Adverse reactions to vaccines practice parameter 2012 update, Presented by Sasikarn Suesirisawad, MD.

1. Sasikarn Suesirisawad, MD

2.  Anaphylactic reaction to vaccines are estimated
to occur at 1/million doses.
 Fatalities from vaccine-induced anaphylaxis are
exceedingly rare.(B)
 All serious event occurring after vaccine
administration should reported to Vaccine
Adverse Event Reporting System(VAER), even if
it is not certain that vaccine was causal.(C)
Kelso et al. J Allergy Clin Immunol 2012 Jul;130(1):25-43

3.  Mild local reaction and constitutional
symptom are common and do not
contraindicate future doses.
 DTH can cause injection-site nodule, this is
not contraindication to subsequent
vaccination.(C)
Kelso et al. J Allergy Clin Immunol 2012 Jul;130(1):25-43

4. Classification
of
Vaccine Allergy

5. Adverse reactions to vaccine
IgE-mediated reactions Non-IgE-mediated reactions
Vaccine Specific vaccines Vaccine Specific vaccines
constituents constituents
• Gelatin • Diphtheria • Pertussis • Neomycin • MMR
• Egg • Hib • Pneumococcus • Thimerosal • Meningococcus
• Latex • Hepatitis B • Rabies • Aluminum • Pertussis
• Yeast • Influenza • Tetanus • Tetanus
• ? ATB • JE • Varicella • Typhoid
• ? Thimerosal • MMR • Yellow fever • Varicella
• Meningococcus • Yellow fever
Kelso JM. Adverse reactions to vaccines for infectious disease.
In: Middleton’s Allergy Principles and Practice. 7th ed. 2009:1189-1204

6. • IgE- mediated reaction to vaccines are more
often caused by additive or vaccine
component, such as gelatin, rather than
microbial immunizing agent itself.(B)
Kelso et al. J Allergy Clin Immunol 2012 Jul;130(1):25-43

7.  Partially hydrolyzed collagen of bovine or
porcine origin.
 A stabilizer in many vaccines.
 Responsible for many anaphylactic reactions
to MMR, varicella, JE vaccines.
Kelso JM. Adverse reactions to vaccines for infectious disease.
In: Middleton’s Allergy Principles and Practice. 7th ed. 2009:1189-1204

8. Excipients table. Accessed December 10, 2010,
at http://www.vaccinesafety.edu/components-Excipients.htm

9. Kelso et al. J Allergy Clin Immunol 2012 Jul;130(1):25-43

10.  Concern has existed over administration of
vaccines ‘grown in eggs’ to egg-allergic
recipients.
: MMR vaccine
: PCEC rabies vaccine
: Influenza vaccine
: Yellow fever vaccine
Kelso JM. Adverse reactions to vaccines for infectious disease.
In: Middleton’s Allergy Principles and Practice. 7th ed. 2009:1189-1204

11. Approach in egg-
Vaccine Grown in Egg protein content allergic patient
Measles and mumps Chick embryo Picograms to Administer in usual
fibroblast cell cultures nanograms manner
Purified chick embryo Chick embryo Picograms to Administer in usual
rabies fibroblast cell cultures nanograms manner
Influenza (killed Chick extra-embryonic Micrograms Skin test with vaccine
injected and live allantoic fluid prior to administration
attenuated nasal)
Yellow fever Chick embryos Micrograms Skin test with vaccine
prior to administration
Kelso JM. Adverse reactions to vaccines for infectious disease.
In: Middleton’s Allergy Principles and Practice. 7th ed. 2009:1189-1204

12.  If a person reports a severe (anaphylactic)
allergy to latex, vaccines supplied in vials or
syringes that contain DNR should not be
administered.
 For other latex allergies (e.g., a history of
contact allergy to latex gloves), vaccines
supplied in vials or syringes that contain DNR
or rubber latex can be administered.
Kelso JM. In: Middleton’s Allergy Principles and Practice. 7th ed. 2009:1189-1204.

13.  HBV prepared by harvesting hepatitis B
surface Ag from culture of Saccharomyces
cerevisiae contain up to 5% of yeast protein.
 Yeast associated anaphylaxis after HBV in
sensitized patient appear to be rare event.
 HBV & HPV4 contained yeast protein.
Kelso JM. In: Middleton’s Allergy Principles and Practice. 7th ed. 2009:1189-1204.
Kelso JM. J Allergy Clin Immunol 2012 Jul;130(1):25-43

14. Allergens table. Accessed December 10, 2010,
at http://www.vaccinesafety.edu/components-Excipients.htm

15.  Neomycin, polymyxin B, and streptomycin.
 A single report of immediate-type allergic reaction
to MMR vaccine in person with a history of MP rash
to topical neomycin.
 If a patient gives a history of an immediate-type
reaction, it is appropriate to investigate before
immunization with vaccine containing this
antibiotic. Kelso JM, Li JT. Ann Allergy Asthma Immunol 2009;103:S1-S14.
Kwittken PL, Rosen S, Sweinberg SK. AJDC 1993;147:128–9.
Kelso JM. In: Middleton’s Allergy Principles and Practice. 7th ed. 2009:1189-1204.

16.  Mercury-containing organic compound.
 Preservative in a number of biological and drug
products, including many vaccines.
 A single case report of immediate-type reaction
that may have been caused by thimerosal in
vaccine.
Kelso JM, Li JT. Ann Allergy Asthma Immunol 2009;103:S1-S14.
Zheng W, Dreskin SC. Ann Allergy Asthma Immunol. 2007;99:574–5.

17.  DTP vaccines induce production of IgE in
substantial percentage of recipients who go
on to receive subsequent dose without
systemic reaction.
 CRM 197
 Mutant diphtheria protein
 H influenzae vaccine (HibTITER), Pneumococcal
vaccine (Prevnar), Meningococcal vaccine
(Meningitec, Menjugate, Menveo)
Shinefield HR. Vaccine 2010;28:4335-9.
Kelso JM. In: Middleton’s Allergy Principles and Practice. 7th ed. 2009:1189-1204.

18.  Immediate-type allergic reactions, consisting of
urticaria with or without wheezing occurring 5–60
minutes after vaccination.
 Unusual, late-onset urticaria and angioedema
reaction
 1% of recipients, median interval = 2–3 days
 Usually confined to the skin, some cases have
involved hypotension or respiratory distress.
Kelso JM. Adverse reactions to vaccines for infectious disease.
In: Middleton’s Allergy Principles and Practice. 7th ed. 2009:1189-1204

19. MMR VACCINE VARICELLA VACCINE
• Anaphylactic reactions:  Anaphylactic reactions
2–10 per million doses. : 3 per million doses.
• Allergy to gelatin has  Gelatin allergy is the
been determined to be cause of some of these
likely cause (27–92%). reactions.
• No relationship with
egg allergy.
Kelso JM. In: Middleton’s Allergy Principles and Practice. 7th ed. 2009:1189-1204

20.  Risk to be 1:600,000 vaccine doses.
 180,895 reports to VAERS
 107 reports of pre-existing yeast allergies
 11 reports described probable or possible anaphylaxis after
HBV; 4 cases were described after other vaccines
 The possible association between reaction to HBV
and yeast allergy.
DiMiceli L et al. Vaccine 2006;24:703-7.
.
Kelso JM. In: Middleton’s Allergy Principles and Practice. 7th ed. 2009:1189-1204

21.  12,424 reports to VAERS
 3.1/100,000 doses for hypersensitivity reactions
 0.1/100,000 doses for anaphylaxis
 269,680 doses of qHPV vaccine
 2.6/100,000 doses for anaphylaxis
 Girl anaphylaxis 1 hr after HPV(Gardasil),
ID test with Gardasil, which contains polysorbate 80(PS80)
positive, SPT to bivalent vaccine negative, SPT with PS80
positive
Slade BA et al. JAMA 2009;302:750-7.
Brotherton JM et al. CMAJ 2008; 179(6):525-33
Badiu I et al. BMJ Case report 2012;10.1136

22.  2 case reports of anaphylaxis in child who received
23-valent pneumococcal vaccine.
 IgE antibody to vaccine demonstrated by skin testing
and in vitro assay.
Ponvert C, Ardelean-Jaby D, Colin-Gorski A,et al. Vaccine 2001;19:4588-91.
Ponvert C Scheinmann P, de Blic J. Vaccine 2011;10:8256-7.
 7-valent pneumococcal vaccine
 14 of the 4,154 VAERS reports
Wise RP, Iskander J, Pratt RD, et al. JAMA 2004; 292(14):1702-1710.

23. YELLOW FEVER VACCINE INFLUENZA VACCINE
 Anaphylaxis reactions 7  Anaphylaxis 0.024 per
per million doses. 100,000 doses.
 Related to  None of which was
egg, chicken, and fatal, and none of
gelatin. which occurred in
persons known to be
allergic to eggs.
Kelso JM. Adverse reactions to vaccines for infectious disease.
In: Middleton’s Allergy Principles and Practice. 7th ed. 2009:1189-1204

25.  1% of the general population demonstrates DTH by
patch testing to neomycin.
 Skin patch testing: 100-1000 mcg of neomycin.
 Delayed-type contact dermatitis to neomycin
 Small, temporary erythematous, pruritic papules at the
injection sites 48-96 hours after vaccination.
 Immunization can proceed in the usual fashion.
Kelso JM. In: Middleton’s Allergy Principles and Practice. 7th ed. 2009:1189-1204
Madaan A, Maddox DE. Immunol Allergy Clin N Am 2003;23:555-588

26. Allergens table. Accessed December 10, 2010,
at http://www.vaccinesafety.edu/components-Excipients.htm

27.  DTH to thimerosal is reported.
 Single case report of a generalized MP rash
attributed to thimerosal in influenza vaccine.
Lee-Wong M, Resnick D, Chong K. Ann Allergy Asthma Immunol 2005;94:90-4.
 May have large local reactions.
 Not contraindication to receive thimerosal-
containing vaccine.
Kelso JM In: Middleton’s Allergy Principles and Practice. 7th ed. 2009:1189-1204.

28. Allergens table. Accessed December 10, 2010,
at http://www.vaccinesafety.edu/components-Excipients.htm

29.  Enhance immunogenicity of vaccines.
 Subcutaneous nodules are relatively common but
usually resolve within a few weeks to months.
 Higher incidence of contact allergy to aluminum.
 No reports of anaphylaxis have been attributed
specifically to aluminum.
Kelso JM. In: Middleton’s Allergy Principles and Practice. 7th ed. 2009:1189-1204
Madaan A, Maddox DE. Immunol Allergy Clin N Am 2003;23:555-588

30.  Mild local reactions are relatively common.
 Arthus reaction has been postulated.
 In such individuals antitoxin levels should be
evaluated before determining the need for a
subsequent booster.
Moylett EH, Celine Hanson IC. JACI 2004;114:1010-1020

31.  Many cases consistent with serum sickness have
been reported.
 The timing of the reactions is from 2 to 21 days after
vaccine administration.
 The symptoms have included those typical of serum
sickness such as arthralgia, fever, malaise, urticaria
has been prominent feature.
Kelso JM. Adverse reactions to vaccines for infectious disease.
In: Middleton’s Allergy Principles and Practice. 7th ed. 2009:1189-1204

32. Kelso et al. J Allergy Clin Immunol 2012 Jul;130(1):25-43

33.  Probable anaphylactic reaction: reaction occurring
within 4 hr of vaccination and S/S ≥ 1 systems
 Dermatologic
 Respiratory
 Cardiovascular
 GI
 Possible anaphylactic reaction
 S/S from only 1 system
 S/S from ≥ 1 system but occurring > 4 hr after vaccination
Kelso et al. J Allergy Clin Immunol 2012 Jul;130(1):25-43

34.  Vaccine skin test
 SPT full strength vaccine (consider dilution of life-
threatening reaction)
 If SPT negative, ID test with 0.02 ml vaccine 1:100.
 Vaccine ingredient skin test/ in vitro test
 SPT with commercial extract of
egg(influenza&yellow fever)or Saccharomyces cerevisiae yeast(HBV& quadivalent HPV)
 SPT with sugared gelatin ( Jello-O 1tsp in 5 ml NSS)
 sIgE to vaccine contain gelatin
( influenza, MMR, rabies, varicella, yellow fever, zoster)
 sIgE to latex
Kelso et al. J Allergy Clin Immunol 2012 Jul;130(1):25-43

35. Wood RA et al. Pediatrics 2008;122:e771-7.

36.  If level associated with protection from
disease, consider withholding additional
doses although magnitude and duration of
immunity may be less than if all doses
received
Kelso et al. J Allergy Clin Immunol 2012 Jul;130(1):25-43

38. Kelso et al. J Allergy Clin Immunol 2012 Jul;130(1):25-43

39.  Some nonanaphylactic reactions to vaccine
might also require evaluation, but only few
are absolute contraindication to future doses.
Kelso et al. J Allergy Clin Immunol 2012 Jul;130(1):25-43

40.  Person with GBS within 6 weeks of influenza
vaccination should avoid subsequent
immunization with influenza vaccine.
 MMR + varicella: 2 fold higher risk of FS
 Recipient of MMR can have thrombocytopenia.
 Rubella vaccine can cause acute arthritis in 15%
of adult women.
Kelso et al. J Allergy Clin Immunol 2012 Jul;130(1):25-43

41.  Pertussis vaccine: encephalopathy occurring
within 7 days following vaccine, absolute
contraindication.
 5% of tetanus toxoid-containing vaccine
cause large local swelling at injection
site, Arthus reaction.
Kelso et al. J Allergy Clin Immunol 2012 Jul;130(1):25-43

42.  Varicella vaccine: reaction occur at injection
site 3% and more generalize in 3%.
 Yellow fever
 encephalopathy.
 vaccine-associated viscerotrophic disease has
occurred in immunocompromised, thymus
disorder and age > 60 yr contraindication.
Kelso et al. J Allergy Clin Immunol 2012 Jul;130(1):25-43

43.  Pregnant women should not be vaccinated
with live vaccine.
 Pregnant woman should be given inactivated
influenza vaccine, tetanus, HBV
Kelso et al. J Allergy Clin Immunol 2012 Jul;130(1):25-43

44.  Live vaccine should not be given to persons
who are immune compromised because of
risk of generalized infection with immunizing
agent.
Kelso et al. J Allergy Clin Immunol 2012 Jul;130(1):25-43

45. Kelso et al. J Allergy Clin Immunol 2012 Jul;130(1):25-43

46.  Specific vaccines or vaccination in general
have been purported to have long-term
consequences, including
atopy, autism, multiple sclerosis.
Epidemiologic studies have not supported
such associations.
Kelso et al. J Allergy Clin Immunol 2012 Jul;130(1):25-43

47. How to give influenza vaccine
in egg-allergic patients

48.  2002: 2 doses or multi-dose graded vaccination protocol
depending on results of skin testing & egg content of vaccine.
Zeiger RS. JACI 2002;110:834-40.
 2009: Safe administration of influenza vaccine containing 1.2
mcg/ml of egg protein to egg allergic patients, initially in a 2-
dose protocol (10% and 90%) and later as a single dose.
Kelso JM, Li JT. Ann Allergy Asthma Immunol 2009;103:S1-S14
 2009: Children with known severe allergic reactions
(hives, angioedema, allergic asthma, systemic anaphylaxis) to
chicken or egg proteins should not receive TIV.
AAP Red Book 2009

52.  2-step graded challenge  Single dose without use of graded
 10% of the age dose, with a 30-minute challenge.
observation, then  Individuals should be observed for 30
 90% of dose, with a 30-minute minutes
observation  The same TIV brand should be used
 The same TIV brand should be used for booster vaccinations.
for booster vaccinations.  Children who need a booster dose
 Children who need a booster dose can receive this without prior vaccine
can receive this without prior vaccine skin testing, and as a single dose.
skin testing, and as a single dose.
 If reaction is observed at any of the
steps, subsequent steps should be
withheld, and the patient should be
evaluated by an expert in vaccine
allergy.
Greenhawt MJ et al. Ann Allergy Asthma Immunol 2011;106:11-6.

53.  2009-2010: diagnosis of egg allergy
 Full strength vaccine SPT
 Negative: full dose
 Positive, equivocal: vaccination 2-step protocol
( 10 %- 3o min-90%)
Luke Webb. JACI July 2011

54.  152 pts (292 vaccination with seasonal and/or H1N1
influenza)
 34(22%) of 152 pt had history of anaphylaxis to egg.
 87(57%) pt had history of type I allergic to egg.
 31(20%) pts had not knowingly consumed egg or no
reaction but had level of egg IgE > 95% of predictive egg
allergy.
Luke Webb. JACI July 2011

55.  Age 7 mo-30 yr (median 3 yr)
 SPT performed before 85% of challenges
 1 pt positive SPT, 6 pt equivocal
 285(97%) performed by using single dosing:
 65 vaccination(23%) in history severe egg allergy
 No systemic reaction in any pt
 2 pt with negative vaccine SPT developed mild local reaction, both to
full dose.
▪ 1 pt of these had history anaphylaxis to egg with egg SPT28 mm and sIgE 7.8
kU/L
 1 pt sIgE 42 kU/L developed redness at injection site 24 hr after
vaccination.
Luke Webb. JACI July 2011

56.  Threshold of ovalbumin tolerate by most pt
with egg allergy may higher than 1.2 μg/ml.
 Most individual with egg allergy can safely
vaccinated by single dose of influenza
vaccine.
 Do not support use of skin testing as
predictor of reaction to vaccination.
Luke Webb. JACI July 2011

57. P<0.006
Laura E. Howe, MD. Ann Allegy Asthma Immunol. 2011;106:446-447

58.  Retrospective review of TIV immunization
pattern for egg allergic children ages 6-36 mo
at University of Michigan Allergy clinic from
Oct 2004-Feb 2009.
 193 potential EAC, 140 met inclusion criteria:
135 received TIV; none had significant
complication: 5(4%) were not vaccinated
after positive skin test
Laura E. Howe, MD. Ann Allegy Asthma Immunol. 2011;106:446-447

59.  28 of 135(21%) safely received first TIV
without skin test
 17 children anaphylaxis to egg; 14(82%) safely
received TIV (2 with positive SPT, 9 with
negative SPT, 3 with no pretesting).
 Only minor reaction reported in 7 pt, none of
whom had history anaphylaxis.
Laura E. Howe, MD. Ann Allegy Asthma Immunol. 2011;106:446-447

60.  Prospective 69 EAC & 14 non-EAC during 2009-2010
influenza immunization.
 34 EAC(49%) received SPT to TIV, 6 positive test(18%).
 If TIV test positive, vaccine administered in 2 steps.
 68 0f 69 EAC tolerate single-dose administration of TIV as
either first or booster dose.
 No serious allergic reaction to TIV
 2 EAC had lip or mouth itching and hives and 2 non-EAC
had hives and fever or rash.
Laura E. Howe, MD. Ann Allegy Asthma Immunol. 2011;106:446-447

61.  Ovalbumin ranged from 0.3-1.087
μg/mL(always used Sanofi-Pasteur TIV)
 TIV skin test not necessary
 Allergic children tolerate TIV as single dose
 No difference in TIV tolerance between EAC
with and without history of egg-induced
anaphylaxis.
Laura E. Howe, MD. Ann Allegy Asthma Immunol. 2011;106:446-447

62. Kelso JM. JACI 2010;126(6):1302-1304

63. Ovalbumin level reported for 2009-2010
Kristi K. McKinney. JACI June 2011

64. Kelso et al. J Allergy Clin Immunol 2012 Jul;130(1):25-43

65.  Vaxigrip
 Not more than 0.05 mcg/0.5 ml
 Influvac
 Not more than 1 mcg/0.5 ml
 Agrippal S1
 Not more than 0.4 mcg/ml
Available at: httpwww.aap1.fda.moph.go.th
Accessed December 10, 2010

66. Kelso et al. J Allergy Clin Immunol 2012 Jul;130(1):25-43

67.  Patient with egg allergy should receive
influenza vaccination(TIV) because risk of
vaccination are outweight by risk of not
vaccinating.(A)
 Persons with history of suspected egg allergy
should be evaluated by allergist to determine
status of their egg allergy, but this should not
delay their influenza vaccination.(A)
Kelso et al. J Allergy Clin Immunol 2012 Jul;130(1):25-43

68.  A growing number of studies suggest that
influenza vaccines can safely administered, even
to patient with history of anaphylaxis to egg
ingestion.(B)
 Skin testing with influenza vaccine itself in
patient with egg (but without history of reaction
to vaccine itself) dose not reliably identify
patient who are at increase risk of reacting to
vaccine and not recommended.(A)
Kelso et al. J Allergy Clin Immunol 2012 Jul;130(1):25-43

69.  Influenza vaccine can be administered as
single dose to patients with egg allergy.
 All influenza vaccine available in US contain
low amounts of ovalbumin.(A)
Kelso et al. J Allergy Clin Immunol 2012 Jul;130(1):25-43

70.  Patient with egg allergy  Patient with egg allergy
should receive influenza with history only hives
vaccines in setting in after egg ingestion can
which clinicians receive influenza vaccine
experienced in in primary care provider’s
recognizing and treating office provided
anaphylaxis and appropriated personnel
equipment to manage and equipment are
anaphylaxis are available, whereas those
immediately available with history more severe
and should be observed reaction to egg ingestion
for 30 min after should receive their
vaccination.(A) vaccine in allergist’s
office.(C)
Kelso et al. J Allergy Clin Immunol 2012 Jul;130(1):25-43

71.  Although intranasally administered LAIV
contains low amount of ovalbumin, all
published studies to date have evaluated
injectable TIV, and thus TIV rather than LAIV
should be used for recipients with egg
allergy.(C)
Kelso et al. J Allergy Clin Immunol 2012 Jul;130(1):25-43

72.  Patient with history of allergic reaction to
influenza vaccine itself, additional evaluation
is appropriate, including skin testing with
vaccine and vaccine ingredients.
 Patient with positive skin test result, vaccine
can administered in multiple divided doses or
can be withheld.
Kelso et al. J Allergy Clin Immunol 2012 Jul;130(1):25-43

74. Kelso et al. J Allergy Clin Immunol 2012 Jul;130(1):25-43

75. Kelso et al. J Allergy Clin Immunol 2012 Jul;130(1):25-43

76. Kelso et al. J Allergy Clin Immunol 2012 Jul;130(1):25-43

80. Category of evidence
Ia Evidence from meta-analysis of RCT
Ib Evidence from at least 1 RCT
IIa Evidence from at least 1 controlled study without RCT
IIb Evidence from at least 1 other type of quasiexperimental study
III Evidence from nonexperimental descriptive studies
IV Evidence from expert committee reports or opinion or autorities
Strength of recommendation
A Directly based on category I evidence
B Directly based on category II evidence or extrapolated from category I
C Directly based on category III evidence or extrapolated from category I or II
D Directly based on category IV evidence or extrapolated from category I or II or III
E Based on consensus of the joint task force on practice parameter