World Allergy Organization: International Consensus on Vaccine Allergy

This report presents the International Consensus (ICON) on allergic reactions to vaccines, developed by the World Allergy Organization (WAO) in collaboration with several international allergy and immunology organizations. The document addresses the evaluation and management of allergic reactions to vaccines, including definitions of immediate allergic reactions and anaphylaxis, distinguishing between association and causality, and approaches to patients with a history of allergic reactions to vaccines or their components. It provides guidelines for practitioners worldwide to identify and manage allergic reactions following immunization, offering a framework for evaluating and further managing patients. The methodology involved a review of the literature and the active participation of representatives from various allergy organizations. The consensus covers topics such as methodology, definitions, allergic reactions to specific vaccines, allergic reactions to vaccine components, and approaches to patients with a history of vaccine allergies or allergies to vaccine components. The report also addresses unmet needs and suggests future research directions.

CONSENSUS DOCUMENT Open Access
InternationalConsensus (ICON):allergic
reactions to vaccines
Stephen C.Dreskin1*
, NealA.Halsey2
, John M.Kelso3
, Robert A.Wood4
, Donna S.Hummell5
, Kathryn M.Edwards6
,
Jean-Christoph Caubet7
, Renata J.M.Engler8
, MichaelS.Gold9
, Claude Ponvert10
, PascalDemoly11
,
Mario Sanchez-Borges12
, Antonella Muraro13
, James T.Li14
, Menachem Rottem15 and Lanny J.Rosenwasser16
Abstract
Background:Routine immunization,one of the most effective public health interventions,has effectively reduced
death and morbidity due to a variety of infectious diseases.However,allergic reactions to vaccines occur very rarely
and can be life threatening.Given the large numbers of vaccines administered worldwide,there is a need for an
international consensus regarding the evaluation and management of allergic reactions to vaccines.
Methods: Following a review ofthe literature,and with the active participation ofrepresentatives from the
World Allergy Organization (WAO),the European Academy ofAllergy and ClinicalImmunology (EAACI),the
American Academy ofAllergy,Asthma,and Immunology (AAAAI),and the American College ofAllergy,
Asthma,and Immunology (ACAAI),the final committee was formed with the purpose of having members who
represented a wide-range ofcountries,had previously worked on vaccine safety,and included both allergist/
immunologists as wellas vaccinologists.
Results:Consensus was reached on a variety oftopics,including:definition ofimmediate allergic reactions,
including anaphylaxis,approaches to distinguish association from causality,approaches to patients with a
history ofan allergic reaction to a previous vaccine,and approaches to patients with a history ofan allergic
reaction to components ofvaccines.
Conclusions:This documentprovides comprehensive and internationally accepted guidelines and access to
on-line documents to help practitioners around the world identify allergic reactions following immunization
It also provides a framework for the evaluation and further management of patients who present either fol
allergic reaction to a vaccine or with a history of allergy to a component of vaccines.
Keywords: Allergy,Allergic reactions,Anaphylaxis,Causality,Components,International,Consensus,Vaccine
Introduction
Routine immunization,one ofthe most effective public
health interventions,has effectively reduced death and
morbidity due to a variety ofinfectious diseases [1,2].
Very rarely,allergic reactionsto vaccinesoccur,and
can be life threatening [3–6].Estimates of allergic reac-
tions to vaccines including immediate hypersensitivity
reactions,range from 1 in 50,000 to 1 in 1,000,000
doses [7–9].The most concerning of these,anaphylaxis,
has been estimated to occur at a rate ofapproximately
one per 100,000 to one per 1,000,000 doses for most
commonly administered vaccines [8,10,11] (B)1. The
true rate of allergic reactions is unknown because most
reactions are not reported.
Allergic reactions need to be distinguished from clinical
manifestations that occur coincidental to vaccination (e.g.
becoming anxious),vasovagalresponses,localinjection-
site reactions(eitherimmediateor delayed),and the
oculorespiratory syndrome (ORS).Allergic reactions are
generally immediate and IgE-mediated.Symptomsvary
from relatively minorcutaneoussignsand symptoms
(erythema and itching) to multisystem effects (anaphyl-
axis) that can include the cutaneous,respiratory,
gastrointestinal,and/or cardiovascular systems.Allergic
* Correspondence:[e-mail]
1Division of Allergy and ClinicalImmunology,Department of Medicine,
University of Colorado Denver Schoolof Medicine,Aurora,CO,USA
Fulllist of author information is available at the end of the article
© 2016 Dreskin et al.Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
InternationalLicense (http://creativecommons.org/licenses/by/4.0/),which permits unrestricted use,distribution,and
reproduction in any medium,provided you give appropriate credit to the originalauthor(s) and the source,provide a link to
the Creative Commons license,and indicate if changes were made.The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article,unless otherwise stated.
Dreskin et al.World Allergy Organization Journal(2016) 9:32
DOI10.1186/s40413-016-0120-5

reactions can be due to allergy to vaccine antigens (por-
tions oforganisms or toxoids),residualmedia used to
grow organisms,stabilizers,preservatives,or other
excipients [6](B). Given the increasing prevalence of
allergic disease throughout the world [12–15],it is not
surprising that there are increasing concerns about pos-
sible allergic reactions following vaccines and concerns
about vaccine components.
Patients may have clinicalcomplaints that occur im-
mediatelysubsequentto administration ofa vaccine
that may or may not be compatible with an allergic re-
action,but nonetheless have significantimpacton the
patient’s perception ofvaccines and their willingness to
undergo further vaccination.In addition,patients may
have complaints thathave a delayed onsetrelative to
having received avaccinethat raise concernsabout
delayed allergic or other immunologic reactions to vac-
cine components.
A variety ofvery usefuldocumentsin the literature
have addressed many of these concerns [3–6],but none
have addressed allof these issues or have presented an
internationalconsensus.For this reason,the World Al-
lergy Organization (WAO) initiated an effort to publish
this InternationalCONsensus (ICON)on allergic reac-
tions to vaccines.The intent of this document is to iden-
tify themes thatcommonly occur in a large variety of
settings and to provide a comprehensive reference for a
systematic approach to the problems related to allergic
reactions to vaccines.
Following the above introduction (PartI), this docu-
ment is organized to firstdescribe ourmethodology,
process,and to provide definitions (PartII). In subse-
quentsections,we review allergic reactions to specific
vaccines (Part III) and then allergic reactions to compo-
nents ofvaccines (Part IV).Finally,we address the rec-
ommended approach to the patient with a history of an
allergic reaction to vaccines (Part V) and to the patient
with a history ofan allergic reaction to an exogenous
substance (e.g.food,drug,or latex) that may be found in
a vaccineor its packaging (PartVI). In closing, we
addressunmetneedsand offersuggestionsfor future
research (PartVII). Since somespecificvaccinesare
discussed from severalpoints ofview,some redundancy
is unavoidable.
Methodology
Participants
Under the auspices ofWAO, a working committee was
formed,consisting ofDrs. Rosenwasser,Dreskin,and
Halsey.Following a review of the literature,and with the
active participation of representatives from the European
Academy ofAllergy and ClinicalImmunology (EAACI),
the American Academy of Allergy,Asthma,and Immun-
ology (AAAAI), the American College of Allergy, Asthma,
and Immunology(ACAAI), the final committeewas
formed with the purpose ofhaving members who repre-
sented a wide-range ofcountries,had previously worked
on vaccine safety,and included both allergist/immunolo-
gists as well as vaccinologists.
Process
Following email contact,a conference call was convened
during which participantsagreed to write orto help
write specific parts of this ICON,relying heavily on pre-
viously published ICONs as well as a practice parameter
on adverse reactions to vaccines and other reviews of al-
lergic reactionsto vaccines[3–6].The first draftof a
complete document was then compiled by Drs.Dreskin
and Halsey and subsequently sent to allparticipants for
finalediting.A second conference callwas then held to
discussdifferencesin opinion.Then a final draftwas
sent to participants for their review.This draft was then
sent to an independent committee (chosen on the basis
of participating in previousICONs) and their com-
mentscirculated back to the committee fordecision
regardingfurther alteration.A final documentwas
then approved by the Board ofDirectors ofthe spon-
soring organizations.
Definitions
Immediate reactions that are not allergic (Immediate
non-allergic reactions)
Local,injection site reactions (swelling,redness,and/
or soreness)and constitutionalsymptoms,especially
fever,are common afterthe administration ofmany
vaccinesand are notcontraindicationsto subsequent
vaccination [16] (D).
Immediate allergic reactions
Immediate hypersensitivity or allergic reactions to vac-
cines are rare but potentially serious adverse events that
require investigation and understanding ofthe associ-
ated risks in order to properly counsel patients regarding
the risk versusbenefitratio for the administration of
future vaccines.In this document,“allergy” willbe used
interchangeablywith “immediatehypersensitivity”and
“IgE-mediated reaction” as descriptors to denote a pre-
sumed underlying IgE-mediated immune mechanism for
an adverse event.We use the term “immediate” to dis-
tinguish these allergic reactions from those that may be
mediated by antibodiesother than IgE or by T cells
(commonly seen in immunologic reactions to drugs).
Limited immediate allergic reactions
Allergic reactions to vaccines may be mild and limited
in the scope of symptomsand involvementof organ
systems,or even localized to the site of vaccine adminis-
tration.Thus, typicalsigns ofan allergic reaction may
Dreskin et al.World Allergy Organization Journal(2016) 9:32 Page 2 of 21

include bronchoconstriction,rhinoconjunctivitis,gastro-
intestinalsymptoms,and/orcharacteristic skin lesions
such asgeneralized urticaria and/orangioedema [17],
occurring as a sole sign with an onsetwithin minutes
and less than 4 h post-vaccination [4] (D).
Anaphylaxis
Definition of Anaphylaxis
Anaphylaxis is the most severe form of an IgE-mediated re-
action,encompassing a spectrum ofsymptomsand in-
volvementof severalorgan systems.For the majority of
instances,anaphylaxis occurs within minutes following an
exposure to an allergen.The InternationalConsensus on
(ICON) Anaphylaxis published in 2014 reviewed defini-
tions proposed by WAO;the Joint Task Force on Practice
Parameters,representing the AAAAI,the ACAAI,and the
Joint Council of Allergy,Asthma,and Immunology
(JCAAI); and the EAACI. In this consensusdocu-
ment,all organizations have agreed upon the concept
thatanaphylaxis is a “serious,generalized or systemic,
allergicor hypersensitivityreaction thatcan be life-
threatening or fatal” [18] (D).
The NationalInstitutes ofAllergy and Infectious Dis-
eases (NIAID) / Food Allergy and Anaphylaxis Network
(FAAN) criteria developed in 2006 by an NIH meeting
of experts in the fields ofallergy and immunology de-
fined anaphylaxis as one of three scenarios:1) The acute
onset of an illness within minutes or hours with involve-
mentof: skin and/or mucosa (pruritus,flushing,hives,
angioedema),and eitherrespiratory compromise (dys-
pnea,wheeze/bronchospasm,decreased peak expiratory
flow,stridor,hypoxemia) OR decreased blood pressure/
end organ dysfunction (collapse,syncope,incontinence)
2) Two or more of the following that occur rapidly after
exposure to a likely allergen for that patient:skin and/
or mucosa;respiratory compromise;decreased blood
pressure/end organ dysfunction;persistentGI symp-
toms (vomiting,crampy abdominalpain,diarrhea)3)
The following within minutes or hours after exposure
of a known allergen forthat patient:decreased blood
pressure [19] (D).
Alternativecriteriaincludethosedeveloped bythe
Brighton Collaboration Working Group for case defini-
tions [20] (D).These criteria are not intended to distin-
guish differinglevelsof severityof anaphylaxis,but
instead denote different levels of diagnostic certainty,as
the definition is used primarily for epidemiologic studies.
A Level1 case definition has the highestlevelof diag-
nostic certainty,with progressively lowercertainty for
levels 2 and 3,respectively.Because these levels do not
directly define severity,it is possible for a very severe
clinicalevent to be classified as a level2 or 3,based on
the available information.Furthermore,appropriate rapid
treatmentof an incipientimmediatehypersensitivity
reaction with intramuscularepinephrine may modulate
the severity of the reaction [18] (D).
Although most episodes of anaphylaxis involve cuta-
neous symptoms ofurticaria and/or angioedema,this
is not universally the case.Skin and/or mucosalsigns
may be absent in 10–20 % of all episodes,and
hypotension in infantsoften remainsunrecognized.
Unique aspects of anaphylaxis in infants,including be-
havioralchanges and challenges regarding recognition
of cardiovascularsigns has recentlybeen reviewed
[21].In general,underreporting of anaphylaxis is likely
common [22] (D).
Most episodes of anaphylaxis occur with a sudden on-
set and rapid progression [23] (D).Biphasic reactions are
also described,in which an initialclinicalpresentation
resolves with or without treatment,to be followed later
(up to 72 h) by a recurrence [24,25] (D).Protracted ana-
phylaxis (lasting up to severaldays withoutresolution)
has also been described,but is uncommon and the lit-
erature consists only of case reports or smallseries [26]
(D). Protracted anaphylaxis has been reported following
administration of vaccines [11] (D).
It is therefore not possible to assign a strict time frame
(time from exposure to onsetof symptoms)upon the
definition ofanaphylaxis in relation to a potentialtrig-
gering event,such as an immunization.The AAAAI and
ACAAI Joint Task Force on Practice Parameters advised
considering events with onset within 4 h ofvaccine ad-
ministration as possibly consistentwith anaphylaxis [4]
(D). Guidelinesfrom the EAACI note thatsymptoms
and signs of anaphylaxis usually occur within 2 h of ex-
posure to the allergen and this is even faster following
exposureto parenteralmedicationsor insect stings
(venom) [27] (D).A review ofa registry ofanaphylactic
reactions in the UK found that the median time to re-
spiratory or cardiac arrest for reactions to venom (a par-
enteralexposure) was 15 min,with the longest interval
being 120 min [28] (D).
The differentialdiagnosis of,and the potentialtriggers
for, anaphylaxismustbe considered wheneveran epi-
sode appearsto coincide with vaccine administration,
since assessing the likelihood of causality (i.e.the vaccine
causing anaphylaxis) is heavily dependent upon there be-
ing no alternative cause that can be implicated (Table 1)
[29] (D).
The WAO has suggested removing the term “anaphy-
lactoid” from use,and this is supported by the most re-
centupdate ofanaphylaxis published by the JointTask
Force on Practice Parameters,representing the AAAAI,
the ACAAI, and the JCAAI [29](D). Historically,this
term referred to thesamesyndromeas anaphylaxis
that was caused by immune mechanisms,but not in-
volving serum IgE specific for an allergen.Other non-
IgE-mediatedimmunologicmechanismsmay cause
Dreskin et al.World Allergy Organization Journal(2016) 9:32 Page 3 of 21

anaphylaxis.For example,IgG-mediated and immune
complex-mediated anaphylaxishas been reported for
certain medications and biologic agents [30](D), and
non-immuneactivation ofmast cells and basophils
may occur[31]. However,it is now recognized that
because anaphylaxis is a syndrome,with specific clin-
ical features,and becausethe underlyingimmune
mechanismscannoteasily be ascertained atthe time
of the event,it is essentialto treat all episodesthat
fall into this categorythe same.Non-IgE-mediated
events willnot be discussed in this documentexcept
as they may be considered in the differentialdiagnosis
for an adverse event (Table 1).
The CDC and FDA supported passive surveillance sys-
tem,Vaccine Adverse Event Reporting System (VAERS),
uses the term “serious” to include death,hospitalization
or prolongation ofhospitalization,persistentor signifi-
cantdisability/incapacity,or is life threatening.In this
document,we use “serious” throughout the document in
the same manneras cliniciansuse the term and not
precisely as defined by VAERS.
Differential diagnosis of anaphylaxis
There are a number of immediate adverse events follow-
ing immunization thatcould be misdiagnosed as ana-
phylaxis.For example,sudden eventssuch assyncope
following immunization may be confused with anaphyl-
axis.Many of these adverse events occur more commonly
than vaccine related anaphylaxis and alternative diagnoses
should be considered when a case definition for anaphyl-
axis is not met.
Anaphylaxis (allcauses) usually presents with charac-
teristic and predictable multi-system findings;less than
10 % of episodes present with sudden onset of hypotension
(manifest as collapse/unresponsiveness) without concomi-
tant respiratorymanifestationsand/or cutaneoussigns
(erythema,urticariaor angioedema).When sudden
collapse or acute respiratory symptoms occur without
skin changesfollowing immunization,anaphylaxis
should be considered.
Adverse events,other than anaphylaxis,that commonly
result in sudden collapse and unresponsiveness following
immunization include,in an infant,a Hypotonic Hypore-
sponsive Episode (HHE). HHE is characterized by the sud-
den onset of unresponsiveness,hypotonia and pallor,and
usually presents 1-to-6 h after immunization [32]. Cardio-
vascularcompromise and specifically hypotension does
not occur in HHE. Vasovagal syncope can occur at all ages
and is now a frequently reported adverse event since ado-
lescents are at increased risk and adolescent vaccination is
widely promoted in some countries [33]. In vasovagal syn-
cope,hypotension is transient and associated with brady-
cardia rather than tachycardia as would occur typically in
anaphylaxis.Sudden unresponsivenessdue to a febrile
seizure following immunization isfrequently associated
with tonic-clonic motor movements and no cardiovascu-
lar compromise.
Acute respiratory distress with cough and stridor may
occur following minor unintentionalaspiration of an oral
vaccine (oral polio or rotavirus vaccine) and may be mis-
taken for anaphylaxis.In very rare instances,an error in
vaccine administration may resultin acute collapse and
unresponsiveness thatis neither HHE or vasovagalsyn-
cope.For example,inadvertent injection ofa medication
(for example a muscle relaxant) rather than the vaccine or
following injection of staphylococcal toxin from a contam-
inated vial leading to Toxic Shock Syndrome [34, 35].
The oculo-respiratory syndrome (ORS) is defined by the
onset within 24 h ofimmunization ofat least one ofthe
following symptoms: bilateral red eyes or respiratory symp
toms (cough, sore throat, difficulty swallowing, wheeze, dif-
ficulty breathing,chest tightness) or facial edema [36]. The
condition was primarily associated with two Influenza vac-
cines which contained high amounts ofaggregated viron
particles that triggered the signs and symptoms that were
not a Type I hypersensitivity reaction [37, 38]. Refinements
in manufacturing resulted in marked reductions in the in-
cidence of this problem.Although ORS symptoms usually
begin severalhoursaftervaccination [37],making the
symptoms less likely to be due to immediate hypersensitiv
ity,a detailed assessment,including skin testing,may be
required to differentiate ORS from anaphylaxis.
Epidemiology of anaphylaxis
Anaphylaxisfollowing vaccine administration isa rare
event,estimated to occur at a rate of approximately 1 per
million vaccine doses(B) [8]. Fatalitiesare exceedingly
rare [39] (D).More frequent acute events that occur fol-
lowing administration ofvaccines may be confused with
anaphylaxis,including vasovagal reactions,panic (anxiety)
Table 1 Differentialdiagnosis of anaphylaxis
Anaphylaxis due to other allergenic or externalexposures:
Food (including scombroidosis),medication,insect venom,
exercise,heat,cold,idiopathic.
Anaphylaxis due to excess histamine production:
Systemic mastocytosis,mast cellactivation syndromes.
Flushing syndromes
Red man syndrome (vancomycin or other medication),carcinoid,
postmenopausal,alcohol-related,vasoactive-peptide tumors
(e.g.pancreatic VIPoma,medullary thyroid carcinoma).
Miscellaneous
Vasovagal episodes,panic attacks,vocal cord dysfunction,C1 inhibitor
deficiency syndromes (hereditary and acquired),pheochromocytoma,
neurologic process (seizure/stroke),cardiovascular process (myocardial
infarction,embolism),capillary leak syndrome,dehydration,
hypoglycemia.
Dreskin et al.World Allergy Organization Journal(2016) 9:32 Page 4 of 21

attacks,and vocal cord dysfunction (Table 1).The correct
diagnosis is critically dependent upon obtaining essential
details in the history surrounding the event [40] (D).This
may provide details ofexposure to allergens other than
vaccines, or may discern other possible alternative diagno-
ses (Table 1).An accurate history is also essential to con-
firm that the timing of the event (onset in minutes to 4 h,
see above) is compatible with the biologic plausibility of
anaphylaxis to a vaccine.
Delayed reactions
Rarely,delayed-type hypersensitivity to a vaccine con-
stituent (e.g.aluminum) may cause an injection site nod-
ule, but this is not usually a contraindicationto
subsequent vaccination.Delayed anaphylaxis (onset 3 to
6 h after exposure)is a conceptthathas recently been
well described but in the context of individuals that have
been bitten by the lone star tick and then develop IgE to
a component of red meat,galactose-alpha-1,3-galactose
(alpha-gal)[41].One patientwith alpha galallergy has
safely received a gelatin containing vaccine and the au-
thors found no documented published reports ofalpha
galallergy resulting in anaphylaxis following vaccines in
other patients with alpha galallergy [42].Of note,the
route ofexposure with red meat (ingestion) is different
from the route of administration of vaccines (parenteral)
and a delayed response due possibly to metabolic pro-
cesses is more likely.Thus,vaccine-related allergic reac-
tions including anaphylaxis should occur more quickly
than seen in patientswith allergyto red meat.Any
vaccine-related reactions occurring more than 4 h after
administration of a vaccine are unlikely to be immediate
hypersensitivity reactions [43].
Other immunologic reactions
Possible non-IgE-mediated reactions to vaccines include
a broad range of adverse events following immunization
(AEFI) and are commonly listed on the package inserts.
These includemild feverand local reactionsto life
threatening infections following live vaccines inappropri-
ately given to patients with immune deficiencies.Known
side-effects from vaccinesare detailed on the relevant
Centersfor Disease Control(CDC) website [44].The
GlobalVaccine Safety Initiative addressing comprehen-
sive AEFI considerationsis reviewedon the WHO
website [45].
Association versus causality
Adverse events that temporally follow immunization are
often attributed to the vaccine,suggesting a causallink
to a componentof the vaccine or to the immunologic
response to the vaccine.Many AEFI are coincidental
events that are falsely attributed to vaccines because of
the temporal association.Causality,particularly with rare
eventsand/or complexmultifactorialdisorderswith
documented delays in diagnosis (e.g.narcolepsy),can be
difficult to prove or disprove.For these reasons,careful
analyses ofmany AEFIshave failed to substantiate or
rule out a causal association.
Reports oftemporalassociations do not provide sup-
port for causality,but may indicate a need forfuture
carefulstudy to collect supportive data for a causalhy-
pothesis [46].Controlled trials are usefulfor identifying
an association between administration ofa vaccine and
common events that may occur within a relatively short
time period following an immunization,but are notas
helpfulfor events thatoccur rarely or are significantly
delayed in onset.In the case ofhypersensitivity reac-
tions,especially anaphylaxis,which has an abruptand
sudden onset usually within minutes following the aller-
genic exposure,a causalrelationship is assumed when
there are no otherexposures such as food thatcould
have caused the adverse event.Even when such a tem-
poral association ismade,other evidenceshould be
sought when possible to identify the allergen responsible
and to confirm the absence of evidence that points to an
alternate cause.
The Causality Working Group of the Clinical
Immunization Safety Assessmentnetwork have recently
published an algorithm to help guide the systematic evalu-
ation of an AEFI to help determine further steps to care
for specific patients [47] (D) and to provide an assessment
tool to help evaluate causality [48] (D).
In addition,the Institute ofMedicine (IOM) engaged
committees of experts to review the epidemiologic,clin-
ical and biological evidence regarding causal associations
with adverse health effects and specific vaccines covered
by the U.S. VaccineInjury CompensationProgram
(VICP). The latestreview,titled “AdverseEffectsof
Vaccines:Evidenceand Causality”,is availableonline
[49].The reportclassifies the evidence regarding many
potential associations between specific vaccines and spe-
cific adverse events as a) convincingly supporting,b) fa-
voring a causalrelationship orc) rejectinga causal
relationship.For a large number of other potentialasso-
ciations,it was determined “Evidence is inadequate to
accept or reject a causal relationship”.
Internationalefforts to support globalstandardization
of case definitions for further research on adverse events
are summarized by the Brighton Collaboration and pro-
vide an evolving profile of the questions raised about ad-
verse eventspossibly linked to vaccines[50].Further
discussion of the spectrum of AEFI-vaccine questions is
beyond the scope of this review.
Allergic reactions to specific vaccines
In the sections that follow the allergic reactions to several
of the commonly administered vaccines will be reviewed.
Dreskin et al.World Allergy Organization Journal(2016) 9:32 Page 5 of 21

Diphtheria, Tetanus,acellular Pertussis (DTaP) vaccine
Hypersensitivity reactions to diphtheria,tetanus and per-
tussis toxoid containing vaccines are very rare.Most re-
ports concern injection site reactions,and among these
are delayed hypersensitivity to aluminum included in the
vaccine asan adjuvant[51–53](C for Jackson,D for
Beveridge and for Bergfors).Jackson et al.reported post-
vaccination rates of fever,seizures,medically-attended in-
jection site reactions, and urticaria responses within 7 days
of immunization with DTaP between 1997 and 2000 in a
retrospectivepopulation ofpatientsfrom the Group
Health Cooperative,an health-maintenance organization
based in Seattle,WA with an enrollment of >360,000 per-
sons,including approximately 27,000 children under age
7 years [54] (C). They found an overall rate of 3.9 episodes
of urticaria reported per 10,000 doses ofvaccine distrib-
uted. There was a trend toward increased rate of urticarial
reactions with successive administration ofthe first four
doses,with the highestrate of8.9 cases per 10,000 for
dose number 4 administered at age 15 months.The rate
then fellto 2.5 for dose number 5,administered atage
5 years.Of the totalof 30 visits for rashes diagnosed as
consistentwith urticaria,four presented on the day of
vaccination,11 had onsetfrom days 1 through 3 post-
vaccination, and 15 had onset from days 5 through 7 post-
vaccination.No episodesof anaphylaxiswere reported
[54].Cheng et al.evaluated events suspected or reported
to be anaphylaxis in Australian children (<18 yo)from
2007 to 2013 and estimated a rate of0.36 casesper
100,000 doses for DTaP [11].
DTP vaccines prior to 1997,but notsince,contained
traces of gelatin,either poorly hydrolyzed bovine gelatin
as reported in Japan,or hydrolyzed porcinegelatin.
Some have speculated thatthis may have resulted in
gelatin sensitization in selectpopulations [55,56] (D),
but this has notbeen established as a cause for aller-
gic reactions to DTaP,and others refute this connec-
tion [57] (D).
Influenza vaccine
Influenza vaccines are unique in that the vaccine formu-
lation changes often,based upon the strains of influenza
projected to circulate in the upcoming season.In 2009,
in response to a globalinfluenza pandemic,a monova-
lentvaccine for pandemic influenza (H1N1)was intro-
duced separatelyfrom the recommendedseasonal
influenzavaccine.Subsequentlythe H1N1 pandemic
vaccinecomponenthas been included asthe H1N1
component of the seasonalvaccine.Most influenza vac-
cines marketed currently are produced in embryonated
chicken eggs,and therefore contain smallamountsof
egg proteins,mostnotably ovalbumin,the amounts of
which may vary by vaccine manufacturerand vaccine
lot.A new recombinant influenza vaccine produced in a
baculovirus-insectcell system (Flublok®)is currently li-
censed in the United States only for recipients aged 18–49
years.This vaccine has reduced immunogenicity in chil-
dren when compared with standard egg-grown vaccines
[58](B). Anotherrecently licensed influenza vaccine is
produced in cell culture (Flucelvax®) [59].
A previous severe allergic reaction to influenza vaccine,
regardless ofthe componentsuspected ofbeing respon-
sible for the reaction,requires evaluation before future re-
ceipt of the vaccine in question or an alternative vaccine.
A 2014 publication reviewed the 2011 report of the In-
stituteof Medicineconcerning the adverse effectsof
childhood vaccinesand also updated thefindingsby
searching the following databases:DARE (Database of
Abstracts of Reviews of Effects),the Cochrane Database
of SystematicReviews(CochraneReviews),Cochrane
Central Registerof Controlled Trials (CENTRAL),
PubMed,Excerpta Medica dataBASE (EMBASE),Cumu-
lative Index to Nursing and Allied Health (CINAHL),
ToxicologyLiteratureOnline (TOXLINE), Advisory
Committeeon Immunization Practices(ACIP) state-
ments,and vaccine package inserts.In this extensive re-
view of adverseeventsreportedfollowinginfluenza
immunization,anaphylaxiswas not commented upon,
due to its infrequent occurrence [60] (D).
An analysisof reportsto VAERS of reactionsfol-
lowing the 2009 administration ofthe H1N1 monova-
lent influenza vaccine revealed an overallrate of10.7
immediate hypersensitivity reactionsper million vac-
cine dosesdistributed,with a 2-fold higherrate for
live attenuatedvaccineas comparedto inactivated
vaccine [61].The rate ofanaphylaxis was 0.8 per mil-
lion doses,with no significantdifferencesby type of
vaccineor manufacturer.A Vaccine SafetyDatalink
study (VSD)covering influenza vaccine immunizations
in the 2012–2013 influenza season failed to find an in-
crease in risk ofanaphylaxis related to influenza vaccine
administration compared with historicalcontrols,adjust-
ing for age and site.Among over 3.3 million first doses of
Inactivated Influenza Vaccine (IIV) administered to indi-
viduals age 6 months and older,there were seven cases of
reported anaphylaxis and no cases of anaphylaxis reported
among 232,406 first doses of Live Attenuated Monovalent
Influenza Vaccine (LAMV) administered.This compared
with 18 cases ofanaphylaxis per 11.2 million doses IIV
and two cases per 338,000 doses of LAMV in the histor-
ical seasonsof 2005–2006 through 2009–2010 [62](C).
Similarly,a review ofreported adverse events following
immunization for pandemic monovalent H1N1 vaccine in
Latin American and theCaribbean in the2009–2010
season reported anaphylaxis as 7.6 % ofthe 1000 events
supposedly attributable to vaccinesand immunizations,
representing a rate of 0.53 cases per million doses (0.41–
0.64,95 % CI). Of these,45/76 casesoccurred in age
Dreskin et al.World Allergy Organization Journal(2016) 9:32 Page 6 of 21

group 18–59 years,and 14 occurred in those under age
2 years [63] (D).
Egg allergy does not appear to impart an increased risk
of an anaphylactic reaction to immunization with either
inactivated orlive attenuated influenzavaccinescur-
rently available in the United Statesand Europe (dis-
cussed in detailbelow under the heading "Approach to
the patientwith possibleallergiesto foods or other
materials thatmay also be components ofvaccines or
vaccine packaging").Although cases of immediate hyper-
sensitivity reaction such as urticaria may occur,they ap-
pear to be no more common in egg-allergic than non-
egg-allergic vaccine recipients [64,65] (D).A review of
articles in 2008 relating to allergic reactions,asthma,or
food allergy yielded a numberof casesof anaphylaxis
following LAIV,although no evidence was found ofa
directcausalrelationship to egg allergy [66](D). Egg
proteins are notthe only componentof influenza vac-
cines that may be responsible for an immediate allergic
reaction.
The preservative,thimerosal,has been rarely impli-
cated as causing allergic reactions to influenza vaccines
but has not clearly demonstrated to be responsible [67]
(D).Latex may be present in the rubber stopper of some
vaccine vials and plungers in some prefilled syringes,but
this appears to be a very rare issue for latex-sensitive in-
dividuals[68] (C). IgE directed toward theinfluenza
componentitselfis rarely implicated in hypersensitivity
reactions [4,43] (D). Other allergic or hypersensitivity
reactions described following immunization with influ-
enza vaccine may not be IgE-mediated [43].
The United States joint task force on Practice Param-
eters of the AAAAI and ACAAI states that “special pre-
cautions regarding medicalsetting and waiting periods
after administration ofIIV to egg-allergicrecipients
beyond those recommended forany vaccine are not
warranted." [139] (D).The Canadian NationalAdvisory
Committeeon Immunization (NACI) Immunization
Guide Chapter on Influenza and Statement on Seasonal
Influenza Vaccine for 2015–2016 states “regarding ad-
ministration ofinfluenza vaccine to egg allergic per-
sons,after careful review,NACI has concluded that egg
allergic individuals may be vaccinated against influenza
using trivalentinfluenza vaccine (TIV)withoutprior
influenza vaccine skin test and with the fulldose,irre-
spective ofa pastsevere reaction to egg and without
any particularconsideration,including immunization
setting [69].
Measles Mumps and Rubella (MMR) vaccines
Most casesof anaphylaxisassociated with MMR vac-
cines have been traced to the content of gelatin,which is
used asa stabilizer.Reportsof anaphylaxisfollowing
MMR have been reported for severaldecades,but the
highestrate occurred prior to 1998,when the vaccines
contained 0.2 % gelatin,with most reports coming from
Japan.Nakayama etal. reported 366 cases ofclinical
reactions to MMR,of which 34 were anaphylaxis,76
urticaria,and 215 cases had non-urticarialgeneralized
eruption,while 41 had local reactionsonly. When
serum was available,IgE antibodies to gelatin were de-
tected in 25/27 (93 %) of those with anaphylaxis,27/48
(56 %) of those with urticaria,8/90 (9 %) of those with
a generalized eruption,0/41 with a localreaction only,
and 0/29 controlsubjects [55] (C).Dramatic decreases
in anaphylaxis/allergic reactionsto live measlesvac-
cineswere observed in Japan immediately aftereach
manufacturer marketed vaccines that were gelatin-free
or contained a hypoallergenic form of gelatin.Since the
end of 1998 reports of anaphylaxis/allergic reactions to
live measles vaccines had almostdisappeared [70,71].
(D) D’Souza etal. reported adverse eventsfollowing
immunization to MMR in a review of the Measles Con-
trol Campaign (MCC) conducted in Australiafrom
Augustto November 1998.There was only one ana-
phylactic reaction,giving a rate of0.06 per100,000
doses administered.The combined rate for anaphylaxis
and allergic reactionswas 1.06 per100,000.The au-
thors concluded that the benefits ofthe MCC far out-
weighed the risks ofserious adverse events associated
with immunization [72] (D).
In a separate report from VAERS,the rate of anaphyl-
actic reactionsreported aftermeaslesvirus-containing
immunization in the United Statesbetween 1991 and
1997 was 1.8 per one million doses distributed.Cases of
anaphylaxis reported to VAERS during this time period
were identified retrospectively and 57 subjects were re-
cruited into a follow up study to investigate allergenic
sensitization in relation to the event.Self-reported his-
tory offood allergy was present more frequently in the
interviewed study subjects compared with controls who
had also receivedvaccinewithout clinical reaction.
Serum IgE analysison 22 subjectsshowed thatsix
(27 %)tested positive for anti-gelatin IgE,and none of
27 controls tested positive for anti-gelatin IgE.The levels
of IgE antibody against egg and against all three viral an-
tigens did notdiffer among study subjects and among
controls [57] (D).
Concerns regarding risk ofallergic reaction following
MMR immunization of subjects who have clinical allergy
to egg have been laid to rest.The manufacture ofvac-
cinescontaining live virusproduced in chick embryo
cultures (measles and mumps)and human diploid cell
culture (rubella) has resulted in a vaccine that contains
no,or at most picogram quantities of egg protein,insuf-
ficient to cause an allergic reaction [73,74].In addition
to those reports mentioned above,this has been con-
firmed in Iran [75](D), Denmark [76](D), Spain [77]
Dreskin et al.World Allergy Organization Journal(2016) 9:32 Page 7 of 21

(D), Finland [78] (D),and the United States [79,80] (C
or D).Persons with egg allergy can safely receive measles
vaccine or MMR.
Minor allergic reactions with MMR vaccine are also
infrequent.A prospective review ofpatients referred to
an emergency department vaccination service in Dublin,
Ireland included allreferred casesfor immunization
from January 1,2006 through December 31,2010.Of
the total446 vaccinesadministered during the study
period,310 (69.5 %) were MMR.The majority ofcases
(261/310,84.2 %)had been referred from the commu-
nity for suspected egg allergy.Only six patients (1.3 %)
experienced an immediate reaction to the vaccine and
all reactions were minor [81] (D).
Varicella vaccine
Varicella vaccinescontain an attenuated live strain of
varicella virus (Oka)combined with other components,
includinggelatin asa stabilizer.From May 1, 1995
through April30,1999,when over 16.1 million doses of
Varivax (Merck) were distributed,a post-marketing
safety study reported a totalof seven cases ofanaphyl-
axis in children ages 3 to 8 years.All but one occurred
shortly after vaccine administration.Symptoms consisted
of wheezing,stridor,swollen lips,urticaria,hypotension,
coughing and itching.All affected were treated appropri-
ately and recovered.In addition,there were 1349 cases
of post-immunization rashes ofwhich 4 % were classi-
fied as consistent with hypersensitivity [82] (D).
A separate post-licensure study ofthe VAERS database
from March 17,1995 through July 25,1998 revealed 6574
case reports of adverse events after varicella immunization,
a rate of67.5 reports per 100,000 doses distributed.Ap-
proximately 4 % ofreports were categorized as serious,
including 14 deaths.The mostfrequently reported were
rashes,possible vaccine failures and injection site reac-
tions.There were 30 cases of reported anaphylaxis,none
of which resulted in fatality [83] (D).
Similar to reports from Japan implicating the gelatin
ingredientof MMR vaccine asa potentialtriggerfor
anaphylaxis,Sakaguchiet al. reported thatanaphylaxis
following administration of the varicella vaccine was as-
sociated with IgE antibody directed toward the gelatin
component [84] (D).The estimated incidence ofsevere
anaphylaxis associated with varicella vaccine from 1994
to 1996 in Japan was 10.3 cases per million doses of vac-
cine administered [85](D). Ozakiet al.reported a rate
of 28 serious anaphylactic reactions and 139 non-serious
allergicreactionsfollowing gelatin-containing varicella
vaccine from 1994 to 1999,when 1.41 million doses of
varicella vaccine were distributed in Japan.All nine sera
available from children with anaphylaxis were found to
testpositive for anti-gelatin IgE,whereas 55 ofthe 70
availableserafrom children with non-seriousallergic
reactions were positive.Conversely,there were no cases
of anaphylaxis and only five cases of non-serious allergic
reactions from 1999 to 2000 when 1.3 million doses of
gelatin-free varicella vaccine were distributed [86].The
authors concluded that the newer vaccine was safe and
also provided data that the immunogenicity was compar-
able to the earlier gelatin-containing vaccine [86] (D).
Japanese encephalitis vaccine (JE-VC)
Vaccination is the single most important measure in pre-
venting this disease.In March 2009,the U.S.Food and
Drug Administration (FDA) licensed an inactivated, Vero
cell culture-derived JE-VC (Ixiaro®)for use in adults.
The vaccinereplaced theprior JapaneseEncephalitis
Vaccine (JEV)thatwas derived from mouse brain and
was licensed based on clinicaltrial safety data in 3558
JE-VC recipients.
A summary ofthe adverse events reported to VAERS
for adults(≥17 years)who received JE-VC from May
2009 through April2012 was recently published and in-
cluded data on 275,848 JE-VC dosesdistributed [87].
Over the 3 year period,42 adverse events following vac-
cination with JE-VC were reported to VAERS foran
overallreporting rate of 15.2 adverse events per 100,000
dosesdistributed.Of the 42 totalreports,five (12 %)
were classified as serious for a reporting rate of1.8 per
100,000 doses distributed;there were no deaths.Hyper-
sensitivity reactions (N = 12)were the mostcommonly
reported type ofadverse event,with a rate of4.4 per
100,000 doses distributed;no cases ofanaphylaxis were
reported.Three adverse eventsof the centralnervous
system were reported (one case ofencephalitis and two
seizures) for a rate of 1.1 per 100,000;all occurred after
receiptof JE-VC with other vaccines.In conclusion,
these post-marketing surveillance data suggesta good
safety profile forJE-VC consistentwith findingsfrom
pre-licensure clinical trials [87].
The newer inactivated Vero cellculture derived JE-VC
vaccine does not contain potentialmouse brain antigens
nor gelatin as did the oldervaccine,but does contain
some protamine sulfate from the virus preparation step
that requiresprotaminesulfatetreatmentto remove
contaminating DNA and proteins.Protamine has been
characterized as an allergen in the context of insulin al-
lergy with protamine specific IgE contributing to the re-
actions[88].Clinicaltrialssafety data (lessthan 5000
vaccinees) did not show the serious systemic hypersensi-
tivity reactions described with the older vaccine.Adverse
events consistent with systemic hypersensitivity were ob-
served atsimilar frequencies in recipients ofthe new
vaccine (3.5 %)and the placebo (3.7 %)group.The
placebo contained phosphate buffered saline and alum
adjuvantso it was not an “inert” placebo.While stud-
ies to date suggestreduced riskof hypersensitivity
Dreskin et al.World Allergy Organization Journal(2016) 9:32 Page 8 of 21

reactions with the gelatin free newervaccine,the ac-
tual incidenceof potentiallyIgE-mediated reactions
remains undefined.The package insert includes a cau-
tion in the setting ofprior JEV reaction history and a
documented hypersensitivity to protamine.Evaluation
of future vacinees with serious immediate hypersensi-
tivity reactions meritconsideration ofprotamine as a
relevant allergen [89,90].
Rabies vaccine
From October 1997 through December 2005,the Vac-
cine Adverse Event Reporting System (VAERS) received
336 reports ofAEFIs to the purified chick embryo Cell
(PCEC,RabAvert) vaccine,20 of which were classified as
serious,following vaccination in the U.S.Of the 20 ser-
ious AEFIs,three were classified as possible anaphylaxis.
Most reported AEFIsare non-seriousand consistent
with pre-licensure safety data [91].
Reactions to the human diploid rabies vaccines were
also reported from Poland [3].In 289 patients receiving
rabies diploid vaccine produced by Merieux,postvacci-
nation reactions (14 %)included mainly localreactions
with reddening,edema and pain atthe injection site.
These changes were short-lasting and resolved spontan-
eously in most cases.Systemic reactions included mainly
feverwith malaise(2 %), headachesand low mood
(1.7 %).These reactions were also short-lasting and left
no sequelae.Allergic reactions of the type ofhyperergic
purpura and urticariawere found in only isolated
cases (0.3 %) [92].
Tick-borne Encephalitis (TBE) vaccine
TBE vaccines target members ofthe virus family Flavi-
viridae that is one of the major human pathogenic flavi-
viruses causing potentially serious neurologic disease via
threesubtypes(European,Far Eastern and Siberian).
The diseaseburden related to thispathogenicvirus
group continuesto be of greatconcern [93,94].The
TBE vaccine is not licensed in the US but is widely used
in western and centralEurope with over100 million
doses administered between 1980 and 2010 and major
successin preventing TBE viralinfections[95]. The
safety surveillance experience has been reassuring.Im-
mediate hypersensitivity reactions and anaphylaxis have
not been reported as a post-marketing safety surveillance
concern.In a PubMed search in Aprilof 2015,only two
publicationscan be found describinggelatin-induced
urticaria and anaphylaxis (allassociated with the older
formulation).For post marketing surveillance ofimme-
diateallergic reactions,only one publication in 2004
reported a frequency of two per 100,000 doses with pre-
sumed linkage to the polygeline constituent.The newer
vaccineintroducedin 2002 (without polygelinefor
pediatricpopulations)demonstrated“no serious or
unexpected adverse events related to vaccination were
reported … more than 3000 voluntary subjects” [96].As
discussedabove with Japaneseencephalitisvaccine,
whether or notprotamine may become a clinically im-
portant allergen for susceptible individuals remains to be
seen [97].Finally,the package insertfor the Canadian
licensed vaccine states that"In the large clinicaltrials
conducted to date,there were no reports in adults or
children of serious clinical events,such as seizures,or of
systemic allergic reactions,considered to be causally re-
lated to the vaccination." [98].
Allergic reactions to vaccine components
Vaccines contain whole organisms or parts of organisms
and/or inactivated toxins (toxoids) that induce protective
immune responses.These vaccine antigens rarely,if ever,
are the cause ofhypersensitivity reactions.Recently,the
mutant,non-toxic form of diphtheriatoxin (CRM
(197)),used as a carrierprotein in Prevnar-13,was
implicated asa cause ofanaphylaxisin a 12 month
old infant [99] (D). CRM (197) had previously been
implicated as the allergen in a reaction to a Hib con-
jugate vaccine [100].Other vaccine componentsthat
can induce allergic responsesinclude residualmedia
used to grow the organisms(e.g. yeast),adjuvants
(e.g.aluminum salts),stabilizers (e.g.gelatin),antibiotics,
preservatives(e.g.thimerosal)and traceamountsof
latex from vaccinevial stoppersor syringeplungers
in some vaccines (Table 2)[101,102].A complete list
of all vaccine components thatcould be potentialal-
lergenscan be found atthe website ofthe Institute
Table 2 Recommended approach to patients with possible
allergies to components of vaccines
ComponentVaccines Recommendation
Egg MMR Give vaccine in usual manner
without special precautions
Influenza Give vaccine in usual manner
without special precautions
Yellow Fever Skin test with vaccine and if
positive,administer in graded
doses under observation
Gelatin See Table 4 Skin test with vaccine and
if positive,administer in
graded doses under
observation
Milk DTaP Give vaccine without special
precautions
Tdap
Yeast Hepatitis B Skin test with vaccine and if
positive,administer in graded
doses under observationQuadrivalent HPV
Latex http://www.cdc.gov/
vaccines/pubs/pinkbook/
downloads/appendices/B/
latex-table.pdf.Also,see
[116].
Give vaccine without specific
precautions
Dreskin et al.World Allergy Organization Journal(2016) 9:32 Page 9 of 21

for VaccineSafetyof the Johns Hopkins University
BloombergSchool of Public Health [103].Many of
these componentsare presentin small amountsthat
are usually insufficientto induce allergic reactions in
most individualswith possible hypersensitivity to the
component.However,individualswith unusually high
levelsof IgE antibody can theoretically reactto very
small amountsof these antigensand develop severe
reactions,including anaphylaxis.
Residual media
Residualsmallamounts ofmedia to grow organisms are
often found in both inactivated and live vaccines.For ex-
ample, viruses are grown in cell lines.No intact cells from
these celllines persist in live or inactivated vaccines,and
purification removes most of the cellular material, but it is
impossible to remove all of the components.
Adjuvants
Adjuvants are used to enhance the immune response to
vaccines.Aluminum hydroxideand aluminum phos-
phate are the most common adjuvants used in vaccines.
No immediatehypersensitivityreactionshave been
documented due to these adjuvants.However,contact
allergy and smallgranulomas or nodules with persistent
urticaria at the site may occur following aluminum con-
taining vaccinesand were observedin 38 of 4758
(0.83 %) prospectively followed children [104].These ur-
ticarialgranulomasusually persistfor severalmonths
and rarely up to severalyears.Follow up 5 to 9 years
after initialdiagnosis in affected children revealed that
the majorityof children wereno longer positiveto
aluminum contact allergy testing [105].Larger recurrent
nodules at the sites of injection of aluminum containing
vaccines have been reported rarely and have resulted in
biopsies to rule outtumors in predisposed individuals
[106].An increased rate of anaphylaxis and other imme-
diate hypersensitivity reactions was reported in Canada
associated with an AS03 (trade name fora squalene-
based immunologicadjuvantused in variousvaccine
productsby GlaxoSmithKline)adjuvantedpandemic
H1N1 influenza vaccine [107].A case–controlstudy re-
vealed higher rates of food allergy in affected individuals,
but no evidence that the reactions were due to this adju-
vant has been provided [108].No increased risk of aller-
gic reactionswasnoted in a systematic review ofthe
safety of the MF59 (trade name for a squalene-based im-
munologic adjuvantby Novartis)adjuvanted influenza
vaccine in children used in Europe [109].This vaccine
has been licensed for use in persons ≥ 65 years of age in
the U.S.and there is no indication of an increase in re-
ports ofallergic reactions in clinicaltrials in the elderly
to date [110].
Antimicrobial agents
Gentamycin,tetracycline,neomycin,streptomycin,and
polymyxin B are used during the production process for
vaccines to prevent growth of bacteria or fungi [103].Al-
though most of these antimicrobials are removed during
the purification process,trace amounts may be present
in some vaccines.These antimicrobialagents can cause
contactor rarely systemichypersensitivityreactions
when used in clinicalsettings attherapeutic doses (e.g.
treatmentof an infection).However,allergic reactions
associated with the trace amounts presentin vaccines
have not been well documented [111].
Preservatives
Thimerosal and 2-phenoxyethanol are used in multidose
vials of vaccines to prevent bacterial growth.Thimerosal
was used in severalvaccines used in the United States
until 2001,but was removed as a preservative in vaccines
used in young infants as a precautionary measure because
of theoreticalconcernsaboutmercurytoxicity[102].
Some multi-dose vialsof inactivated influenza vaccines
contain thimerosaland trace amounts may be found in
some other vaccines where thimerosalwas used during
the production process,but most was removed from
the final product.Thimerosalin vaccineshas been
associated with contactallergyand rarelywith sys-
temic allergic reactions[112,113].2-Phenoxyethanol
and phenolhave notbeen associated with immediate
hypersensitivity reactions.
Latex
Naturallatex can cause immediate hypersensitivity re-
actions,including anaphylaxis [114].Latex is present in
the rubber stoppers on some vaccine vials,and on the
plungers in some prefilled vaccinessyringes(see
Table 2).There are reports of immediate hypersensitiv-
ity reactionsto latex in this setting,but in most
instances,specific studies have not been done to deter-
mine that latex was the cause ofthe immediate hyper-
sensitivityreaction [43,115]. Nevertheless,patients
with severe latex allergy should avoid vaccines packaged
with latex-containing stoppers and syringe plungers if pos-
sible. Alternative vaccines without the risk ofexposure
to natural latex may be available.Syntheticlatex
which is not allergenic,has replaced naturallatex in
mostproducts.A list of vaccines thatcontain natural
latex in the packaging can be found in the index of
the CDC Pink Book [116].
Approach to the patient with a history of an allergic
reaction to a vaccine
Severalexcellentpracticeparameters,reviews,and
guidelineshave been published describing the clinical
managementof patients with suspected vaccine allergy
Dreskin et al.World Allergy Organization Journal(2016) 9:32 Page 10 of 21

[4, 117–120].The approach suggested by Caubetand
colleagues[120]is reproduced,with minor modifica-
tions, here in Fig.1.Caveats that may alter management
for specific patients are mentioned in the legend to Fig.1
and are discussed in more detailby Wood etal. [119]
and Kelso et al.[4].
Approach to the patient with concerns regarding possible
allergic reactions to vaccines
Some recommendations may change so the reader is en-
couraged to accessthe most up to date information
whenever possible,such as from the Centers for Disease
Control(www.cdc.gov/vaccines).Investigation of allergic
reactions following the receipt of multiple vaccines sim-
ultaneouslyand/or combined vaccinesis increasingly
common and can be challenging.If serologic orskin
testingare indicated theinvestigatormay chooseto
prioritize the evaluations based on what they suspect to
be the most likely allergens.When proceeding to the ad-
ministration ofadditionaldosesof indicated vaccines,
the investigator willneed to assess each vaccine separ-
atelywhen possible.Conjugatepolysaccharide-protein
vaccines may require investigation ofthe proteins that
are conjugated to the polysaccharides as wellas other
vaccine components as the plain polysaccharides are less
likely causes of allergic reactions.
Most questions aboutvaccine allergy result from two
generalconcerns.The first relates to patients who have
had a possible reaction to priorvaccination,while the
second relates to patients with a known allergy – such
as egg allergy – that might put them at risk for specific
immunizations (see below under the heading "Approach
to the patientwith possible allergies to foods or other
materials thatmay also be components ofvaccines or
vaccine packaging").Here we willfocus on the patient
presenting with concerns regarding a suspected reaction
to a prior vaccine.The specific approach to these pa-
tients needs to carefully consider several key questions:
1. Was the reported event consistent with an IgE
mediated allergy in terms of signs,symptoms,and
timing? For example,the patient with a history of
urticaria,angioedema,and respiratory distress
occurring five minutes after vaccine administration
is very different from the patient experiencing a
non-specific rash 24 h after the vaccine was given
(See Definitions,above).
2. Has the patient experienced a documented or
suspected anaphylaxis or rash to any prior
vaccines? Ifso,this might help to focus the
evaluation on specific vaccine constituents that
are common among the vaccines suspected of
causing reactions.
3. Will the patient need additional doses of this
vaccine or other vaccines with common constituents?
Even if the patient will not need additional doses of
the vaccine, an allergic reaction could indicate
hypersensitivity to a vaccine component that might
Fig. 1 Management of patients with suspected hypersensitivity to a vaccine and patients with known allergy to a vaccine component
from Caubet et al.2014;Printed with permission of Wiley) [120].*For egg allergic patients,see text (Approach to the patient with possible allergies to
foods or other materials that may also be components of vaccines or vaccine packaging).**For patients with a positive skin test to a vaccine,consider
risk benefit analysis based on serologic evidence of current immunity and level of risk for target disease.See Wood et al.[119]
Dreskin et al.World Allergy Organization Journal(2016) 9:32 Page 11 of 21

be in other vaccines the patient will receive. Thus, a
thorough evaluation is needed even if no further doses
of the suspect vaccine are required.
With these questions in mind,each patient can then be
approached individually using a combination of clinical as-
sessment, laboratory testing, and cautious re-administration
of necessary immunizations.
Clinical assessment
The clinician should firstdecide iffuture doses ofthe
vaccine are truly needed.This assessment needs to con-
sider the risk of re-vaccination against the risk of acquir-
ing the vaccinepreventablediseaseand of acquired
disease severity.Some vaccines may be considered less
important than others based upon the likely risk ofex-
posure and presence ofunderlying risk factors.Since
many vaccinesare given asa series,some individuals
may mount protective responses from the doses already
administered and fewer than the recommended number
of doses may produce lasting immunity.It may therefore
be a reasonable option to measure and monitor IgG ti-
ters to assess the level of protection and the need for fu-
ture doses,recognizing thatantibody levelsare not a
usefulmeasure ofprotection forall vaccines and that
immunity might wane over time.
Allergy testing with vaccines and vaccine constituents
If it is determined thatadditionaldosesof a vaccine
should be administered,skin testing with the vaccine
and/or vaccine constituents should be performed.This
process may be relatively simple if only a single vaccine
antigen wasadministered orfar more complicated if
multiplevaccinesor multivalentvaccines(e.g.MMR)
were given at the same visit,which is certainly the norm
for the typical pediatric encounter.
A number ofapproaches to vaccine skin testing have
been suggested butcurrentguidelines recommend that
testing be initiated with a prick skin testto the full
strength vaccine,unless the patient has a history ofse-
vere anaphylaxis in which case it is appropriate to dilute
the vaccine 1:10 or even 1:100 to initiate prick skin test-
ing [4,118] (D).If the prick skin test with full-strength
vaccine is negative,an intradermaltest with the vaccine
diluted 1:100 should then be performed.All tests need
to be interpreted carefully with appropriate positive and
negative controls,recognizing thatfalsely positive skin
test results may occur.These may be the result oftrue
but clinically irrelevantIgE responses or to irritantef-
fects of the vaccine.A case controlstudy of a child with
a history ofanaphylaxis to the 23-valentpneumococcal
vaccine positive skin tests and in vitro IgE tests to the
whole vaccine,included nine controls [121] (C).In one
study irritant reactions were common at concentrations
of 1:10 or undiluted vaccines,especially with influenza,
MMR, and varicella vaccines [122].At the 1:100 concen-
tration,rates ofirritant reactions were far less common
with the most frequent being 5 % for DT and DTaP and
15 % for influenza.It is also important to recognize that
delayed responses(12–24 h)to vaccine skin testsare
common,most likely representing previously established
cell-mediated immunity,or immune complex formation
in patients with high titers ofantibody to vaccine com-
ponents [123] (D),and should not raise concern in the
evaluation of IgE-mediated vaccine allergy [122].
If the suspected vaccine contains specific constituents
known to be potentially allergenic,testing should also be
conducted forthose components.These primarily in-
clude egg (for reactions to yellow fever or influenza vac-
cines),gelatin (see Table 3 forthe gelatin contentof
specific vaccines),latex,and yeast.Skin test reagents for
egg and yeast are commercially available.Prick skin test
solutions for gelatin can be prepared by dissolving one
teaspoon ofgelatin powder in 5 mL ofnormalsaline.
Skin test extracts for latex are commercially available in
many countries but not in the United States.In addition
to skin testing, in vitro testing for allergen-specific
IgE is availablein most commerciallaboratoriesfor
egg,gelatin,latex,and yeast.For gelatin,it is import-
ant that assays forboth porcine and bovine products
be conducted.
Examples ofskin and serologic testing thatwould be
appropriate in the evaluation ofsuspected reactions to
specific vaccines are presented in Table 4.
Administration of vaccines to patients with a history of a
suspected prior allergic reaction
If both skin and in vitro testing are negative,especially if
the intradermalskin test to the vaccine is negative,the
chance thatthe patienthas an IgE-mediated allergy to
the vaccine or to any vaccine constituentis very small.
The usualdose of the vaccine can therefore be adminis-
tered with atleasta 30 min observation period after
vaccination in a facility where anaphylaxis can be recog-
nized and managed with epinephrine and other support-
ive treatments.
If skin or in vitro testing to the vaccine or a vaccine
component is positive,alternative approaches to vaccin-
ation should be considered.However,if the vaccine is
considered necessary – that is,the benefit of the vaccine
clearly outweighs the potentialrisk of vaccine adminis-
tration – it is usually possible to safely administer the
vaccine using a graded dose protocol[4]. These deci-
sions should be carefully considered on a case-by-case
basis,recognizingthat even administrationusing a
graded dose protocolstill carries a threoreticalrisk of
anaphylaxis.This should be conducted with informed
consent and only in a setting preparedto treat
Dreskin et al.World Allergy Organization Journal(2016) 9:32 Page 12 of 21