Adverse reactions to vaccine

Adverse reaction
to vaccine
Pornsiri Sae-lim , MD
Pediatric Allergy and Immunology Department
King Chulalongkorn Memorial Hospital

Content
• Introduction
• Clinical manifestation
• IgE – mediated reaction to vaccine
• Non IgE– mediated reaction to vaccine : clinical , presentation , cupit, specific
vaccine
• Diagnosis and management

Introduction : Vaccine
• Active immunization
• Administration of all or part of a microorganism or a modified
product of a microorganism
• To evoke an immunologic response and clinical protection
• Allergic reaction: Rare
- Sensitive to any ingredient in the vaccine
- Mostly directed to additive
- Screening for allergy to a vaccine or a vaccine component is
indicated
Redbook 32th edition, AAP, 2021-2014

Evolution of an Immunization Program
John M. Kelso. Middleton 9th edition. 2020.

VAERS Table of
Reportable
Events
Following
Vaccination:
VAERS_Table_of
_Reportable_Ev
ents_Following_
Vaccination.pdf
(hhs.gov)

Vaccine Ingredients
•Antigens
•Conjugates
•Adjunvants
•Stabilizers
•Preservative
•Antibiotics
•Diluent
www.cdc.gov/vaccinesafety/vaccine/index.html

http://www.vaccinesafety.edu/components.htm
http://www.cdc.gov/vaccines/pubs/pinkbook/appendix/index.htm

ADJUVANTS
• to improve the immune response to antigens
• not provide immunity
• Not all vaccines use adjuvants , ex : Lived vaccine
• may cause local & systemic reactions more frequently compared with
nonadjuvanted vaccines
• Aluminum salts :
• used safely in the United States since the 1930s and remains widely in use
• vaccines that contain subunit antigens of a cell (eg, hepatitis B vaccine) or
toxoids (eg, diphtheria and tetanus toxoids)

• Newer adjuvants currently in use
• Oil-in-water emulsions : adjuvanted influenza vaccine
• Deacylated monophosphoryl lipid A & saponin in a liposomal formulation :
recombinant zoster vaccine
• Cytosine-phosphate-guanine enriched oligodeoxynucleotide motifs : Heplisav-B

Villarreal, The Journal of Allergy and Clinical Immunology: In Practice 2020

STABILIZERS
• to help ensure that vaccine potency is not affected by adverse conditions such as
heat and abnormal pH during the vaccine manufacturing process or during transport
and storage
• Sugars: lactose or sucrose in H influenzas type b vaccines
• Amino acids: glycine or monosodium salt of glutamic acid in live attenuated
influenza vaccine
• Proteins : gelatin in MMR , varicella vaccine and some inactivated influenza
vaccines

PRESERVATIVES
• multidose vials of vaccines as a safety measure to prevent the growth of
microorganisms
• thimerosal, formaldehyde, and phenol derivatives
ANTIBIOTICS
• As a class of preservatives
• used during the vaccine manufacturing process to inhibit bacterial growth >> trace amounts
can remain in the final product
• neomycin, gentamicin, and polymyxin B

CLINICAL MANIFESTATIONS
• Common vaccine adverse reactions usually are mild to moderate in
severity , no permanent sequelae
•ocal inflammation after administration of either DTaP, Td, or Tdap
vaccines,
•Fever and rash 1 to 2 weeks after administration of MMR or MMRV
vaccines

Type of reaction
• Local vs Systemic reaction
• Immediate vs Non immediated
• IgE vs Non IgE Mediated Reactions

Immunoglobulin E–Mediated Reactions
• Estimates of true immediate reactions to vaccines range from 1 in 50 000 doses
• the DTP vaccine to 0.5 - 1 reaction per million doses for other vaccines
• Predominantly systemic reaction
• Start within an hour from vaccination (from a few minutes to 4 hr)
John M. Kelso. Middleton 9th edition. 2020

• wide range of symptoms affecting the skin and the respiratory and cardiovascular systems
• Dermatologic: urticaria, flushing, angioedema, pruritus
• Respiratory:
rhinoconjunctivitis (red, watery, itchy eyes, stuffy, runny, itchy nose, sneezing),
upper airway edema (change in voice, difficulty swallowing, difficulty breathing, stridor)
bronchospasm/asthma (cough, wheeze, shortness of breath, chest tightness)
• Cardiovascular: hypotension, tachycardia, palpitations, light-headedness, loss of consciousness
(Hypotension or loss of consciousness with pallor and bradycardia is more likely to be related to a
vasovagal reaction)
• Gastrointestinal: cramping, nausea, vomiting, diarrhea

Anaphylaxis after vaccination : rates
adapted from NcNeil et al., 2016. Brighton Collaboration case definition
Nilsson L, Vaccination and allergy: EAACI position paper, practical aspects. Pediatric Allergy and Immunology. 2017

Vaccination-triggered anaphylaxis rates for major vaccines

Differentiation of anaphylaxis and vasovagal reaction

Immunoglobulin
E–Mediated
Reactions :
Vaccine
component
Gelatin
Egg
Cow's milk
Latex
Yeast
Dextran

Gelatin
• Animal protein : bovine or porcine origin
• Stabilizing agent : added to Live & inactivated vaccines
• gelatin-containing vaccines : MMR , rabies, varicella vaccines, and also
earlier in Japanese encephalitis and influenza vaccines
• A new Japanese encephalitis vaccine does not contain gelatin
• Gelatin is also a source of alpha-gal
McNeil , Vaccine-associated hypersensitivity. Journal of Allergy and Clinical Immunology 2018

Gelatin and alpha-gal allergy
• In the southeastern United States, galactose-a-1,3-galactose (alpha-gal) sensitivity has emerged
as a cause of red meat allergy that is causally linked to bites from the lone star tick
• Alpha-gal sensitivity often presents with delayed anaphylaxis (3-6 hours) after ingestion of red
meat, with lesser degrees of reactivity to milk and gelatin
• A recent report identified vaccine–induced anaphylaxis associated with alphagal allergy in a 63-
year-old patient after receiving varicella zoster virus immunization

Gelatin and alpha-gal allergy
Stone Jr, Cosby A., et al. , The journal of allergy and clinical immunology. In practice ,2019

Gelatin
• Negative history of allergy to the ingestion of gelatin >> may not exclude
an allergic reaction to gelatin injected with the vaccine
• Incidence of gelatin allergy among vaccine recipients suffering
anaphylactic reactions has been higher in Japan
•Strong association between gelatin allergy and HLA -DR9
(unique to Asians)

Children with Gelatin allergy (ingestion)
* administer a gelatin-free alternative vaccine if available *
Skin testing with gelatin-containing vaccine should be
performed prior to vaccination
• Positive : administered in graded doses under
observation
• Negative : vaccine will be given in the usual
manner + observe for at least 30 minutes
Zudaire, ,Anales de Pediatría (English Edition) 2015

Egg
• Ovalbumin
• Vaccines cultured in chicken embryo fibroblasts have lower concentrations
of egg protein than cultured in embryonic eggs
•Measles and mumps vaccines
•Yellow fever vaccine
•Influenzae vaccine

Contamination by culture media in the preparation of vaccines

• MMR vaccine
• not contain egg proteins capable of triggering an allergic reaction
• all children ( include anaphylaxis reaction ) : routinely vaccinated
• Yellow fever vaccine
• Egg-allergic children, including those who have had anaphylaxis, were successfully vaccinated
with yellow fever vaccines with no serious adverse events reported
• may contain significant amounts of egg proteins
• evaluated by an allergist or pediatric allergist
• Negative : usual manner
• Positive : graded doses in a hospital setting
Children with Egg allergy

Children with Egg allergy
• Influenzae vaccine
• may contain traces of ovalbumin
• Egg allergy: CDC & Advisory Committee on Immunization Practices (ACIP)
• Mild egg allergy : receive any licensed and recommended age-appropriate
flu vaccine & no longer need to be observed for 30 minutes
• Severe egg allergy : under the supervision of a health care provider who is
capable of recognizing and managing serious allergic conditions

Milk
• Milk proteins : used as growth media in DTaP and Tdap vaccines
• contain trace (nanogram) quantities of bovine casein
• rarely cause anaphylaxis
• Many children with milk allergy tolerate the DTaP and Tdap vaccines
• Standard practice for DTaP vaccination for all children (including who with milk allergy)
is recommended
• Caution is advised >> administering booster doses in highly sensitive children with
milk allergy
• Some additional observation after vaccination in those with very high levels of milk
sensitivity Michael M. Journal of Allergy and Clinical Immunology,2018

Milk
• However, should a milk allergic patient suffer an allergic reaction to one of DTaP and Tdap
vaccines, the possibility of milk protein contaminating the vaccine should be considered
• Cholera and tetanus-containing vaccines and perhaps pneumococcal conjugate, oral typhoid,
and some conjugated Hib type b and meningococcal vaccines could also contain miniscule
amounts of milk protein

Yeast
• Saccharomyces cerevisiae ( known as baker's or brewer's yeast )
• Residual yeast protein : viral proteins grown in S. cerevisiae
• Vaccines contain yeast protein, including hepatitis B vaccines (up to 25 mg
per dose) and human papillomavirus vaccines (<7 mcg per 0.5 mL dose)
• Smaller amounts of residual yeast protein : Cholera , pneumococcal
conjugate, oral typhoid, and some meningococcal vaccines
• Very rarely be caused by allergy to S. cerevisiae
• 1% to 2% of subjects had anti-yeast IgE antibodies before immunization >>
no significant rise in IgE after receiving HBV vaccine

Yeast
• Yeast associated anaphylaxis after administration of HBV vaccine in sensitized
patients appears to be a rare event
• If the patient has a history of immediate-type allergy to baker’s or brewer’s yeast
and a positive skin test or serum-specific IgE response to S. cerevisiae >> an
appropriate precaution is skin testing with yeast containing vaccines
• Positive : administered in graded doses under observation
• Negative : vaccine will be given in the usual manner + observe for at least 30
minutes

Latex
• Dry natural rubber (DNR) latex /synthetic rubber
• Vaccine vial stoppers or syringe plunger tips
• Difficult to elute latex allergen from these molded rubber products
• Flexible latex products
• Gloves and balloons from
• Latex allergen can be easily eluted
Allergic reactions to vaccines caused by latex in the packaging are exceedingly rare
Dreskin et al. World Allergy Organization Journal 2016

Latex
• Latex allergic patients
• using non-latex gloves for the injection
• vaccinated in a latex-free environment
• prepared to treat unusual allergic conditions and reactions
History of latex-precipitated anaphylaxis
receive vaccines from vials with nonlatex stoppers
• Available preparation has a latex stopper >> remove stopper & drawn up directly from the
vial without passing the needle through the stopper
• Available vaccine contains latex in the packaging , Ex : prefilled syringe >> vaccine can still
be administered, but the patient should be observed for at least 30 minutes afterward
John M. Kelso. Middleton 9th edition. 2020
Dreskin et al. World Allergy Organization Journal 2016

Dextran
• Used as a medium nutrient or as a stabilizer
• Implicated in allergic reactions to a particular brand of MMR vaccine previously used
in Italy and Brazil
• The reactions were related to the presence of IgG antibodies to dextran
• the mechanism was hypothesized to be complement activation and
anaphylatoxin release
• This brand of vaccine has been withdrawn from the market
Sampath, Vanitha, et al. "Vaccines and Allergic reactions: the past, the current COVID‐19 pandemic, and future perspectives." Allergy (2021).

Non immunoglobulin E–Mediated Reactions
• Generally local and confined to the site of infection
• Minor, self-limited side effects
• pain, warmth, tenderness, swelling, and erythema
• Inflammatory respond
• Develop hour – day after vaccination

• Mild local reactions :
• non-specific inflammation due to the injection itself & injection of foreign
material
• Large local reactions :
• 24- 72 hours after vaccine administration
• 1/4 of the children , after a fifth dose of DTaP vaccine in four- to five-year-olds
• secondary to T-cell infiltration are often associated with prolonged and very
effective immunity

• Chronic subcutaneous nodules with itching and eczema :
• Nonspecific inflammation or irritant reactions usually induced by adjuvants,
such as aluminum
• Serum sickness :
• Reported after human diploid cell rabies vaccine
• Onset of symptoms from 2 to 21 days after vaccine administration
• Arthralgia, fever, and malaise, and urticaria has been a prominent feature.

local vaccine reactions

Non IgE –
Mediated
Reactions :
Vaccine
component
Thimerosal
Formaldehyde & beta-
propiolactone (BPL)
Antimicrobials
Aluminum

Thimerosal
• Additive : bactericidal agent
• associated with contact allergy and rarely with systemic allergic reactions
• 50% mercury by weight ( mercury is neurotoxic)
• Thimerosal has decreased dramatically due to theoretical concerns about
cumulative mercury exposure in children

Thimerosal
• All vaccines routinely recommended for children 6 years of age and younger in the
United States are available in formulations that do not contain thimerosal
• Some multidose vials of inactivated influenza vaccines contain thimerosal
• Patch testing can be performed for the diagnosis of allergic contact dermatitis, but
this is not helpful in relation to vaccination
• Contact sensitivity : not a contraindication to receiving vaccines containing them

Formaldehyde & beta-propiolactone (BPL)
used to inactivate viruses during the production of vaccines
• BPL :
• BPL altered human albumin contained in the HDCV >> develop an immune complex-like
reaction in the 2–21 days that follow
• BPL to inactivate SARS-CoV-2 : SinoPharm, Sinovac
• Formaldehyde :
• reported to aggravate eczematous dermatitis following hepatitis B vaccination
• Formaldehyde-specific contact dermatitis had also been reported following formaldehyde-
containing influenza vaccine
• hypothesized : introduction of carbonyl groups on antigens by formaldehyde in vaccines
profoundly affects its immunogenicity

Aluminum
• most common adjuvants used in vaccines
• Aluminum hydroxide and aluminum phosphate
• may cause formation of persistent nodules palpable at the injection site
Antimicrobials
• Gentamycin, tetracycline, neomycin, streptomycin, and polymyxin B are used during
the production process for vaccines
• most of these antimicrobials are removed during the purification process, trace amounts
may be present in some vaccines
• antimicrobial agents can cause contact or rarely systemic hypersensitivity reactions
• trace amounts present in vaccines have not been well documented
Dreskin et al. World Allergy Organization Journal (2016) 9:32

• retrospective study
• suspected vaccination granulomas
• referred to the department of pediatric dermatology in CHI, Crumlin between 2010 and 2018
• review medical records including laboratory & radiological investigations
Kelly, Eimear, et al, Acta Paediatrica , 2020

• Thirteen cases were identified
• Most presentation : 9 Children >> intense
pruritus at the vaccination site
• Most findings : palpable nodules and
lichenification
• AI Patch testing: Eight of nine children in
the series patch tested >> positive
• Follow-up interview : median symptom
duration was 12 (range: 3-120) months
• 2 Children : Reported recurrence of the
lesions on subsequent vaccination
• Biopsy : nodular lymphoid infiltrate of the
dermis and subcutis

Report
• Etiology : remains unknown
• Cumulative aluminum exposure & repeated administration of Al adsorbed
vaccines & young age have been cited as risk factor
•10 of the children in this series had received three doses of the DTaP-
IPV/HiB vaccine prior to symptom onset
• Contact allergy to Al has been demonstrated in 85%-95% following the
development of persistently itchy nodular granulomatous reactions to Al-
adsorbed vaccines

Non–IgE–mediated Reactions : Specific Vaccines
Vaccine Reaction
DTP - Seizures, encephalopathy, hypotonic-hyporesponsive episodes
(HHE), inconsolable crying
- ↓ incidence >> conversion from whole-cell to acellular pertussis
vaccines
- Encephalopathy reactions are a contraindication to further pertussis
vaccination
Polio - OPV : vaccine-associated paralytic poliomyelitis (VAPP)
Rotavirus - Intussusception : risk is far outweighed by the benefits of
vaccination

Vaccine Reaction
Tetanus Arthus reactions :
- Intervals shorter than 10 years >> associated with increased rates
of Arthus reactions
Varicella - Varicella-like lesions (the injection site 4% , generalized varicella-
like rashes 4% )
Yellow Fever - Vaccine-associated encephalitis
- Yellow fever vaccine–associated neurotropic disease (YEL-AND)
- yellow fever vaccine–associated viscerotropic disease (YEL-AVD)

Vaccine Reaction
Influenzae Febrile seizures
- simultaneously with conjugated pneumococcal vaccine
Narcolepsy : particular brand of an adjuvanted monovalent 2009 H1N1 influenza
vaccine
MMR • Transient rashes (5%)
• Late-onset fever 7 to 12 days after administration (15%) -> increased risk of
febrile seizures
• Thrombocytopenia within 2 months of vaccination
MMRV • Double risk of febrile seizures only for the first dose of the vaccines
Rubella • Transient arthralgia due to direct infection of the joints by the virus (15% of
adult female vaccine recipients)

Approach to a Suspected Immunoglobulin E– Mediated Reaction to a Vaccine

SKIN TESTING WITH
VACCINES AND VACCINE
CONSTITUENTS
Dreskin SC, ICON: allergic reactions to vaccines. World Allergy Organ J. 2016
Vaccine skin tests may cause false (or clinically irrelevant)
positive reactions. Thus if skin testing gives a positive
reaction, also perform on normal control subjects

Vaccine component skin tests
• Prick tests with commercial extracts of egg, milk, or Saccharomyces cerevisiae yeast
• Prick test with sugared gelatin (e.g., Jell-O): dissolve 1 teaspoon of gelatin powder in 5 mL of
normal saline. Vaccines that contain gelatin
• Prick test with latex: soak 2 fingers of latex glove or a toy balloon in 5 mL of normal saline
Vitro assays for specific IgE antibody to egg, gelatin, latex, milk, and yeast also are commercially
available as an alternative or complement to skin testing

History of severe reaction & positive vaccine
skin test & fewer than the recommended
number of doses already received
>> consider measuring level of IgG
antibodies to immunizing agent

If the measured level is
associated with protection
from disease, consider
withholding additional
doses, although magnitude
and duration of immunity
may be less than if all
doses received

Vaccine administration in graded doses

Pre- immunization testing and immunization in patients who had a
suspected previous allergic reaction to a vaccine

Controversies Regarding Long-term Consequences Of Vaccination
• Atopy:
• BCG vaccine : unlikely to be associated with protection against the risk of allergic sensitization
and disease
• DTP & measles vaccine : not increase the risk of allergic disease
Overall, the bulk of the evidence >> refute the idea that immunization causes atopy
• Autism : MMR vaccine , Thimerosal
• No relationship between MMR vaccine and autism & thimerosal-containing vaccines and autism
• Autoimmune Diseases :
• Guillain-Barré syndrome, multiple sclerosis, type 1 diabetes, optic neuritis, and transverse myelitis
• “evidence is inadequate to accept or reject a causal relationship.”

Population-specific considerations for vaccination
Population Considerations
Healthy (A) Follow routine guidelines/schedule for vaccination.
(B) Monitor mRNA vaccine recipients for 15–30 minutes per local guidelines
History of food allergies Egg: Proceed with vaccination under supervision.
Yeast: Seek allergist evaluation prior to Hepatitis A, B, HPV, DTaP,
Meningococcal, Pneumococcal vaccines.
Gelatin: Seek allergist evaluation prior to MMR, Zoster, Influenza, Rabies, Yellow
fever, Typhoid vaccines.
History of immunosuppression (A) Defer live vaccination.
(B) Administer vaccine prior to immunosuppression if possible.
History of vaccine, drug, or
antibiotic allergy
(A) Refer to allergist.
(B) Identify specific components that may be similar in other vaccines.
(C) Graded administration of vaccine/drug after discussion of risks and benefit

Future safety
research
objectives

Summary
• Mild adverse reactions : self-limited , common
Serious complications : rare
• Immunoglobulin E (IgE)–mediated : related to the immunizing agent , protein
constituent >> Skin testing may be helpful
• Non–IgE-mediated : associated with specific vaccines and may preclude further
doses

Adverse reactions to vaccine

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