adverse reactions to vaccine for infectious diseases

Adverse Reactions to Vaccines for Infectious Diseases

Lalita Tearprasert; M.D.10 June 2016

Outline

• Overview of vaccine adverse events• Clinical manifestations• Potential allergen in vaccines• Diagnosis and management

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Overview of vaccine adverse events

• Approximately 220 million doses of vaccines distributed in the United States each year

• All serious events occurring after vaccine administration should be reported to the Vaccine Adverse Event Reporting System (VAERS)

• Patients with suspected allergy to vaccines or vaccine components - should be evaluated by an allergist/immunologist - unnecessarily be advised to avoid subsequent immunization - most patients can receive vaccination safely

Middleton's 8th edition.Kelso et al. J Allergy Clin Immunol. July 2012.(Practice parameter 2012).

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https://vaers.hhs.gov/index

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• Approximately 20 vaccines are currently in use• Each year billions of doses are administered worldwide• Vaccine-induced AE ranges between 3 - 83/100,000

vaccine doses according to worldwide post-marketing surveillance data

Vaccine adverse events

Caubet et al. Pediatric Allergy and Immunology 25 (2014) 394–403.

Access from http://thaihpvc.fda.moph.go.th 30 May2016.Spontaneous report of adverse drug reaction 2014.

Thailand : Report of vaccine ADR 2014 = 1.31%

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http://thaihpvc.fda.moph

http://go.th

Clinical manifestations of hypersensitivity reactions to vaccines

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Type of reactions

• Immunoglobulin E–Mediated >> predominantly systemic reactions

• Non–Immunoglobulin E–Mediated >> generally local and confined to the site of injection

Middleton's 8th edition.Fritsche SWISS MED WKLY 2010;140(17–18):238–246.


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IgE-mediated

• Occur within minutes - hours• Sign & Symptom - Anaphylaxis - Flushing - Urticaria and/or angioedema - Rhinitis, wheezing - Syncope, Faintness - Hypotension• Anaphylaxis after vaccination is rare• More often caused by additive or residual vaccine components• Particular importance allergen : egg, yeast, gelatin and latex



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• Enrolled 9 Vaccine Safety Datalink sites• January 1, 2009 through December 31, 2011• 9.3 million subjects available annually (2.1 million children and 7.2 million adults)• Results

- 33 confirmed vaccine-triggered anaphylaxis cases that occurred after 25,173,965

vaccine doses

- Rate of anaphylaxis was 1.31 (95% CI, 0.90-1.84) per million vaccine doses

- Did not vary significantly by age or sex• Conclusions

- Anaphylaxis after vaccination is rare in all age groups

- Despite its rarity, anaphylaxis is a potentially life-threatening medical emergency

MCNEIL ET AL. J Allergy Clin Immunol 2016;137:868-78.

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Non-IgE-mediated

• Minor, self-limited side effects• Develop hours - days after vaccination• Local (injection site) reactions as well as mild systemic reactions such as fever, serum sickness• Inflammatory response• Not considered as an allergy



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• Common • Inflammation response• Pain, redness and swelling at the injection site • Occur within 48 hours of vaccination

Mild local reactions



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Rosli R. et al.PLOS ONE | DOI:10.1371/journal.pone.0155385 June 1, 2016.

Retrospective study in MalaysiaFrom 2000 to 2013

total of 61996 reports

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Large local reactions • Less common• Local Immune complex mediated• Occurring typically within 24–72 h after vaccination• Particularly vaccine containing toxoids and/or adjuvants eg. Tetanus



- Rate of local reactions higher after receiving multiple dose of certain vaccines - Swellings at the injection-site are not contraindication for further vaccinations

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Arthus reaction ( Localized type III )

Janeway 8th edition.

• Pain, swelling, induration and edema• Usually begins within 48 hours following immunization• Infant < 4 months, probably due to high levels of maternal antibodies• May be seen with too frequent boosters of tetanus-containing vaccines• Most arthus reactions resolve within 1 week

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Other form of local reaction• Extensive limb swelling• Subcutaneous nodules (esp. vaccines containing aluminum salts)• Local eczema - T-cell mediated reactions - starting from 2–8 hours up to 2 days - may extend beyond the injection area or may even become generalized (esp. vaccines containing aluminum hydroxide, thimerosal, or formaldehyde)



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Potential allergens in vaccines

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• Antigen - Virus, Bacteria, Toxin

Active components • Prevent contamination e.g., repeated puncture of a multi-dose vaccine vial - Magnesium, Thimerosal

Adjuvants• Enhance immune response to vaccine - Aluminum

Antibiotics• Prevent bacterial contamination - Neomycin, Gentamycin Polymycin B

Preservatives

• Protect the vaccine from adverse conditions such as the freeze-drying process - Sugar : Lactose, Sucrose - Amino acid : Glycine - Protein : Gelatin, Albumin

Stabilizers

Trace components• Left over from vaccine production process - Formaldehyde

www.FDA.govAccess from 30 May 2016.

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http://www.FDA.gov

Immunoglobulin E-mediated reactions

Gelatin

Egg

Latex

Yeast

Milk

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Gelatin

• Added to many vaccines as a stabilizer• First case report of an allergic reaction to the gelatin component of a vaccine : Anaphylaxis• Cause anaphylaxis to MMR, Varicella• Incidence anaphylactic reactions to gelatin : high in Japan• A genetic susceptibility to gelatin allergy " HLA-DR9 " (unique to Asians esp. Japan)

Middleton's 8th edition.Caubet et al. Pediatric Allergy and Immunology 25 (2014) 394–403.

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• Partial hydrolysis of collagen extracted from connective tissues of animals, such as cows or pigs• Highly cross-reactive in patients sensitized to pork or beef


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John M. Kelso, et al. J ALLERGY CLIN IMMUNOL 1993;91:867-72.

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Vaccine manufacturers in Japan and Germany removed gelatin or changed to a less allergenic gelatin in vaccines

Nakayama T. Onoda K.Vaccine 25 (2007) 570–576. Caubet et al. Pediatric Allergy and Immunology 25 (2014) 394–403.

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- MMR - Typhoid - Influenza - Yellow fever - JE - Zorter - Varicella - Rabies

Gelatin- containing vaccine

Kelso J. J Allergy Clin Immunol 2014;133:1509-18.

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MMR

Priorix® Trimovax® MMR ®Priorix-Tetra®

(MMRV)

MMR II®(MMR)

ProQuad®(MMRV)

Company GSK Sanofi Pasteur SII/ Masu GSK Merck Merck

Gelatin No Gelatin + + No Gelatin 14.5 mg. <11 mg.

https://www.ovg.ox.ac.uk/vaccine-ingredientsวีระชัย วัฒนวีระเดช. คู่มือวัคซีน 2016-2017 และปัญหาที่พบบ่อย

Thailand

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https://www.ovg.ox.ac.uk/vaccine-ingredients

Influenza

Fluarix® Fluazone® Vaxigrip® Fluad® Influvac® Agrippal®

Company GSK Sanofipasteur

Sanofipasteur

NV/ Biogenetech

Abbott Lab.

NV/ Biogenetech

Egg(ovalbumin) ≤ 0.05 mcg. 0.1 mcg. 0.05 mcg. + + +

Gelatin no 250 mcg. no no no no

Centers for Disease Control and Prevention’s (CDC). August 7, 2015 / 64(30);818-825.วีระชัย วัฒนวีระเดช. คู่มือวัคซีน 2016-2017 และปัญหาที่พบบ่อย

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JE(Beijing)GPO® CD-JEVAX® IMOJEV®

Menufacturer GPO Chengdu, ChinaConcentrated purified in USA then full process in

Thailand

Live/ Inactived Inactived Live-attenuated Live-attenuated (Recombinant)

Adjuvant None None None

Preservative Thimerosal None None

Stabilizer + Gelatin < 4.8 mg. No Gelatin

http://drug.fda.moph.go.th Access 6 June 2016.

JE

วีระชัย วัฒนวีระเดช. คู่มือวัคซีน 2016-2017 และปัญหาที่พบบ่อย

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http://drug.fda.moph.go.th

Varicella

Varilrix® Varivax®Varicella Vaccine-GCC®

Okavax® ProQuad®(MMRV)

Company GSK MSD Green cross/ Biogenetech

Sanofipasteur Merck

Gelatin No Gelatin 12.5 mg. 12.5 mg. No Gelatin <11 mg.

Access 6 June 2016.http://drug.fda.moph.go.th

Thailand


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T. Ozaki et al. / Vaccine 23 (2005) 1205–1208.

1999

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Removal of gelatin is thought to be an important factor that decreased the reports of adverse events

T. Ozaki et al. / Vaccine 23 (2005) 1205–1208.

No significant difference in immunogenicity between gelatin-containing and gelatin-free varicella vaccine

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• Rabies • Typhoid • Yellow fever • Zorter

http://www.chop.edu/centers-programs/vaccine-education-center/www.vaccinesafety.edu/components-Allergens.htm

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Egg (Ovalbumin)

Administration of vaccines “grown in eggs”

to egg-allergic recipients ??

Middleton's 8th edition.

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- Yellow fever - Influenza - MMR - Rabies (PCEC)

Egg-containing vaccine


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Amount of residual egg proteins


Highest

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" Small amount of egg proteins lead to allergic reaction "

Ovalbumin in vaccine

www.vaccinesafety.edu/components-Allergens.htm

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• In 1983 : 2 egg-allergic children who have anaphylaxis to measles vaccine• Later : More studies found no adverse reaction• Grown in chick embryo fibroblast cultures (not actually in eggs cultures) and contain negligible or no egg protein

MMR


Current recommendations indicate that MMR vaccine can be given routinely to children with egg allergy without previous skin testing

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Influenza • Egg protein : Influenza > MMR vaccine• Recent year, Influenza vaccine contain very low amount of egg protein (ovalbumin)• Trivalent inactivated influenza vaccine (TIV) can be administered safely as a single dose• LAIV, although containing the lowest amount of ovalbumin per dose, has not been formally studied for safety in egg-allergic individuals• Clinical history might not identify all persons allergic to egg proteins present in influenza or yellow fever vaccines• Skin testing is not predictive of reactions


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Kelso et al. J Allergy Clin Immunol. July 2012.(Practice parameter 2012)

All influenza vaccines available in the United States contain low amounts of ovalbumin

Lowest

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Sanofipasteur

NV/ Biogenetech

Abbott Lab.

NV/ Biogenetech

Egg(ovalbumin) ≤ 0.05 mcg. 0.1 mcg. 0.05 mcg. + + +


วีระชัย วัฒนวีระเดช. คู่มือวัคซีน 2016-2017 และปัญหาที่พบบ่อยCenters for Disease Control and Prevention’s (CDC). August 7, 2015 / 64(30);818-825.

Thailand 40

Yellow fever • Cultured in chicken embryos• Anaphylactic reactions in egg-allergic persons have been reported• Patients presenting for yellow fever vaccination are routinely asked if they are allergic to eggs• Allergy to a heat-labile egg protein has been described - The affected patient ate cooked eggs without difficulty and denied egg allergy when asked before receiving yellow fever vaccine


The vaccine, which is not heated during manufacturing, would still contain egg proteins that would otherwise be destroyed by heat

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Rabies

• Currently cell-culture derived vaccines are used 1.) Human diploid cell vaccine (HDCV), or Rabies Vaccine BP eg. Imovax® 2.) Purified chick embryo cell (PCEC) rabies vaccine, eg. Rabipur®, RabAvert®

Imovax ® rabies vaccine should be given to persons with a history of hypersensitivity reactions to egg or egg products

(If Imovax® vaccine is not available, Rabipur® & RabAvert® vaccine should be administered with strict medical monitoring)

Rabies: the green book, chapter 27; Public Health England (April 2013)

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Latex• Latex can be processed in 2 different ways 1.) Natural rubber latex (NRL) - medical gloves, catheters 2.) Dry rubber latex (DRL) - vial stoppers, syringe plungers• Package inserts for many vaccines : Vial, Prefilled syringes• Storage of liquid in a vial in which the liquid is in contact with rubber latex stopper can cause the release of latex allergens

Middleton's 8th edition.M. Russell et al. / Vaccine 23 (2004) 664–667.


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Latex in vaccine packaging

Middleton's 8th edition.Kelso et al. J Allergy Clin Immunol. July 2012.(Practice parameter 2012)

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The latex content of vaccine packaging is updated regularly by the CDC www.cdc.gov/vaccines/pubs/ pinkbook/pink-appendx.htm

• Since November 1990, VAERS recieved >160,000 reports• Reports submitted from 1 January 1991 - 15 October 2003• 147 (0.1%) reports mentioned a history of latex allergy in the vaccine recipient• Of the 147, 28 (19%) developed a possible allergic adverse event

M. Russell et al. / Vaccine 23 (2004) 664–667.

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Recommendation

• Patients with a history of latex-precipitated anaphylaxis can safely receive vaccines from vials with nonlatex stoppers

• If the only available preparation has a latex stopper, the stopper should be removed and the vaccine drawn up directly from the vial

• If the only available vaccine contains latex in the packaging that cannot be avoided, such as in a prefilled syringe, the vaccine can still be administered, but the patient should be observed for at least 30 minutes afterward


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• If a person reports a severe (anaphylactic) allergy to latex, vaccines supplied in vials or syringes that contain natural rubber should not be administered, unless the benefit of vaccination outweighs the risk of an allergic reaction to the vaccine


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Yeast

• Hepatitis B and human papillomavirus vaccines are manufactured using recombinant strains of Saccharomyces cerevisiae (common bakers' yeast) and contain residual yeast proteins


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- Hepatitis B - HPV

Yeast-containing vaccine


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http://www.genscript.com/recombinant-vaccine.html. Access 6 June 2016.

Hepatitis B

Final vaccine products contain up to 5% yeast protein


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http://www.genscript.com/recombinant-vaccine.html

Engerix-B Euvax-B Hepavax Gene

Twinrix(Hep AB)

Yeast < 5% + + < 5%

Currently no yeast-free hepatitis B vaccines

Amount of yeast is < 10 picograms of yeast DNA/dose

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Human papilloma virus (HPV)

Individuals that are allergic to yeast can turn to Cervarix(Carvarix: Tip of prefilled syringes is natural latex)

Monie et al. Biologics: Targets & Therapy 2008:2(1).

Cervarix: LatexGardasil: Yeast

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Milk

• Prepared in a medium derived from cow's milk proteins• May contain trace (nanogram) quantities of residual casein • Anaphylactic reactions are rare


DTaP or Tdap

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Non-Immunoglobulin E-mediated

Neomycin

Thimerosal

Aluminum

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Neomycin

• Approximately 1% of the general population demonstrates delayed-type hypersensitivity by patch testing to neomycin• However, the amount of neomycin found in vaccines is not believed to trigger DTR• Immediate-type : rare• Only single case of anaphylaxis has been linked to a neomycin-containing vaccine• Revaccination is not strictly contraindicated


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Neomycin-containing vaccine56

www.vaccinesafety.edu/components-Allergens.htm

Fritsche SWISS MED WKLY 2010;140(17–18):238–246.Caubet et al. Pediatric Allergy and Immunology 25 (2014) 394–403.

Antibiotic containing vaccine

• Some vaccines (i.e. polio, MMR, and influenza vaccines) may contain traces of antibiotics

• No report of confirmed immediate hypersensitivity reactions from ATB in vaccines

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Thimerosal

• Mercury derivative• Most effective preservative, improving vaccine stability• Most : Non-immediate hypersensitivity reactions eg. contact dermatitis, generalized maculopapular rash• Not been clearly documented to cause immediate hypersensitivity reactions• Vast majority tolerate such immunizations uneventfully• However, if possible, alternative vaccines not containing this preservative should be chosen to decrease the risk of local reaction



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http://vaccinesafety.edu/thi-table.htm.

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Aluminum• Adjuvant : hasten antivaccinal humoral immunity• Persistent itching, subcutaneous nodules, or granulomas at the injection site, Hyper- and hypopigmentation, hypertrichosis, and lichenification• Transient but can sometimes persist for a few weeks or even years• May cause formation of persistent nodules palpable at the injection site


In aluminum-sensitized patients requiring a vaccine containing aluminum, the injection should be administered

deep enough as intramuscular administration may prevent theformation of granulomas

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L.A. Echeverría-Zudaire et al. Allergol Immunopathol (Madr). 2015;43(3):304-325.

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Reaction to specific vaccines

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MMR

• 5% transient rashes (vaccine-induced modified measles)• 15% late-onset fever 5 to 12 days • 25-34 : 100,000 febrile seizures - MMRV increased risk to double, only for the first dose • Thrombocytopenia within 2 months of vaccination• 15% Acute arthritis in adult women (Rubella) Transient arthalgia in children (Rubella)

None of these events are contraindications to the administration of subsequent doses of MMR vaccine


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Diphtheria

• Local reactions : more frequent in persons who have made anti-diphtheria IgE • Generalized reactions : rarely


DTP64

Tetanus• 5% Large local swelling at the injection site (Arthus reaction)

• New vaccines were recommended in 2006 for 11- 64 years >> Td , Tdap -Recommended interval between doses of Td had been 10 years (shorter intervals: increased rates of Arthus reactions)

• Association with GBS and a rare local neurologic event (brachial neuritis)


Neither GBS nor brachial neuritis is a contraindication to the receipt of additional doses of tetanus-containing vaccines

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Pertussis

• Given in combination with diphtheria and tetanus toxoids• Most serious adverse effect related to pertussis vaccine - encephalopathy - seizures - hypotonic-hyporesponsive episodes (HHE): within 48 hr. - inconsolable crying


- Reactions decreased dramatically with conversion from whole-cell (DTP) to acellular (DTaP) pertussis vaccines - Risk 0-10: 10,000

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Appendix V-Guide to Contraindications and Precautions to Immunizations, Redbook 2015.

Varicella• 3% reactions occur at the injection site

• Vaccine-induced illness, particularly the appearance of varicella

lesions

• 3% Rash typically appears within 3 weeks of vaccination

(wild-type virus)

• Zorter-type rash can rarely appear after a varicella vaccination

and might contain either vaccine-strain or wild-type virus


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Yellow fever• Serious adverse effect of yellow fever vaccine is encephalitis

• 4 : 1000 infants

• Greatest in infants younger than 9 months of age

• Should not be given to any infant younger than 6 months

(relatively contraindicated)


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Influenza

• Rate of anaphylaxis after influenza vaccination is very low (About 0.024 case per 100,000 vaccines) - None of which occurred in persons known to be allergic to eggs

• Risk for Guillain-Barre syndrome (GBS)


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Diagnosis & Management

Accurate diagnosis of vaccine allergy is importantnot only to prevent serious or life-threatening reactions,

but also unnecessary vaccine restriction


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1.) Clinical history

2.) In vivo tests (i.e. skin tests) and in vitro tests (i.e. specific IgE)

Diagnosis of vaccine allergy

No single investigation alone is sufficiently predictive


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+/- IgE

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Fritsche SWISS MED WKLY 2010;140(17–18):238–246.

Important questions in patients with positive history after vaccination

History

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Non-immediated reaction

+/- IgE

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• Helpful to demonstrate a delayed hypersensitivity to preservatives or adjuvants

• 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 - no reason to withhold administration of a vaccine

Patch test


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- Should not be considered as a reason for avoiding (re)vaccination - Most : Subside spontaneously - Can treat with cool packs, and/or analgesic drugs (medications may reduce the immune response to vaccination and should not be administered empirically or prophylactically) - Difficult to distinguish from an infectious cellulitis

Local reactions


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Immediated reaction

+/- IgE

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Suggested approach to immediated-type allergic reactions to vaccines

+/- IgE

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Wood et al. PEDIATRICS Volume 122, Number 3, September 2008.

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Skin tests

• Prick test with full strength vaccine (consider dilution if hx of life-threatening reaction)

• Intradermal skin test with 0.02 ml. (1:100)

if negative

Kelso et al. J Allergy Clin Immunol. July 2012.(Practice parameter 2012)

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• Main purpose of these is to identify patients who are at real risk of developing a severe anaphylactic reaction in case of re-exposure

• Sensitivity and the specificity are not optimal

• Vaccine skin tests may false positive (non standardized --> irritant)

• Intradermal skin tests with some vaccines, such as tetanus toxoid, can also induce delayed-type hypersensitivity

Skin tests


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Vaccine ingredient skin tests / In vitro

Prick test with sugared gelatin : 5 grams (1 tsp) of gelatin power in NSS 5 ml.

Gelatin

Egg, Yeast Prick test with commercial extracts of egg, Saccharomyces cerevisiae

Latex sIgE to latex

Caubet et al. Pediatric Allergy and Immunology 25 (2014) 394–403.Kelso et al. J Allergy Clin Immunol. July 2012. (Practice parameter 2012)

Specific IgE available for egg, gelatin, latex, and yeast

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Prepare gelatin for SPT• Dissolving 1 teaspoon (5 g) of any sugared gelatin powder (for example Jell-O) in 5 mL of normal saline

• Not a standardized, validated, US FDA-approved method

Kelso et al. J Allergy Clin Immunol. July 2012. (Practice parameter 2012)

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• Soak 2 fingers of latex glove or a toy balloon in 5 mL of normal saline

Prepare latex for SPT


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Kelso et al. J Allergy Clin Immunol. July 2012. (Practice parameter 2012)

" Graded dose vaccine "

Positive skin tests86

• Observed for at least 30 min afterward

• Some authors still recommend to administer the vaccine in 2 doses (10% followed 30 min later by the remaining 90%) if the patient has a history strongly suggestive of a severe anaphylactic reaction

• No reports of patients with negative intradermal skin test to a vaccine reacting to subsequent administration of that vaccine

Negative skin tests


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RiskBenefit

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Measuring levels of IgG antibodies can help determine whether subsequent doses are required

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Egg-allergic patients & vaccinations

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Centers for Disease Control and Prevention’s (CDC) Advisory Committee on Immunization Practices.August 7, 2015 / 64(30);818-825.

Egg-allergic patients & Influenza vaccine

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Skin testing (skin prick test and/or intradermal test) with influenza vaccine

• Does not recommended, Unnecessary - Does not reliably identify patients with increased risk of reacting to the vaccine - May false positive


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Sanofipasteur

NV/ Biogenetech

Abbott Lab.

NV/ Biogenetech

Egg(ovalbumin) ≤ 0.05 mcg. + 0.05 mcg. + + +


Kelso et al. J Allergy Clin Immunol. July 2012. (Practice parameter 2012)Centers for Disease Control and Prevention’s (CDC). August 7, 2015 / 64(30);818-825.


Ovalbumin content ranged from 0.008 to 0.71 mg per 0.5 mL dose

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There is now a consensus that inactivated influenza vaccines with a low ovalbumin content

(< 0.12 μg/mL, equivalent to 0.06 μg for a 0.5 mL dose) are safe for use in people with egg allergy

Des Roches A, et al. J Allergy Clin Immunol 2012;130:1213-6.e1.

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Recommendation

• Only TIV should be administered to egg-allergic patients • Patients with a history of only hives after egg ingestion can receive TIV at their primary care provider's office

• Persons with a history of more severe reactions after egg ingestion should be referred to an allergist to receive TIV


- Must available the proper medications and resuscitative equipment to treat potential anaphylaxis - Must observe the patient for 30 minutes

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Centers for Disease Control and Prevention’s (CDC). August 7, 2015 / 64(30);818-825.

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Turner P, et al. BMJ 2015; 351: h6291

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Take home message• 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 with skin tests to the vaccine and its components

• Patients with suspected allergy to vaccines or vaccine components should be evaluated by an allergist/immunologist and unnecessarily advised to avoid subsequent immunization

• Most of the patients labeled as allergic to a vaccine may tolerate a subsequent injection of the vaccine without clinical reaction

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Thank You

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• Tetanus toxin is produced by growing Clostridium tetani in a modified Latham medium derived from bovine casein or grown in modified Mueller-Miller casamino acid medium

Results• 6/8 of the patients had prior acute allergic reactions to cow's milk• All had an increased milk-specific IgE within 2 years of reaction to vaccine• These children tolerated their initial vaccinations but reacted to booster doses

Kattan JD, et al. J Allergy Clin Immunol 2011; 128: 215-8.

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Kattan JD, et al. J Allergy Clin Immunol 2011; 128: 215-8.

Conclusion• Continuing the standard practice for DTP vaccination in all children, but advise caution when administering booster doses in highly sensitive milk allergic children

adverse reactions to vaccine for infectious diseases

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