Adverse reactions to vaccines practice parameter 2012 update

Adverse reactions to vaccinesSasikarn Suesirisawad, MD

Introduction

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

Introduction

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)


Classificationof

Vaccine Allergy

Adverse reactions to vaccine

Vaccine constituents

Specific vaccines Specific vaccinesVaccine constituents

• Gelatin

• Egg

• Latex

• Yeast

• ? ATB

• ? Thimerosal

• Diphtheria

• Hib

• Hepatitis B

• Influenza

• JE

• MMR

• Meningococcus

• Pertussis

• Pneumococcus

• Rabies

• Tetanus

• Varicella

• Yellow fever

• Neomycin

• Thimerosal

• Aluminum

• MMR

• Meningococcus

• Pertussis

• Tetanus

• Typhoid

• Varicella

• Yellow fever

IgE-mediated reactions Non-IgE-mediated reactions

Kelso JM. Adverse reactions to vaccines for infectious disease. In: Middleton’s Allergy Principles and Practice. 7th ed. 2009:1189-1204

IgE-mediated reaction to vaccines

• IgE- mediated reaction to vaccines are more often caused by additive or vaccine component, such as gelatin, rather than microbial immunizing agent itself.(B)


Gelatin

Partially hydrolyzed collagen of bovine or porcine origin.

A stabilizer in many vaccines.

Responsible for many anaphylactic reactions to MMR, varicella, JE vaccines.


Gelatin content of vaccines

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

Gelatin content of vaccine 2011


Egg

Concern has existed over administration of vaccines ‘grown in eggs’ to egg-allergic recipients.

: MMR vaccine: PCEC rabies vaccine: Influenza vaccine: Yellow fever vaccine


Egg content in vaccine

Vaccine Grown inEgg protein

content

Approach in egg-allergic

patientMeasles and mumps

Chick embryo fibroblast cell cultures

Picograms to nanograms

Administer in usual manner

Purified chick embryo rabies

Chick embryo fibroblast cell cultures

Picograms to nanograms

Administer in usual manner

Influenza (killed injected and live attenuated nasal)

Chick extra-embryonic allantoic fluid

Micrograms Skin test with vaccine prior to administration

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


Latex

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.

Yeast

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

Yeast content of vaccines

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

Antimicrobial agents

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.

Thimerosal

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.

Zheng W, Dreskin SC. Ann Allergy Asthma Immunol. 2007;99:574–5.

Kelso JM, Li JT. Ann Allergy Asthma Immunol 2009;103:S1-S14.

Diphtheria-Tetanus-Pertussis 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.

Japanese encephalitis vaccine 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.


MMR & Varicella vaccines

MMR VACCINE

• Anaphylactic reactions: 2–10 per million doses.

• Allergy to gelatin has been determined to be likely cause (27–92%).

• No relationship with egg allergy.

VARICELLA VACCINE

Anaphylactic reactions : 3 per million doses.

Gelatin allergy is the cause of some of these reactions.

Kelso JM. In: Middleton’s Allergy Principles and Practice. 7th ed. 2009:1189-1204

HBV vaccines

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

HPV vaccines

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

Pneumococcal vaccine

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.

7-valent pneumococcal vaccine 14 of the 4,154 VAERS reports

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.

Wise RP, Iskander J, Pratt RD, et al. JAMA 2004; 292(14):1702-1710.

Influenza & Yellow Fever Vaccines

YELLOW FEVER VACCINE

Anaphylaxis reactions 7 per million doses.

Related to egg, chicken, and gelatin.

INFLUENZA VACCINE

Anaphylaxis 0.024 per 100,000 doses.

None of which was fatal, and none of which occurred in persons known to be allergic to eggs.


Non-IgE-mediated reaction to vaccines

Neomycin

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. 2009:1189-1204Madaan A, Maddox DE. Immunol Allergy Clin N Am 2003;23:555-588

Neomycin content of vaccines


Thimerosal

DTH to thimerosal is reported. Single case report of a generalized MP

rash attributed to thimerosal in influenza vaccine.

May have large local reactions. Not contraindication to receive

thimerosal-containing vaccine.

Lee-Wong M, Resnick D, Chong K. Ann Allergy Asthma Immunol 2005;94:90-4.

Kelso JM In: Middleton’s Allergy Principles and Practice. 7th ed. 2009:1189-1204.

Thimerosal content of vaccines


Aluminum

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

Tetanus toxoid

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

Rabies

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.


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Suggested approach to suspected adverse vaccine reaction


Are nature and timing of reaction consistent with anaphylaxis?

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

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

Skin test with vaccine and component including egg, gelatin, latex or yeast

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


An Approach to Skin and In Vitro Testing for Specific Vaccines

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

If fewer than recommended number of doses received, consider measuring level of IgG Ab to immunizing

agent 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


Level of antibody associated with protection from vaccine-

preventable disease

Administration of vaccine in graded doses


Adverse reaction to vaccines practice parameter 2012 update

Some nonanaphylactic reactions to vaccine might also require evaluation, but only few are absolute contraindication to future doses.


Summary Statement 10

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.



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.



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.



Pregnant women should not be vaccinated with live vaccine.

Pregnant woman should be given inactivated influenza vaccine, tetanus, HBV



Live vaccine should not be given to persons who are immune compromised because of risk of generalized infection with immunizing agent.


Live versus killed vaccines



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.


How to give influenza vaccine

in egg-allergic patients

Many different vaccination protocols

2002: 2 doses or multi-dose graded vaccination protocol depending on results of skin testing & egg content of vaccine.

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.

2009: Children with known severe allergic reactions (hives, angioedema, allergic asthma, systemic anaphylaxis) to chicken or egg proteins should not receive TIV.

Zeiger RS. JACI 2002;110:834-40.

Kelso JM, Li JT. Ann Allergy Asthma Immunol 2009;103:S1-S14

AAP Red Book 2009

BSACI guideline

BSACI guideline

2 approaches for vaccination in egg allergy

2-step graded challenge 10% of the age dose, with a

30-minute observation, then 90% of dose, with a 30-minute

observation The same TIV brand should be

used for booster vaccinations. Children who need a booster

dose can receive this without prior vaccine 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.

Single dose without use of graded challenge.

Individuals should be observed for 30 minutes

The same TIV brand should be used for booster vaccinations.

Children who need a booster dose can receive this without prior vaccine skin testing, and as a single dose.

Greenhawt MJ et al. Ann Allergy Asthma Immunol 2011;106:11-6.

Single dose influenza vaccination of patients with egg allergy in

multicenter study

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


multicenter study 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.



multicenter study 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.



multicenter study 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.


Safe administration of seasonal influenza vaccine to children with egg

allergy of all severities

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

P<0.006



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




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.



allergy of all severities 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.




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.


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

Ovalbumin level reported for 2009-2010

Kristi K. McKinney. JACI June 2011


Other TIV brand in Thailand

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.thAccessed December 10, 2010

Administering influenza vaccine to recipients with egg allergy



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)



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)



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)



Patient with egg allergy should receive influenza vaccines in setting in which clinicians experienced in recognizing and treating anaphylaxis and equipment to manage anaphylaxis are immediately available and should be observed for 30 min after vaccination.(A)

Patient with egg allergy with history only hives after egg ingestion can receive influenza vaccine in primary care provider’s office provided appropriated personnel and equipment are available, whereas those with history more severe reaction to egg ingestion should receive their vaccine in allergist’s office.(C)



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)



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.


Thank you


Excipient in vaccine


Excipient in vaccine


Classification of recommendations and evidence

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 autoritiesStrength 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

Health & Medicine

Adverse reactions to vaccines practice parameter 2012 update