BMJ | 17 octoBer 2009 | VoluMe 339
For the full versions of these articles see bmj.com
Egg allergy affects about 2.6% of preschool children
by 3 years of age, and influenza immunisation using
egg based vaccines has been classified as a “relative
contra indication” (prescribe with extra caution) in this
patient group.1 Until now the numbers of children with
egg allergy requiring immunisation has been low, but this
may change with the potential for a mass immunisation
campaign. This article reviews the literature on the safety
of flu vaccines and provides guidelines for the admin-
istration of these vaccines to children with egg allergy.
Although egg-free flu vaccines are expected to be avail-
able for this season, the provision of sufficient amounts of
this vaccine cannot be guaranteed at the time of writing,
and a pragmatic strategy for the safe immunisation of
children with egg allergy is required.
Sources and selection criteria
We identified articles using PubMed and the search
terms “influenza” and “egg allergy”. We identified fur-
ther references within relevant papers. We found two
randomised clinical trials, but most evidence comes
from small case series.
what vaccines are available?
This season two varieties of flu vaccine will be available:
a pandemic A/H1N1 strain and the normal trivalent
seasonal flu vaccine that will contain an A/H1N1 virus
but will not protect against the pandemic strain. There
is an egg-free flu vaccine for seasonal immunisation,
and it is anticipated that there will be one available for
the pandemic strain (table 1). These egg-free vaccines
are produced using new viral culture techniques in a
mammalian cell line.2 3 Inactivated, split flu virus, split
virion, subunit, or surface antigen flu vaccines are grown
in hens’ eggs and contain residual allergenic egg white
proteins. Some but not all of last season’s flu vaccines
(2008) reported maximum egg protein content above
the proposed safety cut-off of 1.2 μg/ml, with levels up
to 2 μg/ml. Virosomal vaccines are highly purified, and
although still grown in egg cultures, often have much less
residual egg protein.4
what is the evidence for the current contraindications?
According to the Department of Health guidance on
immunisation in the Green Book and manufacturer’s
product characteristics, flu immunisation is contraindi-
cated by a confirmed anaphylaxis to a previous dose of
the vaccine, to any component of the vaccine, or to egg
products.5 Despite the use of anaphylaxis as a severity
cut-off, flu vaccines have been used cautiously in indi-
viduals with egg allergy. We will look at the evidence for
each of these contraindications in turn.
Anaphylaxis as an adverse event after immunisation
is a rare event at about one in a million doses.6 7 There
recommendations for the
administration of influenza vaccine
in children allergic to egg
M Erlewyn-Lajeunesse,1 N Brathwaite,2 J S A Lucas,1 3 J O Warner4
1Southampton University Hospitals
NHS Trust, Southampton
2King’s College Hospital, London
3Infection Inflammation and
Immunology, School of Medicine,
University of Southampton,
4Imperial College and Imperial
College Healthcare NHS Trust,
M lajeunesse, the children’s
Allergy clinic, Southampton
university Hospitals NHS trust,
Southampton So16 6YD
Cite this as: BMJ 2009;339:b3680
Egg-free, mammalian culture based flu vaccines should be
given preferentially to individuals allergic to egg
If an egg-free vaccine is not available, only vaccines with a
stated maximum egg content <1.2 μg/ml (0.6 μg per dose)
should be used in individuals allergic to egg
If egg based vaccine is administered to individuals with
egg allergy, this should be done in a centre experienced in
the management of anaphylaxis
A single dose protocol is recommended for those with less
severe egg allergy
A two dose, split protocol can be used in those with
anaphylaxis to egg or those with moderate or uncontrolled
table 1 | Brands of influenza vaccine available in the UK for the
autumn 2009 immunisation campaign*
Vaccine choice for
individuals with egg allergy
*These brands will change between seasons, as will the egg content of
†Standard vaccine types containing hens’ egg protein are described as
inactivated, split flu virus, split virion, subunit, or surface antigen.
‡Brands that contain hens’ egg protein and are used in individuals with
egg allergy should have a stated ovalbumin content preferably <1.2 μg/ml
or 0.6 μg/dose to be in keeping with safety data (see text).
BMJ | 17 octoBer 2009 | VoluMe 339 913
is a paucity of published data on the risk of allergic reac-
tion to flu vaccine.8 A large population based study in
the United States in 1976 found 11 episodes of non-fatal
anaphylaxis in 48 million doses.9 None of the patients
with an anaphylaxis to the flu vaccine reported a history
of egg allergy.
Excipients in the vaccine can act as allergens in sen-
sitised individuals, as seen with gelatin in the measles,
mumps, and rubella vaccine (MMR vaccine) during the
1990s.10 Common residues of production found in flu
vaccines include the stabiliser polysorbate 80 and anti-
biotics such as gentamicin, neomycin, kanamycin, and
polymyxin B. There are no reports of anaphylaxis to flu
vaccine caused by sensitivity to these agents.
All reported cases of anaphylaxis after flu immunisa-
tion in individuals with egg allergy occurred over 20
years ago. At least one case of fatal anaphylaxis after
influenza vaccine occurred in a child with egg allergy
during the 1970s.11 In 1946 Ratner and Untracht
described two cases of adult anaphylaxis related to flu
vaccine and egg intolerance from their literature review;
they also documented two children who had immediate
allergic reactions to full strength intradermal testing with
flu vaccine.12 The egg content of the vaccines causing
these reactions was likely to have been much higher than
those available today. The ovalbumin content of flu vac-
cines has been shown to change by manufacturer and by
year.13 14 More recently, manufacturers have published
the maximum egg content of their vaccines in their “sum-
mary of product characteristics,” which helps to make an
assessment of their safety in egg allergy.
Can influenza vaccine be given safely in egg allergy?
Several reports have been published of the safe immu-
nisation of individuals allergic to egg with flu vaccines
containing egg (table 2). Initial case series excluded all
who had a positive skin prick or intradermal testing
to the flu vaccine.11 15 16 Later case series showed that
positive skin and intradermal tests to the vaccine did
not predict reactivity, and that individuals with an ana-
phylaxis to egg have been immunised safely using a
split dose protocol (six dose or two dose).17-19
The most convincing evidence comes from a pro-
spective multicentre controlled trial using a split dose
protocol.19 Flu vaccine was administered in two doses
30 minutes apart; the first dose was 1/10th (0.05 ml)
and the second dose 9/10th (0.45 ml) of the recom-
mended dose. The content of egg protein in the vac-
cines used in this trial was known to be less than 1.2
μg/ml (0.6 μg per 0.5 ml dose). Eighty three indi-
viduals with confirmed egg allergy were recruited, of
whom 27 had a convincing history of anaphylaxis to
egg. The 124 control participants without egg allergy
received a standard single dose of the vaccine. All
patients with egg allergy tolerated the split dose vac-
cination protocol without any significant allergic reac-
tion. A controlled study also showed that a virosomal
vaccine with a single dose protocol was safe in those
with egg allergy.20
Although these studies have cautiously established
the safety of flu vaccines in a small sample of indi-
viduals with egg allergy, the studies are too small to
establish the risk of anaphylaxis; however, all subjects
tolerated a cumulative full dose of vaccine.
what do current guidelines say?
The current guidance has interpreted these data in
different ways.14 21 22 The American Academy of Paedi-
atrics’ Red Book has recommended a graded, five injec-
tion protocol after an initial 0.05 ml of 1:10 vaccine
dilution, in a setting with full resuscitation facilities.22
Two variations of a two dose, split protocol have also
been recommended: one using a 1:100 intradermal
test before dosing, whereas the other forgoes diag-
nostics but excludes those with anaphylaxis to egg.14 21
Neither of these guidelines incorporates the evidence
for the safe administration of vaccine either to those
with anaphylaxis to egg or to those apparently sensi-
tised to the vaccine (with a positive intradermal test)
using a two dose split protocol.19 The British Society of
Allergy and Clinical Immunology has recently ratified
gu idelines based on our advice to members of the Pae-
diatric Allergy Group for the 2008 flu season, which
form the basis of our recommendations.23
The following are not
immunisation with flu
A history of egg allergy •?
but now able to eat eggs
A family history of egg •?
allergy—in a sibling or
other family member
A family history of •?
reaction to flu or any
table 2 | Immunisation of individuals allergic to egg with influenza vaccine
Davies and Pepys15
Bierman et al11
Miller et al16
Murphy and Strunk17
Anolik et al18
0/6 (SPT) 6/6 (IDT)
2 single doses, 4 weeks apart
Not given if IDT positive
Six doses, graded‡
All had asthma, 1 wheezed 20
min after second dose
Nil 8/8 (egg allergy group),
4/83 (egg allergy group),
0/44 (egg allergy group),
Not stated Six doses, graded‡
James et al19
SPT neat27/83Split dose§Nil
Esposito et al20
SPT neat11/44 Single dose of virosmal vaccineNil
ITD= intradermal dilutional testing.
SPT=skin prick testing.
*Two (of seven) reported adverse reactions to a previous dose of influenza vaccine.
†Two children allergic to eggs developed a positive IDT result before the second dose of vaccine, which was then withheld.
‡Six dose protocol of 0.05 ml (1:100 dilution); 0.05 ml (1:10); 0.05 ml neat vaccine; then 0.1 ml, 0.15 ml, and 0.2 ml (neat) at intervals of 15 minutes, with a further split dose four weeks later.
§Two dose, split protocol of 1/10th, followed by 9/10th 30 minutes later using a vaccine with <1.2 μg/ml ovalbumin content.
BMJ | 17 octoBer 2009 | VoluMe 339
what should we do?
Given the likelihood of mass immunisation to flu,
including preschool children, a pragmatic approach is
essential to ensure that individuals with egg allergy are
protected, both from the disease and from the risks of
is the child allergic to egg?
Egg allergy is easily diagnosed from a clear history of
immediate allergic reaction to egg or to a food con-
taining egg. All children with immediate reactions to
egg, including those with localised rashes on exposure,
should have skin prick testing or estimation of specific
IgE to confirm the diagnosis. Specialist advice may be
needed if the diagnosis remains uncertain. We have out-
lined clinical decision steps in the algorithm (figure).
Anaphylaxis to chicken meat, feathers, and dander
has been reported as a contraindication to flu vaccine
by some manufacturers. Although such allergies are rare,
no cases of anaphylaxis to flu immunisation in such indi-
viduals have been reported. These rare allergies remain a
theoretical risk and in the absence of any firm clinical data
should be treated in the same way as egg allergy.
Many children outgrow their egg allergy in the first
few years of life. If a child can eat lightly cooked egg
(such as a spoonful of scrambled egg) without reaction
then they are no longer allergic. We do not recommend
testing children allergic to egg by a trial at home of food
containing egg because of the risk of an unsupervised
allergic reaction. A specialist should assess a child’s cur-
rent sensitivity. Children tolerating egg in baked products
(such as cake) but not boiled or scrambled egg are still
potentially at risk of severe reaction.
which vaccine should be used?
We recommend that all individuals with egg allergy
should be immunised with a mammalian culture based
flu vaccine (table 1). If a mammalian cell culture v accine
is not available then we recommend using a virosomal
vaccine for seasonal flu as this has the lowest egg content
of any vaccine based on hens’ egg and has clinical data
to support its use.20
Flu vaccines that contain egg should be used with
caution and only if other vaccines are not available. A
careful assessment should weigh the risks of immuni-
sation against risk of infection with the flu virus. The
risk-benefit for each individual will depend on host fac-
tors such as underlying chronic illness and current or
planned immunosuppression and on viral factors such
as the local prevalence and virulence of the seasonal or
pandemic virus. In keeping with available safety data, the
vaccine should have a stated maximum egg content of
<1.2 μg/ml (0.6 μg per dose).19 The ovalbumin content
of the pandemic vaccine Pandemrix (GSK) is not known.
We recommend that the maximum egg concentration is
added to the “summary of product characteristics” before
Adverse events to any flu vaccine should be reported
to the Medicines Healthcare Regulatory Agency’s Y ellow
Card scheme (http://yellowcard.mhra.gov.uk).
is all egg allergy the same?
Children with positive allergy diagnostics to egg by skin
prick testing or specific IgE estimation have the potential
for a generalised reaction when presented with allergen
via the parenteral route of intramuscular immunisation,
even if reactions on oral exposure have been mild. Until
better safety data are available we recommend that these
individuals are immunised in a facility with staff experi-
enced in treating children with anaphylaxis, most likely
We have divided individuals with egg allergy into
two risk groups based on our opinion of their po tential
for anaphylaxis to the vaccine (table 3).24 Most children
with egg allergy have reactions involving the skin. For
the easy application of our recommendations we have
simplified the diagnosis of anaphylaxis.25 26 If any
uncertainty remains about the nature of the allergic
Algorithm for the immunisation of individuals allergic to egg with influenza vaccine
Is influenza immunisation indicated in an egg allergic individual?
Adverse reaction to previous dose of influenza vaccine?
Immunise with mammalian cell based vaccine
Influenza immunisation contraindicated
Ever eaten egg?
Past adverse reaction to egg?
Previous anaphylaxis to egg?‡
Immunise with single dose schedule in primary care
Immunise with single
dose schedule in hospital
Egg allergy diagnostics?†
Moderate or uncontrolled asthma?§
Previous adverse reaction to a shared
component of the influenza vaccine?
Currently eats eggs without reaction?*
Immunise with split dose schedule in hospital
*Able to eat a portion of eggs (not just egg when baked in foods such as in cakes and biscuits) without immediate
†A positive skin prick test, specific IgE estimation, or food challenge
‡A history of a severe allergic reaction affecting at least one of the following areas: airway (throat tightness, sensation
of closure, stridor, hoarseness); breathing (tachypnoea, respiratory distress, dyspnoea, wheeze, hypoxia); circulation
(collapse, hypotension, shock with or without loss of consciousness, severe abdominal pain)
§Uncontrolled asthma or using preventer drugs at BTS/SIGN step 3 or higher
table 3 | Immunisation with an egg containing vaccine
Worst previous reaction to egg
Lower risk Previous mild gastrointestinal or
dermatological reaction to egg and positive
diagnostics; orpositive diagnostics but never
knowingly exposed to egg
Single dose schedule 0.5 ml intramuscular dose
of a virosomal vaccine or a vaccine with low egg
content (<1.2 μg/ml) if virosomal not available
Higher riskPrevious respiratory or cardiovascular
reaction to egg, and positive diagnostics;
or“lower risk” individual with uncontrolled
asthma treated at BTS/SIGN step 3 or higher
Two dose, split protocol of 0.05 ml
intramuscularly, followed 30 minutes later by 0.45
ml of a virosomal vaccine or a vaccine with low egg
content (<1.2 μg/ml) if virosomal not available
This table considers the approach if an egg-free vaccine is not available. Mild gastrointestinal and dermatological
reactions include urticaria, angio-oedema, and vomiting. Anaphylaxis is characterised by symptoms involving the
airway and respiratory tract, such as pharyngeal oedema, stridor, respiratory distress, and wheeze. Cardiovascular
complications include circulatory shock, hypotension, severe abdominal pain, or collapse. Positive diagnostics
are skin prick and specific IgE tests to egg protein.
BMJ | 17 octoBer 2009 | VoluMe 339 915
reaction they should be considered to be in the
higher risk group.
Asthma is a known risk factor for life threatening
anaphylaxis, and so we have dealt with children with
moderate to severe asthma differently, by including
them in the higher risk group irrespective of the
severity of their previous reactions to egg.27
As an arbitrary cut-off we have used step 3 of the
British Thoracic Society/SIGN guidelines, where a
long acting β2 agonist is added to inhaled corticos-
teroid therapy.28 Children who have uncontrolled
asthma should also be included in the higher risk
group. We do not recommend that children with
acute asthma are immunised; it should be deferred
until they have recovered.
We recommend that high risk children should
always be immunised in secondary care owing to
the availability of advanced paediatric resuscita-
tion facilities. Unlike normal immunisation advice
to wait for 20 minutes after the procedure, we
advise that higher risk patients should remain on
the premises for 60 minutes after immunisation,
in keeping with standard allergen immunotherapy
practice (where allergic reaction is more commonly
encountered) and to refrain from strenuous exercise
for 24 hours.
the a/H1n1 vaccine
The A/H1N1 vaccine is expected to consist of
two doses three weeks apart. Both doses should be
pr ovided in a centre experienced in the manage-
ment of anaphylaxis. The second dose of the same
vaccine can be given in a single 0.5 ml intramuscu-
lar injection provided that the first dose has been
contributions: ME-L wrote the article based on previous documents written
jointly by all authors. JSAL, NB, and JOW edited and reviewed the article.
Funding: No special funding.
competing interests: ME-L has received reimbursement to attend scientific
meetings from GSK and Wyeth and has an unrestricted educational grant for
Sanofi Pasteur MSD.
Provenance and peer review: Not commissioned; externally peer reviewed.
Eggesbo M, Botten G, Halvorsen R, Magnus P. The prevalence of allergy to 1
egg: a population-based study in young children. Allergy 2001;56:403-
Howard MK, Kistner O, Barrett PN. Pre-clinical development of cell culture 2
(Vero)-derived H5N1 pandemic vaccines. Biol Chem 2008;389:569-77.
Barrett PN, Mundt W, Kistner O, Howard MK. Vero cell platform in vaccine 3
production: moving towards cell culture-based viral vaccines. Expert Rev
Kursteiner O, Moser C, Lazar H, Durrer P. Inflexal V—the influenza vaccine 4
with the lowest ovalbumin content. Vaccine 2006;24:6632-5.
Salisbury D, Ramsay M, Noakes K. 5 Immunisation against infectious
disease—the “green book.” 4th ed. London: Stationery Office, 2006.
Bohlke K, Davis RL, Marcy SM, Braun MM, DeStefano F, Black SB, et al. Risk 6
of anaphylaxis after vaccination of children and adolescents. Pediatrics
Peng MM, Jick H. A population-based study of the incidence, cause, 7
and severity of anaphylaxis in the United Kingdom. Arch Intern Med
Coop CA, Balanon SK, White KM, Whisman BA, Rathkopf MM. 8
Anaphylaxis from the influenza virus vaccine. Int Arch Allergy Immunol
Retailliau HF, Curtis AC, Storr G, Caesar G, Eddins DL, Hattwick MA. Illness 9
after influenza vaccination reported through a nationwide surveillance
system, 1976-1977. Am J Epidemiol 1980;111:270-8.
Pool V, Braun MM, Kelso JM, Mootrey G, Chen RT, Yunginger JW, et al. 10
Prevalence of anti-gelatin IgE antibodies in people with anaphylaxis
after measles-mumps rubella vaccine in the United States. Pediatrics
Bierman CW, Shapiro GG, Pierson WE, Taylor JW, Foy HM, Fox JP. 11
Safety of influenza vaccination in allergic children. J Infect Dis
Ratner B, Untracht S. Allergy to virus and rickettsial vaccines. 12
Mark C. Large variations in the ovalbumin content in six European 13
influenza vaccines. Pharmeur Sci Notes 2006;2006(1):27-9.
Zeiger RS. Current issues with influenza vaccination in egg allergy. 14
J Allergy Clin Immunol 2002;110:834-40.
Davies R, Pepys J. Egg allergy, influenza vaccine, and immunoglobulin E 15
antibody. J Allergy Clin Immunol 1976;57:373-83.
Miller JR, Orgel HA, Meltzer EO. The safety of egg-containing vaccines for 16
egg-allergic patients. J Allergy Clin Immunol 1983;71:568-73.
Murphy KR, Strunk RC. Safe administration of influenza vaccine 17
in asthmatic children hypersensitive to egg proteins. J Pediatr
Anolik R, Spiegel W, Posner M, Jakabovics E. Influenza vaccine testing in 18
egg sensitive patients. Ann Allergy 1992;68(1):69.
James JM, Zeiger RS, Lester MR, Fasano MB, Gern JE, Mansfield LE, et al. 19
Safe administration of influenza vaccine to patients with egg allergy.
J Pediatr 1998;133:624-8.
Esposito S, Gasparini C, Martelli A, Zenga A, Tremolati E, Varin E, et al. Safe 20
administration of an inactivated virosomal adjuvanted influenza vaccine
in asthmatic children with egg allergy. Vaccine 2008;26:4664-8.
Piquer-Gibert M, Plaza-Martin A, Martorell-Aragones A, Ferre-Ybarz 21
L, Echeverria-Zudaire L, Bone-Calvo J et al. Recommendations for
administering the triple viral vaccine and antiinfluenza vaccine in patients
with egg allergy. Allergol Immunopathol (Madr) 2007;35:209-12.
Committee on Infectious Diseases, American Academy of Pediatrics. 22
Active immunization. In: Pickering LK, Baker CJ, Long SS, McMillan JA,
eds. Red book: report of the committee of infectious diseases. 27th ed. Elk
Grove Village, IL: American Academy of Pediatrics, 2006:9-54.
Nasser S, Brathwaite N. Swine flu vaccination in patients with egg allergy. 23
Clin Exp Allergy 2009;39:1288-90.
Brown SG. Clinical features and severity grading of anaphylaxis. 24
Clin Immunol 2004;114:371-6.
Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson NF Jr, Bock SA, 25
Branum A, 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;117:391-7.
Ruggeberg JU, Gold MS, Bayas JM, Blum MD, Bonhoeffer J, Friedlander 26
S, et al. Anaphylaxis: case definition and guidelines for data collection,
analysis, and presentation of immunization safety data. Vaccine
Colver AF, Nevantaus H, Macdougall CF, Cant AJ. Severe food-allergic 27
reactions in children across the UK and Ireland, 1998-2000. Acta Paediatr
British Thoracic Society Scottish Intercollegiate Guidelines Network. 28
British guideline on the management of asthma. Thorax 2008;63(suppl
Accepted: 6 September 2009
AdditionAl eduCAtionAl resourCes
NHS Immunisation Information (www.immunisation.nhs. •?
uk)—NHS website giving advice on vaccines, disease,
and immunisation in the UK
For healthcare professionals
•?Immunisation against infectious disease—“the
green book.” (www.dh.gov.uk/en/Publichealth/
DH_4097254)—Department of Health publication
providing advice on immunisation
clinics&Itemid=26)—This website of the British Society
for Allergy and Clinical Immunology provides information
about where the UK NHS and Irish allergy clinics are
located, and what services they operate
tips For non-speCiAlists
Celvapan (Baxter), a pandemic A/H1N1 vaccine, and •?
Optiflu (Novartis), a seasonal influenza vaccine are grown
in a mammalian cell culture system and are egg-free
Other flu vaccines are prepared in hens’ eggs and may •?
contain small amounts of egg protein
Individuals with severe egg allergy face a risk of •?
anaphylaxis with flu vaccines that contain egg