimately Hemolytic anemia

dependent associated with a cell binds to antibody, Thrombocytopenia
cytotoxicity leading to cell or tissue injury.
Neutropenia

III Immune complex Damage is caused by formation or Serum sickness

disease deposition of antigen-antibody Arthus reaction
complexes in vessels or tissue.
Deposition of immune complexes
causes complement activation and/or
recruitment of neutrophils by
interaction of immune complexes with
Fc IgG receptors.

IV Cell-mediated or Antigen exposure activates T cells, Contact

delayed which then mediate tissue injury. dermatitis,
hypersensitivity Depending upon the type of T cell Some morbilliform
activation and the other effector cells reactions
recruited, different subtypes can be
Severe exfoliative
differentiated (ie, types IVa to IVd).
dermatoses (eg,
SJS/TEN)
AGEP
DRESS/DiHS
Interstitial
nephritis
Drug-induced
hepatitis
Other
presentations

IgE: immunoglobulin E; Fc IgG: Fc portion of immunoglobulin G; SJS/TEN: Stevens-Johnson syndrome/toxic

epidermal necrolysis; AGEP: acute-generalized exanthematous pustulosis; DRESS/DiHS: drug rash with
eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome.

Adapted from: Weiss ME, Adkinson NF. Immediate hypersensitivity reactions to penicillin and related
antibiotics. Clin Allergy 1988; 18:515.

Graphic 80466 Version 16.0

Symptoms and signs of anaphylaxis

Skin
Feeling of warmth, flushing (erythema), itching, urticaria, angioedema, and "hair standing on end"
(pilor erection)

Oral
Itching or tingling of lips, tongue, or palate

Edema of lips, tongue, uvula, metallic taste

Respiratory
Nose - Itching, congestion, rhinorrhea, and sneezing

Laryngeal - Itching and "tightness" in the throat, dysphonia, hoarseness, stridor

Lower airways - Shortness of breath (dyspnea), chest tightness, cough, wheezing, and cyanosis

Gastrointestinal
Nausea, abdominal pain, vomiting, diarrhea, and dysphagia (difficulty swallowing)

Cardiovascular
Feeling of faintness or dizziness; syncope, altered mental status, chest pain, palpitations,
tachycardia, bradycardia or other dysrhythmia, hypotension, tunnel vision, difficulty hearing, urinary
or fecal incontinence, and cardiac arrest

Neurologic
Anxiety, apprehension, sense of impending doom, seizures, headache and confusion; young children
may have sudden behavioral changes (cling, cry, become irritable, cease to play)

Ocular
Periorbital itching, erythema and edema, tearing, and conjunctival erythema

Other
Uterine cramps in women and girls

Original figure modified for this publication. Simons FER. Anaphylaxis. J Allergy Clin Immunol 2010;
125:S161. Table used with the permission of Elsevier Inc. All rights reserved.

Graphic 66333 Version 15.0

Diagnostic criteria for anaphylaxis

Anaphylaxis is highly likely when any ONE of the following three criteria is
fulfilled:

1. Acute onset of an illness (minutes to several hours) with involvement of the skin,
mucosal tissue, or both (eg, generalized hives, pruritus or flushing, swollen lips-tongue-
uvula)

AND AT LEAST ONE OF THE FOLLOWING:

A. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, hypoxemia)

B. Reduced BP* or associated symptoms of end-organ dysfunction (eg, hypotonia, collapse,

syncope, incontinence)

2. TWO OR MORE OF THE FOLLOWING that occur rapidly after exposure to a LIKELY
allergen for that patient (minutes to several hours):

A. Involvement of the skin mucosal tissue (eg, generalized hives, itch-flush, swollen lips-tongue-
uvula)

B. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, hypoxemia)

C. Reduced BP* or associated symptoms (eg, hypotonia, collapse, syncope, incontinence)

D. Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting)

3. Reduced BP* after exposure to a KNOWN allergen for that patient (minutes to several
hours):

A. Infants and children - Low systolic BP (age-specific)* or greater than 30% decrease in systolic
BP

B. Adults - Systolic BP of less than 90 mmHg or greater than 30% decrease from that person's
baseline

BP: blood pressure.

* Low systolic blood pressure for children is defined as:
◾ Less than 70 mmHg from 1 month to 1 year
◾ Less than (70 mmHg + [2 x age]) from 1 to 10 years
◾ Less than 90 mmHg from 11 to 17 years

Adapted with permission from: Sampson HA, Munoz-Furlong A, Campbell RL, et al. Second symposium on the
definition and management of anaphylaxis: summary report-Second National Institute of Allergy and
Infectious Disease/Food Allergy and Anaphylaxis Network symposium. J Allergy Clin Immunol 2006; 117:391.
Copyright © 2006 The American Academy of Allergy, Asthma, and Immunology.

Graphic 72225 Version 15.0

Gelatin content of vaccines (subject to change - check package inserts)

Gelatin content in micrograms per

Vaccine
dose

Influenza (Fluzone [trivalent standard dose only], 250 micrograms per 0.5 mL dose*
Sanofi Pasteur)

Influenza (Flumist, Medimmune vaccines) 2000 micrograms per 0.2 mL dose*

Measles, mumps, rubella (Merck) 14,500 micrograms per 0.5 mL dose*

Measles, mumps, rubella, varicella (ProQuad, 11,000 micrograms per 0.5 mL dose*
Merck)

Rabies (RabAvert, Novartis) 12,000 micrograms per 1.0 mL dose*

Varicella (VARIVAX, Oka/Merck) 12,500 micrograms per 0.5 mL dose*

Yellow fever (YF-VAX, Sanofi Pasteur) 7500 micrograms per 0.5 mL dose ¶

Zoster (ZOSTAVAX, Oka/Merck) 15,580 micrograms per 0.65 mL dose*

Typhoid (oral, Vivotif, Berna) Capsule

* Package inserts.
¶ Vaccine manufacturers, personal communication.

Graphic 63833 Version 7.0

Egg content of vaccines (subject to change - check package inserts)

Egg protein Approach in egg-

Vaccine Grown in
content allergic patient

Measles and mumps Chick embryo Picograms to Administer in usual manner

fibroblast cell nanograms
cultures

Purified chick embryo rabies Chick embryo Picograms to Administer in usual manner
fibroblast cell nanograms
cultures

Influenza (killed injected Chick extra- <1 microgram *

and live attenuated nasal) embryonic allantoic
fluid

Yellow fever Chick embryos Micrograms Skin test with vaccine prior
to administration

* Discussed in the UpToDate topic on influenza vaccination in individuals with egg allergy.

Graphic 51011 Version 4.0

 Suggested approach to suspected anaphylaxis to a vaccine

IgE: immunoglobulin E; IgG: immunoglobulin G.

Original figure modified for this publication. Kelso JM, Li JT. Practice Parameters: Adverse reactions to
vaccines. Ann Allergy Asthma Immunol 2009; 103(4 Suppl 2):1-14. Copyright © 2009 American College of
Allergy, Asthma and Immunology.

Graphic 81252 Version 11.0

Contributor Disclosures
John M Kelso, MD Nothing to disclose N Franklin Adkinson, Jr, MD Consultant/Advisory
Boards: Regado; Merck; Boehringer Ingelheim [Hypersensitivity reactions and anaphylaxis in
drugs under development (Fluoroquinolones)]; Pfizer; Alexion; ATYR Pharma; Genzyme/Sanofi;
Synageva [DSMB for drug products under development]; Merck [Allergen immunotherapy products
(Oral tablets for allergen immunotherapy)]. Equity Ownership/Stock Options: AllerQuest [Penicillin
allergy diagnosis (Penicilloyl polylysine)]; DBV Tech [Epicutaneous immunotherapy (Viaskin
patches)]. Anna M Feldweg, MD Nothing to disclose

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found,
these are addressed by vetting through a multi-level review process, and through requirements for
references to be provided to support the content. Appropriately referenced content is required of
all authors and must conform to UpToDate standards of evidence.

Conflict of interest policy