Adverse reactions to vaccines for infectious diseases
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Transcript of Adverse reactions to vaccines for infectious diseases
Adverse Reactions to Vaccines for Infectious Diseases
Suda Sibunruang, M.D.
Picture from www.med.umich.edu
Contents• Overview of vaccine adverse events• Type of reactions• Potential allergens in vaccines • Diagnosis and management
Contents• Overview of vaccine adverse events• Type of reactions• Potential allergens in vaccines • Diagnosis and management
The ideal vaccine should be…• Non- reactogenic • Easy to administer• Highly immunogenic• Long-lasting immunity
No currently available vaccine meets all of these criteria
Moylett E. and Hanson C. J Allergy Clin Immunol 2004;114:1010-20
Access from www.cdc.gov , 4 November 2014
Picture from http://sciencebasedpharmacy.filesAccess 4 November, 2014
Kelso J. and Greenhawt M. Middleton’s Allergy 8th edition, 2013, 1384-1403
Picture from www.vaclib.org
Kelso J. and Greenhawt M. Middleton’s Allergy 8th edition, 2013, 1384-1403
Evolution of an immunization program
Vaccine adverse events (AE)
• 20 vaccines are currently in use• Billions of doses are administered worldwide• Vaccine induced AE ranges between 3- 83 /100,000 doses according to post-marketing surveillance data
Caubet JC., et al. Pediatr Allergy Immunol 2014: 25: 394–403
Moylett E. and Hanson C. J Allergy Clin Immunol 2004;114:1010-20
Allergic reactions to vaccines
• Range from 1/50,000 doses for DTP vaccine to about 1 per 500,000 to 1,000,000 doses for most other vaccines
Wood RA, Setse R, Halsey N. J Allergy Clin Immunol 2007;120:478-81Caubet JC., et al. Pediatr Allergy Immunol 2014: 25: 394–403
Spontaneous reports of adverse drug reaction 2012 ศู�นย์�เฝ้�าระวั งควัามปลอดภั ย์ด�านผล�ตภั ณฑ์�สุ�ขภัาพ สุ าน กงานคณะกรรมการอาหารและย์า
Access from http://thaihpvc.fda.moph.go.th 31 October 2014
Report of vaccine ADR in 2012 688/ 55,747 = 1.23%
Spontaneous reports of adverse drug reaction 2012 ศู�นย์�เฝ้�าระวั งควัามปลอดภั ย์ด�านผล�ตภั ณฑ์�สุ�ขภัาพ สุ าน กงานคณะกรรมการอาหารและย์า
Access from http://thaihpvc.fda.moph.go.th 31 October 2014
Example
Contents• Overview of vaccine adverse events• Type of reactions• Potential allergens in vaccines • Diagnosis and management
Hypersensitivity reactions followingimmunization
• Extent: local - systemic• Timing: immediate - non-immediate• Frequency: common - rare• Severity: minor- moderate- major
Caubet JC., et al. Pediatr Allergy Immunol 2014: 25: 394–403
Hypersensitivity reactions followingimmunization
• Extent: local - systemic• Timing: immediate - non-immediate• Frequency: common - rare• Severity: minor- moderate- major
Caubet JC., et al. Pediatr Allergy Immunol 2014: 25: 394–403
Local reactions• Most frequent adverse event• Often falsely labeled as allergic
Caubet JC. and Ponvert C. Immunol Allergy Clin N Am 2014;34:597-613
Types of local reactions• Mild local reactions• Large local reactions/ Extensive limb swelling• Subcutaneous nodules• Local eczema• Nevi associated with hypertrichosis
Caubet JC. and Ponvert C. Immunol Allergy Clin N Am 2014;34:597-613
Mild local reactions
• Most frequent• Non-specific inflammation - Tissue damage by the puncture - Injection of foreign material
Caubet JC. and Ponvert C. Immunol Allergy Clin N Am 2014;34:597-613
Large local reactions
• Less common • Varied vaccines, particularly those
containing toxoids and/or adjuvants
Caubet JC., et al. Pediatr Allergy Immunol 2014: 25: 394–403Caubet JC. and Ponvert C. Immunol Allergy Clin N Am 2014;34:597-613
Large local reactions
Two patterns1. Typical large local reactions2. Extensive limb swelling
Caubet JC., et al. Pediatr Allergy Immunol 2014: 25: 394–403Caubet JC. and Ponvert C. Immunol Allergy Clin N Am 2014;34:597-613
Typical Large local reactions
• Occur typically within 24–72 h• Result of 2 mechanisms- Antigen/adjuvant Toll Like Receptor (TLR)-induced inflammation - Arthus reaction
Caubet JC., et al. Pediatr Allergy Immunol 2014: 25: 394–403Caubet JC. and Ponvert C. Immunol Allergy Clin N Am 2014;34:597-613
Residual antibodies still present in the host due to previous sensitization
Caubet JC., et al. Pediatr Allergy Immunol 2014: 25: 394–403Caubet JC. and Ponvert C. Immunol Allergy Clin N Am 2014;34:597-613
Picture from http://classconnection.s3.amazonaws.com
Rate of local reactions• Higher after receiving multiple
doses of certain vaccines• Shorter interval between the doses
was not associated with higher rates
Caubet JC., et al. Pediatr Allergy Immunol 2014: 25: 394–403Caubet JC. and Ponvert C. Immunol Allergy Clin N Am 2014;34:597-613
Extensive limb swelling
• Less common but may be impressive• Extend at least to the elbow or knee• Arises within 24 h • Looks like a benign reactive edema • Probably results from extravasation
mechanisms• Usually painless
Caubet JC., et al. Pediatr Allergy Immunol 2014: 25: 394–403Caubet JC. and Ponvert C. Immunol Allergy Clin N Am 2014;34:597-613
Subcutaneous nodules• Common in vaccines containing
aluminium salts (19% of patients)
Caubet JC., et al. Pediatr Allergy Immunol 2014: 25: 394–403Caubet JC. and Ponvert C. Immunol Allergy Clin N Am 2014;34:597-613
Subcutaneous nodules
• Nonspecific inflammation • Correlation between concentration of
aluminium hydroxide and frequency and size of nodules
• Regress within a few weeks• Patch tests are often negative • Few cases of persistent nodules (most of
them had positive patch tests)
Caubet JC. and Ponvert C. Immunol Allergy Clin N Am 2014;34:597-613
Local eczema
• Vaccines containing aluminium hydroxide, thimerosal and formaldehyde
• Reported mainly in adults• May extend beyond the injection area or
become generalized• A non-immediate hypersensitivity has
been suggested by positive patch testsCaubet JC., et al. Pediatr Allergy Immunol 2014: 25: 394–403
Caubet JC. and Ponvert C. Immunol Allergy Clin N Am 2014;34:597-613
Nevi associated with hypertrichosis
• Reported after BCG, tetanus, and smallpox vaccination (rarely)• The causal components responsible
for the reaction, as well as the exact pathomechanisms remain unknown
Caubet JC. and Ponvert C. Immunol Allergy Clin N Am 2014;34:597-613
Systemic reactions• 5–13% of the patients being vaccinated• Most frequent symptoms include fever,
rash, drowsiness and irritability• Most result from non-specific
mechanisms
Caubet JC., et al. Pediatr Allergy Immunol 2014: 25: 394–403
Systemic reactions• Distinguish between immediate
reactions (IgE-mediated) and non-immediate reactions (non-IgE-mediated)• Vasovagal attacks associated with
injections are common
Caubet JC., et al. Pediatr Allergy Immunol 2014: 25: 394–403
Vanlandera A. and Hoppenbrouwers K. Vaccine 2014;32:3147–54
Number of students suffering adverse events following MMR campaign in Australia, 1998 (n=651,615 students)
Adverse event Faint/syncopeSyncopal fitAnaphylaxisHyperventilationRashLocal allergic reactionSevere immediate local reactionArthropathyFeverAnxietyLymphadenopathy
Number 1713432211111
Source : Communicable Disease Intelligence (Australia), 29 October 1998
Bohlke K. et al. J Allergy Clin Immunol 2004;113:536–42
Method: identified anaphylaxis between 1991-1997 from automated databases and reviewed medical record Result: 5 cases of vaccine-associated anaphylaxis after 7,644,049 vaccine doses (0.65 cases/million doses)
Immediate reactions• 1–3 reactions per million vaccine doses • Amounts of patients reported reaction after
first vaccination suggests either a pre-sensitization to a vaccine component or
non-immunologically mediated reaction• Identification is important because risk of life
threatening anaphylaxis if re-exposure
Kelso J. et al. J Allergy Clin Immunol 2012;130:25–43Caubet JC., et al. Pediatr Allergy Immunol 2014: 25: 394–403
Fritsche P.,Helbling A.,Ballmer-Weber BK. Swiss Med Wkly 2010;140:238 – 46
Non-immediate reactions• Common symptoms include MP rash, delayed
onset urticaria, and erythema multiforme• Other immunologic reactions (i.e. serum sickness, Henoch Schonlein Purpura) are even rarer
Caubet JC., et al. Pediatr Allergy Immunol 2014: 25: 394–403
Contents• Overview of vaccine adverse events• Type of reactions• Potential allergens in vaccines • Diagnosis and management
Picture from www.biofarma.co. Access 31 October 2014
Fritsche P.,Helbling A.,Ballmer-Weber BK. Swiss Med Wkly 2010;140:238 – 46
Components of vaccines
Kelso J. et al. J Allergy Clin Immunol 2012;130:25–43
Picture from www.vaccinesafety.edu
Vaccine components• Microbial components• Gelatin• Egg & chicken protein• Milk• Yeast• Latex
• Aluminium• Thimerosal• Antibiotics• Dextran• Rare allergic
components
Microbial components• Anaphylactic reactions have been reported• However, IgE-mediated reactions to vaccines
are more often caused by additive or residual vaccine components
Kelso J. et al. J Allergy Clin Immunol 2012;130:25–43Caubet JC., et al. Pediatr Allergy Immunol 2014: 25: 394–403
Gelatin• Produced by partial hydrolysis of
collagen extracted from connective tissues of animals, such as cows or pigs
• Contains potentially allergenic protein• Bovine and porcine gelatins are
extensively cross-reactive
Kelso J. J Allergy Clin Immunol 2014;133:1509–18
Gelatin• The incidence of gelatin allergy appears
to be higher in Japan, perhaps because of an HLA type (DR 9) common in Japanese
Kelso J. J Allergy Clin Immunol 2014;133:1509–18Caubet JC., et al. Pediatr Allergy Immunol 2014: 25: 394–403
• Influenza (Fluzone, FluMist)• Japanese
encephalitis• MMR• MMRV• Rabies (RabAvert)
• Tick-borne encephalitis
• Typhoid vaccine, live oral
• Varicella• Yellow fever• Zoster
Gelatin-containing vaccines
Kelso J. J Allergy Clin Immunol 2014;133:1509–18
Kelso J. Ann Allergy Asthma Immunol 2013;110:397-401
Ranging from 250 to 15,580 µg per dose
Kelso J. et al. J Allergy Clin Immunol 1993;91:867-72
Kelso J. et al. J Allergy Clin Immunol 1993;91:867-72
Sakaguchi M., et al. J Allergy Clin Immunol 1996;98:1058-61
Objective: relation between systemic allergic reactions to vaccines and the presence of anti-gelatin IgE Patients: 26 children who had systemic immediatereactions to vaccines-containing gelatinControl: 26 children without allergic reactions to vaccines
Sakaguchi M., et al. J Allergy Clin Immunol 1996;98:1058-61
Sakaguchi M., et al. J Allergy Clin Immunol 1996;98:1058-61
• Nine showed severe anaphylaxis (Skin + airways +/- shock)• Ten had mild anaphylaxis (skin +/- airways + others)• Seven had only urticaria
Sakaguchi M., et al. J Allergy Clin Immunol 1996;98:1058-61
All the control children had no anti-gelatin IgE
Sakaguchi M., et al. J Allergy Clin Immunol 1996;98:1058-61
7/26 had allergic reactions on ingestion of gelatin-containingfoods
Sakaguchi M., et al. J Allergy Clin Immunol 1996;98:1058-61
Conclusion: 1. Strong relationship between the systemic reactions and anti-gelatin IgE in the sera2. Questioning of vaccine recipients about allergy associated with the ingestion of gelatin-containing foods may help to prevent anaphylaxis3. It appears that vaccination triggered the later onset of food allergic reactions to gelatin
Recommendation• Patients experienced anaphylaxis after
ingestion of gelatin should be evaluated prior to receiving a gelatin-containing vaccine
• Symptomless consumption of gelatin does not exclude an allergy to gelatin, as other routes of sensitization have been incriminated
Caubet JC., et al. Pediatr Allergy Immunol 2014: 25: 394–403
Recommendation• Patients sensitized to pork or beef are at
higher risk of reaction to gelatins, and caution should be taken when administrating gelatin-containing vaccines
Caubet JC., et al. Pediatr Allergy Immunol 2014: 25: 394–403
Nakayama T. and Onoda K. Vaccine 200;25:570–6
Prick test to gelatin• Dissolve 1 teaspoon (5 grams) of
sugared gelatin powder in 5 cc NSS
Kelso J. et al. J Allergy Clin Immunol 2012;130:25–43
Ovalbumin-containing vaccines
• Influenza (IIV, LAIV)• MMR• Rabies (PCEC)• Yellow fever
Kelso J. J Allergy Clin Immunol 2014;133:1509–18
Picture from www.medindia.net
Picture from http://online.wsj.com
Fritsche P.,Helbling A.,Ballmer-Weber BK. Swiss Med Wkly 2010;140:238 – 46
Kelso J. J Allergy Clin Immunol 2014;133:1509–18Caubet JC., et al. Pediatr Allergy Immunol 2014: 25: 394–403
MMR & PCEC contain negligible of egg protein, thus can be administered to recipients with egg allergy
in the usual manner
Caubet JC., et al. Pediatr Allergy Immunol 2014: 25: 394–403.
Raw egg allergy
Kelso J. J Allergy Clin Immunol 2000;106:990
Raw egg allergy• Vaccine is not heated at any time during
the manufacturing process• Perhaps some of reactions are due to
unrecognized raw egg allergy
Kelso J. J Allergy Clin Immunol 2000;106:990
Rutkowski K. et.al. Int Arch Allergy Immunol 2013;161:274–8
Chicken proteins• Can also be found in some vaccines (i.e.
yellow fever vaccine) • May be responsible for reactions in chicken-
allergic recipients
Caubet JC., et al. Pediatr Allergy Immunol 2014: 25: 394–403
Milk• Casamino acids• Casein• Lactalbumin
Caubet JC., et al. Pediatr Allergy Immunol 2014: 25: 394–403
Casamino acids/casein -containing vaccines
• Growth media for these vaccines contain casamino acids derived from casein
• Nanograms quantities of casein are present in the vaccines
Kelso J. J Allergy Clin Immunol 2014;133:1509–18
Casamino acids-containing vaccines
• DTaP (Daptacel)• DTaP-IPV/Hib (Pentacel)• Td (Tenivac)• Tdap (Adacel)• Meningococcal (Menomune)• Pneumococcal (PCV13 – Prevnar 13)
Kelso J. J Allergy Clin Immunol 2014;133:1509–18
Casein-containing vaccines
• DTaP (Infanrix)• DTaP + HepB + IPV (Pediarix)• DTaP + IPV (Kinrix)• Tdap (Boostrix)• Typhoid (Vivotif)
Kelso J. J Allergy Clin Immunol 2014;133:1509–18
lactalbumin-containing vaccines
• OPV
Kelso J. J Allergy Clin Immunol 2014;133:1509–18
Kattan JD, et al. J Allergy Clin Immunol 2011;128:215-8
Background:Tetanus toxin is produced by growing Clostridium tetani in a modified Latham medium derived from bovine casein or that the C. tetani is grown in modified Mueller-Miller casamino acid mediumMethod: 1. Reviewed 8 children with anaphylaxis to booster doses of DTaP, DTP, or Tdap2. Tested 8 lots of the vaccines for residual casein
Kattan JD, et al. J Allergy Clin Immunol 2011;128:215-8
Result:• 6/8 of the patients had prior acute allergic reactions to cow’s milk• All had an increased milk-specific IgE level documented within 2 years of the reaction to the vaccine
Kattan JD, et al. J Allergy Clin Immunol 2011;128:215-8
Kattan JD, et al. J Allergy Clin Immunol 2011;128:215-8
Conclusion:Continuing the standard practice for DPT vaccination in all children, but advise caution when administering booster doses in highly sensitive milk-allergic children
Yeast• Hepatitis B and human papillomavirus
(HPV) vaccines are manufactured using recombinant strains of Saccharomyces cerevisiae (common bakers’ yeast) and contain residual yeast proteins
Caubet JC., et al. Pediatr Allergy Immunol 2014: 25: 394–403
Picture from www.ied.edu.hk
Yeast protein • Hepatitis B vaccines - up to 25 mg/dose• Quadrivalent HPV vaccine < 7 mg/dose
Kelso J. Ann Allergy Asthma Immunol 2013;110:397-401
DiMiceli L. et al. Vaccine 2006;24:703–7
Period: 1990 – 2004Method: passive surveillanceResult: • 1991–2001,276 million doses of HBV were distributed• 180,895 (all vaccines) AE reports to VAERS• 107 patients had prior history of allergy to yeast• 82/107 received HBV• 15/107 had anaphylaxis (11 HBV+ 4 other vaccines)
DiMiceli L. et al. Vaccine 2006;24:703–7
DiMiceli L. et al. Vaccine 2006;24:703–7
Conclusion:Recombinant yeast derived HBV pose minimal riskof allergic reactions in yeast sensitive individuals
Yeast• Skin tests with yeast-containing vaccines
should be carried out prior to administration to patients with history of yeast allergy
• If positive, vaccine can still be administered, but in graded doses
Caubet JC., et al. Pediatr Allergy Immunol 2014: 25: 394–403
Latex • Contains naturally occurring impurities (e.g., plant proteins and peptides)• Can be processed in 2 different ways1. Natural rubber latex (NRL) - Medical gloves, catheters2. Dry natural rubber (DNR) - Vial stoppers and tip of syringe plungers
Russell M., et al. Vaccine 2004;23:664–7
Latex • Physical contact of the liquid vaccine
with the stopper can cause the release of latex allergens into the solution
• Passing the needle throughout the stopper and by retaining latex allergens in or on the needle
Caubet JC., et al. Pediatr Allergy Immunol 2014: 25: 394–403Kelso J. and Greenhawt M. Middleton’s Allergy 8th edition, 2013, 1384-1403
Latex Theoretical risk • Administration of vaccines that have
been in contact with such packaging could induce immediate-type allergic reactions in latex allergic recipients
Kelso J. Ann Allergy Asthma Immunol 2013;110:397-401
Russell M. et al. Vaccine 2004;23:664–7
Period: 1991 – 2003Method: Reviewed cases with prior allergy to latex and developed immediate reactionsResult: • 167,233 (all vaccines) AE reports to VAERS• 147(0.1%) patients had prior history of allergy to latex• 28/147 (19%) developed a possible allergic AE• 14 cases reported a history of allergy to various drugs, foods or aeroallergens
Russell M. et al. Vaccine 2004;23:664–7
Result (continue):• 11 (39%) received influenza vaccines• 4 (21%) received hepatitis B vaccines• The remaining reported hepatitis A vaccine,MMR tetanus and diphtheria toxoids, IPV, varicella vaccine, anthrax vaccine adsorbed, and yellow fever vaccine
Russell M. et al. Vaccine 2004;23:664–7
Conclusion:• Minimal risk of immediate allergic reactions to immunized latex-sensitive individuals using vaccines that contain DNR in the packaging
“ If a person reports severe allergy to latex, vaccines supplied in vials or syringes that contain natural rubber latex should not be administered
unless the benefit of vaccination clearly outweighs the risk for a potential allergic reaction.
In these cases, providers should be prepared to treat patients who are having an allergic reaction.
For latex allergies other than anaphylaxis, vaccines supplied in vials or syringes that contain
dry, natural rubber or natural rubber latex may be administered ”
General recommendations on immunization: recommendations of ACIP. MMWR 2011;60:RR1-64
Latex• Avoid passing the needle through the
stopper• Stopper should be removed and the
vaccine drawn up directly from the vial
Kelso J. Ann Allergy Asthma Immunol 2013;110:397-401Caubet JC., et al. Pediatr Allergy Immunol 2014: 25: 394–403
Latex • Vaccine vial stoppers and syringe
plungers are made of synthetic rubber and pose no risk to latex-allergic persons
Kelso J. and Greenhawt M. Middleton’s Allergy 8th edition, 2013, 1384-1403
Kelso J. et al. J Allergy Clin Immunol 2012;130:25–43
www.cdc.gov/vaccines/pubs/pinkbook/pink-appendx.htm
Aluminium• Persistent itching, subcutaneous nodules, or
granulomas at the injection site• Hyper- and hypopigmentation, hypertrichosis,
and lichenification have been associated with such nodules
• In rare cases, nodules become inflammatory and turn into an aseptic abscess
• Transient but can sometimes persist for a few weeks or even years
Caubet JC., et al. Pediatr Allergy Immunol 2014: 25: 394–403
Aluminium• In aluminium-sensitized patients requiring a
vaccine containing aluminium, the injection should be administered deep enough as intramuscular administration may prevent the formation of granulomas
Caubet JC., et al. Pediatr Allergy Immunol 2014: 25: 394–403
Thimerosal• One of the most effective preservative,
improving vaccine stability, potency, and safety
• However, it has been less used over the last decades in childhood vaccines, as a precautionary measure due to its mercury content
Caubet JC., et al. Pediatr Allergy Immunol 2014: 25: 394–403
Thimerosal• Not definitely caused immediate reactions• Non-immediate reactions (contact dermatitis and generalized MP rash)
Caubet JC., et al. Pediatr Allergy Immunol 2014: 25: 394–403
Thimerosal• If possible, alternative vaccines not
containing this preservative should be chosen• The vast majority of patients with proven
sensitization to thimerosal as demonstrated by positive patch tests tolerate thimerosal-containing vaccines
Caubet JC., et al. Pediatr Allergy Immunol 2014: 25: 394–403
Fritsche P.,Helbling A.,Ballmer-Weber BK. Swiss Med Wkly 2010;140:238 – 46
Antibiotic containing vaccines
Antibiotics• Some vaccines (i.e. polio, MMR, and
influenza vaccines) may contain traces of antibiotics used for viral culture to avoid bacterial and fungal contamination during the manufacturing process
Caubet JC., et al. Pediatr Allergy Immunol 2014: 25: 394–403
Antibiotics• Although antibiotics in vaccines theoretically
could cause anaphylactic reactions, there is no report of confirmed immediate reactions
• Nevertheless, the few patients who have a confirmed immediate allergy to one of these antibiotics should not receive vaccines containing them
Caubet JC., et al. Pediatr Allergy Immunol 2014: 25: 394–403
Fritsche P.,Helbling A.,Ballmer-Weber BK. Swiss Med Wkly 2010;140:238 – 46
Neomycin containing vaccines in Switzerland
Neomycin• Only single report of anaphylaxis• Topical neomycin is known to elicit contact
dermatitis (delay-type reactions: DTR)• However, amount of neomycin found in
vaccines is not believed to trigger DTR• Thus, these vaccines may be given to patients with DTR to neomycin
Kelso J. et al. J Allergy Clin Immunol 2012;130:25–43Fritsche P.,Helbling A.,Ballmer-Weber BK. Swiss Med Wkly 2010;140:238 – 46
Other antibiotics• Streptomycin, gentamycin, polymyxin B
sulphate and chlortetracycline have been reported to trigger allergic reactions in clinical use
• But… in term of vaccination they have not yet been identified as a causative agent of severe allergic reactions
Fritsche P.,Helbling A.,Ballmer-Weber BK. Swiss Med Wkly 2010;140:238 – 46
Dextran• Immediate reactions to BCG, and to some
MMR vaccines• MMR containing dextran have now been
withdrawn from the market• Now, may present in some rotavirus vaccines• Non-immediate reactions to dextran are rare
Caubet JC., et al. Pediatr Allergy Immunol 2014: 25: 394–403
Rare allergenic components• Polysorbate (Tween), polygelines,
amphotericin B, protamine sulphate and phenol red
• No evidence for hypersensitivity reactions of these substances linked to vaccination
Fritsche P.,Helbling A.,Ballmer-Weber BK. Swiss Med Wkly 2010;140:238 – 46
Contents• Overview of vaccine adverse events• Type of reactions• Potential allergens in vaccines • Diagnosis and management
Diagnosis & Management
“ Accurate diagnosis of vaccine allergy is important not only to prevent serious or even life-threatening reactions, but also
to avoid unnecessary vaccine restriction ”
Caubet JC., et al. Pediatr Allergy Immunol 2014: 25: 394–403.
Two circumstances bring patients to allergists
Kelso J. Ann Allergy Asthma Immunol 2013;110:397-401
1. Experienced adverse events following immunization
2. Possible allergy to some vaccine component, but have never received the vaccine
Kelso J. Ann Allergy Asthma Immunol 2013;110:397-401
1. Experienced adverse events following immunization
Patient received an immunization experienced an adverse event
• Immunization may or may not have caused AE• If causal, the mechanism may or may not have been immunologic• If immunologic,the mechanism may or may not have been IgE mediated
Kelso J. Ann Allergy Asthma Immunol 2013;110:397-401
Whether such patients can receive additional doses of the suspect vaccine ?
Determine nature of AE - IgE mediated ?
Testing for IgE to the vaccine andvaccine components
Kelso J. Ann Allergy Asthma Immunol 2013;110:397-401
Determination of culprit allergen is important because the same ingredient may be
found in other vaccines
Kelso J. Ann Allergy Asthma Immunol 2013;110:397-401
2. Possible allergy to some vaccine components, but have never received the vaccine
Whether such patients can receive vaccines that contain these components ?
Determine nature of reaction - IgE mediated ?
Testing for IgE to suspect allergen
Kelso J. Ann Allergy Asthma Immunol 2013;110:397-401
Even patients have specific IgE to a vaccine and/or vaccine component,
it is still likely that they can be immunized with appropriate precautions
Caubet JC. and Ponvert C. Immunol Allergy Clin N Am 2014;34:597–613
+/- IgE
Start with a detailed history
Wood R., et al. Pediatrics 2008;122:e771–7
Caubet JC. and Ponvert C. Immunol Allergy Clin N Am 2014;34:597–613
+/- IgE
Management of local reactions (1)
• Mostly, local reactions subside spontaneously without sequelae
• No association with a higher rate of systemic reactions on re-exposure
Caubet JC., et al. Pediatr Allergy Immunol 2014: 25: 394–403Caubet JC. and Ponvert C. Immunol Allergy Clin N Am 2014;34:597-613
Management of local reactions (2)
• Usually, no allergy test is required• Serum vaccine-specific antibodies (IgM
or IgG) are indicated in patients with suspicion of Arthus reaction
Caubet JC. and Ponvert C. Immunol Allergy Clin N Am 2014;34:597-613
Patch test• Demonstrate a delayed hypersensitivity to
preservatives or adjuvants• They are not accurate for the purpose of
assessing a patient’s ability to tolerate a vaccine
• Positive patch test may guide clinicians to administer a vaccine free of these components, if available
Caubet JC., et al. Pediatr Allergy Immunol 2014: 25: 394–403
Prevention of local reactions (1)
• Correct needle length Longer needle - -> lower rate of local reactions• Site of injection Injection in the thigh in children < 3 years• Receive a vaccine free of the sensitized
component, if available
Caubet JC. and Ponvert C. Immunol Allergy Clin N Am 2014;34:597-613
Prevention of local reactions (2)
• In patients reporting important local inflammatory reactions after injection of combined vaccines, sequential injections of single or limited numbers of vaccinating agents, every few days, preferably intramuscularly, are usually well tolerated
Caubet JC. and Ponvert C. Immunol Allergy Clin N Am 2014;34:597-613
Caubet JC. and Ponvert C. Immunol Allergy Clin N Am 2014;34:597–613
+/- IgE
Immediate reaction• Allergologic work-up should be carried out
even if no further doses of the suspected vaccine are required
• Potential for cross-reaction with common components in other vaccines and foods
Caubet JC., et al. Pediatr Allergy Immunol 2014: 25: 394–403
Seitz C. et al. Vaccine 2009;27:3885–9
Method: patients diagnosed of vaccine-induced anaphylaxis were subjected to standardized allergy testingObjective: 1. identify vaccination-associated IgE-mediated anaphylaxis 2. proofed reliability of reporting vaccine-induced allergic anaphylaxis by HCW
Seitz C. et al. Vaccine 2009;27:3885–9
Skin & SC Respiratory or CVS or GIHypoxia, hypotension, neuro
Seitz C. et al. Vaccine 2009;27:3885–9
undiluted vaccine for prick testwith positive-negative control
10%;30%;60%1 hr interval
tetanus-/diphtheria-toxoid (17×), hepatitis A/B (8×),TBE (7×), influenza (6×)
without history ofallergy to egg, yeast, ATB
Seitz C. et al. Vaccine 2009;27:3885–9
Seitz C. et al. Vaccine 2009;27:3885–9
Conclusion:• History of anaphylaxis after vaccination may not be absolute contraindication for re-vaccination• All anaphylaxis in fact not induced by an IgE-mediated vaccine allergy
Caubet JC. and Ponvert C. Immunol Allergy Clin N Am 2014;34:597–613
+/- IgE
Wood R., et al. Pediatrics 2008;122:e771–7
Skin test• Should be performed with the same brand
Kelso J. Ann Allergy Asthma Immunol 2013;110:397-401
Prick method with undiluted vaccine
Intradermal skin test with 0.02 cc of vaccine diluted 1:100
If negative
Skin test• If the initial vaccine reaction was life
threatening, it is appropriate to use diluted vaccine for the skin prick test
Caubet JC., et al. Pediatr Allergy Immunol 2014: 25: 394–403
Fritsche P.,Helbling A.,Ballmer-Weber BK. Swiss Med Wkly 2010;140:238 – 46
Diagnostic course of SPT with vaccines
Skin test• If positive skin test result, the same vaccine
skin test should be conducted in several control subjects who have received vaccine without adverse reaction
Kelso J. and Greenhawt M. Middleton’s Allergy 8th edition, 2013, 1384-1403
Skin test• Sensitivity and specificity are not optimal, but the main purpose of these tests is to identify patients who are at real risk of developing a severe anaphylactic reaction in case of re-exposure
Caubet JC., et al. Pediatr Allergy Immunol 2014: 25: 394–403
Skin test• Intradermal skin tests with some
vaccines, such as tetanus toxoid, can also induce delayed-type hypersensitivity responses
Kelso J. et al. J Allergy Clin Immunol 2012;130:25–43
Caubet JC. and Ponvert C. Immunol Allergy Clin N Am 2014;34:597–613
+/- IgE
Observe 30 min afterward
Negative skin test• If the patient has a history strongly
suggestive of a severe anaphylactic reaction• Some authors still recommend to administer
the vaccine in 2 doses (10% followed 30 min later by the remaining 90%)
Caubet JC., et al. Pediatr Allergy Immunol 2014: 25: 394–403
Vaccine administration• Administration of a vaccine should be
performed in a secure environment (trained personnel onsite and emergency drugs available)
Caubet JC., et al. Pediatr Allergy Immunol 2014: 25: 394–403
Caubet JC. and Ponvert C. Immunol Allergy Clin N Am 2014;34:597–613
+/- IgE
Observe 30 min afterward
Risk Benefit
Patient’s immune status to the vaccine
Immune status to the vaccine
• Measurement of antibodies to the immunizing agent in a vaccine
• If a patient has already maintains protective levels of antibody, withholding or delaying subsequent doses may be appropriate
Kelso J. Ann Allergy Asthma Immunol 2013;110:397-401Caubet JC., et al. Pediatr Allergy Immunol 2014: 25: 394–403
Kelso J. Ann Allergy Asthma Immunol 2013;110:397-401
Caubet JC. and Ponvert C. Immunol Allergy Clin N Am 2014;34:597–613
+/- IgE
Observe 30 min afterward
Kelso J. Ann Allergy Asthma Immunol 2013;110:397-401
Rutkowski K. et.al. Int Arch Allergy Immunol 2013;161:274–8
Wood R., et al. Pediatrics 2008;122:e771–7
Micheletti F. et al. Clinical & Experimental Allergy 2012;42:1088-96
Kelso J. Ann Allergy Asthma Immunol 2013;110:397-401
“ Egg allergy of any severity (including anaphylaxis) is not a contraindication to the administration of influenza vaccine but rather a precaution ”
Caubet JC., et al. Pediatr Allergy Immunol 2014: 25: 394–403.
• Skin testing before administration is not recommended because of its low sensitivity and specificity in predicting serious reactions
• Dividing the dose of vaccine is also not required because most even severely egg allergic patients can tolerate the full vaccine dose without reaction
Kelso J. Ann Allergy Asthma Immunol 2013;110:397-401
• 27 published studies• 4172 patients with egg allergy received 4729 doses of inactivated influenza vaccine• Including 513 with severe allergy who
uneventfully received 597 doses
Egg-allergic patients and Influenza vaccinations
Kelso J. J Allergy Clin Immunol 2014;133:1509–18
No cases of anaphylaxis
Very low amount of egg protein present in vaccine
McKinney K. et.al. J Allergy Clin Immunol 2011;127:1629–32
Background:1. Skin test might not be necessary if IIV contains low amount of ovalbumin2. Individual manufacturers produce 18-145 lots of IIV/season
Objective3. Determine ovalbumin content in influenza vaccines 4. Determine the lot-to-lot variability within a manufacturer
Method: Ovalbumin ELISA kit
McKinney K. et.al. J Allergy Clin Immunol 2011;127:1629–32
McKinney K. et.al. J Allergy Clin Immunol 2011;127:1629–32
There is still uncertainty with lot-to-lot variability and variability from year to year and
manufacturer to manufacturer
Prevention and control of seasonal influenza with vaccines. Recommendations of ACIP. MMWR Morb Mortal Wkly Rep 2013;62:1-43
Prevention and control of seasonal influenza with vaccines. Recommendations of ACIP. MMWR Morb Mortal Wkly Rep 2013;62:1-43
Two new IIVs not grown in eggs have beenapproved for patients ≥18 years
Flucelvax: virus propagated in cell culture
FluBlok: recombinant hemagglutinin proteins produced in an insect cell line
Picture from www.flublok.com
Prevention and control of seasonal influenza with vaccines. Recommendations of ACIP. MMWR Morb Mortal Wkly Rep 2013;62:1-43
No published studies on the safety of LAIV in recipients with egg allergy, guidelines recommend
the use of IIV in these patients
Prevention and control of seasonal influenza with vaccines. Recommendations of ACIP. MMWR Morb Mortal Wkly Rep 2013;62:1-43
Recommendations regarding influenza vaccination of persons who report allergy to eggs- US-ACIP,2014–15 influenza season
Kelso J. Ann Allergy Asthma Immunol 2013;110:397-401
“ The only precaution is administration ina setting where anaphylaxis can be recognized and treated and patients should remain under observation for at least 30 minutes after vaccination ”
Egg-allergic patients and vaccinations
• Other vaccines containing egg protein, particularly yellow fever, it is still recommended to test the vaccine before administration. In case of positive testing, the vaccine can be administered in graded doses
Caubet JC., et al. Pediatr Allergy Immunol 2014: 25: 394–403
Allergy to influenza vaccine• Additional evaluation is appropriate,
including skin testing with the vaccine and vaccine ingredients.
• If positive skin test, vaccine can be administered in multiple divided doses or can be withheld
Kelso J. et al. J Allergy Clin Immunol 2012;130:25–43
In summary• Overview of vaccine adverse events• Type of reactions• Potential allergens in vaccines • Diagnosis and management
Take home messages (1)• Mild local reactions and fever after
vaccinations are common and do not contraindicate future doses
• Anaphylaxis to vaccines are rare and should be further evaluated
• If the test are negative, subsequent doses can be administered in the usual manner but under observation
Kelso J. et al. J Allergy Clin Immunol 2012;130:25–43
Take home messages (2)• If the test are positive and the patient
requires subsequent doses, the vaccine can be administered in graded doses under observation
• Some non-anaphylactic reactions to vaccines might also require evaluation, but only a few are contraindications to future doses
Kelso J. et al. J Allergy Clin Immunol 2012;130:25–43
Thank you for your attention