UNDERSTANDING

VACCINE REACTIONS

OVERVIEW Principles of immunization

Types of vaccines and vaccine ingredients

Safety concerns and adverse reactions with

different types of vaccine

Adverse events following immunization common, minor reactions rare, major reactions

Vaccination of high-risk groups Contraindications to vaccination Adverse events associated with particular vaccines Pathogenesis of serious adverse reactions

THE GOAL OF IMMUNIZATION

To prime recipient’s immune response

To generate B and T memory cells

To heighten immune response to pathogens

To minimize adverse effects

To prevent/reduce severity of infectious diseases

To have vaccines of assured quality available for general use

(Ref. Vaccine Overview)

ATTRIBUTES OF A GOOD VACCINE

Appropriate immune response

Long-term protection

Safe

Stable

Affordable

RESPONSE TO IMMUNIZATION

Depends on Viability of antigen

Total dose especially killed vaccine

Route and site of administration

Age of recipient

Patient’s condition and immune state

Genetic factors

TYPES OF ANTIGENS

1. Live attenuated (oral polio, BCG, VZV)

2. Killed vaccine (influenza, IPV, hepatitis A, pertussis)

3. Toxoid (tetanus, diphtheria)

4. Purified (subunit) antigen (meningococcalvaccine, Haemophilus influenzae vaccine)

5. Recombinant antigen (hepatitis B)

6. DNA vaccines (in investigational phase)

7. Synthetic peptides (in investigational phase)

LIVE ATTENUATED VACCINES

Live organisms

reproduce natural infection, without conferring disease

Virulence much reduced

In vitro culture

Select strains that replicate poorly in target organ - minimize damage

LIVE ATTENUATED VACCINES

Undergoes potency testing, neuro-virulence

testing, test for wild-type strains and other

infectious agent

E.g. measles, mumps, rubella, VZV, OPV (sabin),

BCG

KILLED/INACTIVATED VACCINES

Live microorganisms inactivated by heat or chemical means (e.g. formalin)

Final concentrate tested for sterility, microorganism inactivation, potency, endotoxin, residuals concentration, pH, etc.

E.g. Salk polio vaccine, rabies vaccine, hepatitis A vaccine, pertussis vaccine

PURIFIED (SUBUNIT) ANTIGEN

Only parts of pathogen necessary to elicit the immune response are used

Potential toxins are avoided

Need to be conjugated to evoke an adequate T-cell response

POLYSACCHARIDE CONJUGATE VACCINES

Polysaccharide/oligosaccharide of antigen is linked (conjugated) to a protein carrier

increases antibody response and increases of production of memory cells

immunologic response at earlier age

booster effect on subsequent exposure to antigen (via infection /immunization exposure)

E.g. meningococcal vaccine, Haemophilus influenzae type B (Hib) vaccine

RECOMBINANT ANTIGEN VACCINES

Bulk production of antigenic protein using recombinant technique

Recombinant technique - insert DNA from pathogen into expression vehicle(i.e. E. coli, Chinese Hamster ovary cells, yeast, etc)

Antigenic protein produced, harvested and purified before use

Example – recombinant hepatitis B vaccine

METHODS USED TO ENHANCE IMMUNITY

Conjugation e.g. Hib vaccine

Adjuvants - aluminium salts

Why are adjuvants used?

What adverse reactions are associated with their use?

COMPONENTS OF THE VACCINE FORMULATION

Suspending agents e.g. water, salinePreservatives e.g. thiomerosal

Stabilisers e.g. sorbitol and hydrolyzed gelatin - MMR Adjuvants e.g. aluminium Salts

Other substances which may be presentResiduals in the growth mediumAntibiotics, e.g. neomycin, streptomycin - IPV, varicella vaccine

COMBINATION VACCINES

Diphtheria-tetanus-pertussis (DPT) pertussis component has adjuvant effect for diphtheria and tetanus toxoids

Different viruses in one vaccination e.g. OPV-type 1, 2, 3 polioviruses

ROUTE OF ADMINISTRATION

Should elicit immune response with minimal risk

Deep IM preferable for vaccines with adjuvants (depot effect and less granuloma formation)

SC/intradermal - better for live vaccines to lessen risk of neurovascular injury but still immunogenic (e.g. BCG)

WHAT IS AN ADVERSE EVENT FOLLOWING IMMUNIZATION (AEFI)?

A medical incident that takes place after an immunization, causes concern, and is believed to be caused by immunization

Vaccine reaction - caused by vaccine’s inherentproperties

Programme error - caused by error in vaccinepreparation, handling, or administration

Coincidental - happens after immunization but notcaused by it (a chance association)

Injection reaction - anxiety or pain of injection notvaccine

Unknown - cause cannot be determined

VACCINE REACTIONS

Common, minor reactionsvaccine stimulates immune systemsettle on their ownwarn parents and advise how to manage

Rare, more serious reactionsanaphylaxis (serious allergic reaction)vaccine specific reactions

Irritability, malaise & systemic symptoms

COMMON, MINOR REACTIONS

Fever >38oC

BCG

Hib

HepBMeasles/MMRPolio (OPV)

DTP(pertussis)

Tetanus

90-95%

5-15%

Adults: 15%; Children: 5%

~10%

-

Up to 50%

~10%*

-

2-10%

-

5-15%

<1%

Up to 50%

~10%

-

-1-6%

5% rash

<1%**

Up to 55%

~25%

* Rate of local reactions likely to increase with booster doses, up to 50-85%

** Symptoms include diarrhoea, headache, and/or muscle pains

Vaccine Local reaction (pain, swelling, redness)

MANAGEMENT OF COMMON, MINOR REACTIONS

Local reactioncold cloth at injection siteparacetamol

Fever >38°Cgive extra fluidstepid sponging paracetamol

Irritability malaise and systemic symptomsgive extra fluidsparacetamol

RARE, MORE SERIOUS REACTIONS

0.76-1.3 (1st dose)0.17 (subsequent doses)0.15 (contacts)

4-30 daysVaccine-associated paralytic poliomyelitis (VAPP)

Risk is higher for first dose, adults, and immunocompromised

OPV

333331-50

5-12 days15-35 days0-1 hour

Febrile seizuresThrombocytopaeniaAnaphylaxis

Measles/MMR

1-25

0-1 hour1-6 weeks

AnaphylaxisGuillain Barré syndrome

Hep B

Nil knownHib

100-10001-7002

2-6 months1-12 months1-12 months

Suppurative lymphadenitisBCG osteitisDisseminated BCG

BCG

Rate per million doses

Onset interval

ReactionVaccine

RARE, MORE SERIOUS REACTIONS (2)

1000-60 000

570570

200-1

0-24 hours

0-3 days0-24 hours

0-1 hour0-3 days

Persistent (>3 hrs) inconsolable screamingSeizuresHypotonic, hyporesponsive episode (HHE)Anaphylaxis/shockEncephalopathy

DPT

Nil extra to tetanus reactionsTetanus-diphtheria

5-101-66-10

2-28 days0-1 hour1-6 weeks

Brachial neuritisAnaphylaxisSterile abscess

Tetanus

Rate per million doses

Onset interval

ReactionVaccine

RARE, MORE SERIOUS REACTIONS (3)

500-4000 in infants<6 months

5-20

7-21 days

0-1 hours

Post-vaccination Encephalitis

Allergic reaction/anaphylaxis

Yellow fever

10-1000

1-2.3

Serious allergic reaction

Neurological event

Japanese encephalitis

Rate per million doses

Onset intervalReactionVaccine

RARE, MORE SERIOUS REACTIONS

BCG

Hib

HepB

Measles/MMR/MR

Suppurative lymphadenitis BCG osteitis Disseminated BCG infection

1 in 1000 to 1 in 10 000 1 in 3000 to 1 in 100 million ~1 in 1 million

None known

Anaphylaxis 1 in 6-900 000

Febrile seizures Thrombocytopaenia

(low platelets) Severe allergic reaction Anaphylaxis Encephalopathy

1 in 3000 1 in 30 000

~1 in 100 000 ~1 in 1 million <1 in 1 million

Reaction Incidence

RARE, MORE SERIOUS REACTIONS (2)

Tetanus

Pertussis (DPT-

whole cell)

Reaction IncidencePolio(OPV)

Vaccine associated paralytic poliomyelitis

Risk is higher for first dose, adults, and immunocompromised

1 in 2.4-3.3 million doses

1 in 750 000 first dose compared to 1 in 5.1 million for subsequent doses

Brachial neuritis Anaphylaxis

0.5-1 in 100 000 1 in 100 000 to 1 in 2 500 000

Persistent inconsolable screaming Seizures Hypotonic, hyporesponsive episode (HHE) Anaphylaxis Encephalopathy (Note: Risk may be zero)

1 in 15 to 1 in 1000 1 in 1750 to 1 in 12 500

1 in 1000 to 1 in 33 000

1-6 in million

0-1 in 1 million

IMMUNIZATION OF SPECIAL POPULATIONSPREGNANT WOMEN

Safety concerns: potential teratogenicity and induction of abortion

Vaccinate only if indicated

Live viral vaccines usually not recommended

Birth defect unrelated to the vaccine may be falsely attributed to the vaccine

Newer vaccines/regimens may have unknown effects - use with caution

Women (especially adolescents) may not be aware of or disclose pregnancy

should we screen for pregnancy?

IMMUNIZATION OF SPECIAL POPULATIONSIMMUNOCOMPROMISED PATIENTS

Patients may be immunocompromised due to HIV congenital immunological dysfunctionimmunosuppression, e.g. steroids, chemotherapy, etc.

May not respond adequately to vaccination

Risk of disseminated infection from live attenuated vaccines

CONTRAINDICATIONS

True contraindications are rare

Current serious febrile illness delay vaccine administration

History of severe AEFI after previous dose

Evolving neurological disease avoid whole cell pertussis vaccine

(e.g. uncontrolled epilepsy)

Type 1 hypersensitivity to egg - avoid yellow fever & influenza but can use vaccines made in chick fibroblasts

Symptomatic HIV avoid BCG

WHO Immunization Policy 1996

CONTRAINDICATIONS

Anaphylactic reaction to neomicin, streptomycin or polymyxin B

IPV

Immunodeficiency, or immunodeficient household contact*

OPV

Encephalopathy within 7 days of administrationDTP

Anaphylactic reaction to vaccine or vaccine constituentSevere febrile illness

All vaccines

ContraindicationVaccine

* Risk benefit assessment when administered to HIV positive individuals

Adopted from Plotkin pg 66-67

CONTRAINDICATIONS

Anaphylactic reaction to common baker’s yeastHepatitis B

Anaphylactic reaction to egg, immunodeficiencyYellow fever

NoneHib

Anaphylaxis, pregnancy, immunodeficiency*MMR

ContraindicationVaccine

* Risk benefit assessment when administered to HIV-positive individuals

Adopted from Plotkin pg 66-67

ADVERSE EVENTS ASSOCIATED WITH SPECIFIC VACCINES

WHO case definitions are used here

Lack of standardized case definitions in the literaturee.g. fever

The Brighton collaborationdeveloping case definitions for AEFI

promoting global implementation of these definitions

secretariat@brightoncollaboration.orghttp://brightoncollaboration.org

ANAPHYLAXIS

Type 1 hypersensitivity reaction

Circulatory failure

Bronchospasm +/- laryngospasm/laryngeal oedema

respiratory distress

May include pruritis, flushing, angioedema, seizures, vomiting, abdominal cramps & incontinence

Occurs in previously sensitized individuals

ANAPHYLAXIS

Reported less from developing countriesLess sensitization?

Less reporting?

Anaphylaxis is rare (1/1 000 000 vaccinations)

Fainting is common

Untrained staff may misdiagnose fainting/dizzinessfor anaphylaxis or vice versa

Administration of adrenaline in a faint may bedangerous

PROMPT MANAGEMENT IS VITAL!

SEIZURES

Particularly associated with measles and DTP vaccination (pertussis component)

febrile seizures Temp >38afebrile seizures Temp normal

Febrile seizures more common with pertussisAn association with non-febrile seizures has not been proven

ADVERSE REACTIONS TO BCG

Disseminated BCGwidespread infection, 1-12 months after BCG

usually in immunocompromised individual

confirm by isolation of Mycobacterium bovisBCG strain

treat with antituberculous regimen including Rifampicin and Isoniazid

Osteitis/osteomyelitisinfection of the bone with M bovis BCG strain

management as above

ADVERSE REACTIONS TO BCG

Suppurative lymphadenitisoccurs within 2-6 months of BCG vaccination

case definition

1 lymph node> 1.5 cm in size/draining sinus over a lymph node

usually occurs in the axilla, on the same side as innoculation

Managementheals spontaneously over monthsonly treat if sticking to skin or drainingsurgical drainage and local installation ofantituberculous drugsystemic Rx is ineffective

TETANUS VACCINE

Brachial neuritis Presents with pain in shoulder and upper armFollowed by weakness +/- wasting of arm and shoulder musclesSensory loss not prominentOccurs 2-28 days after vaccinationPossibly a manifestation of immune complex diseaseManagement is symptomatic

ENCEPHALOPATHY AND ENCEPHALITIS

Possibly associated with measles & pertussis vaccine

Case definition of encephalopathy2 out of 3 of

seizuresalteration of consciousness lasting for one day or moredistinct change in behavior for one day or more

Temporal relationshipwithin 48 hrs with DTPwithin 7-12 days after measles or MMR

ENCEPHALITIS AND MEASLES VACCINATION

An analysis of claims for encephalitis following measles vaccine in the USA found clustering of events 8-9 days after vaccination (Wetbel 1998, Duclos 1998)

This supports, but does not prove, thepossibility that measles vaccine was causative

Risk is less than 1 case per million

HYPOTONIC HYPOTENSIVE EPISODE (HHE OR SHOCK-COLLAPSE)

Mainly associated with DTP

Case definition

Event of sudden onset occurring within 48 (usually less than 12) hours of vaccinationand lasting from one minute to several hours

In a child < 10 years of age

ALL of the following must be present

limpness (hypotonic)

reduced responsiveness

pallor or cyanosis - or failure to observe/recall

Transient, self-limiting, NOT a contraindication to further vaccination

Case

Following a national immunization day in 1996, cases of paralysis were reported after receiving OPV. On laboratory analysis, the wild virus was found, showing that the children had been infected with wild poliovirus before immunization. The cases of poliovirus were coincidental, and not caused by the vaccine.

POLIO VACCINE - ACUTE FLACCID PARALYSIS

Vaccine associated paralytic poliomyelitis

Occurs within 4-30 days of receipt of OPV or 4-75 days after contact with vaccine recipient

UNPROVEN ASSOCIATIONS AND PUBLIC CONCERNS

Influenza vaccine and Guillaine Barré Syndrome

MMR and autism, Crohn’s disease

Polio and HIV

Hepatitis B and multiple sclerosis

DTP and permanent brain damage

DTP and increased risk of mortality

Aluminium and macrophagic myofasciitis

Bovine spongiform encephalopathy (BSE)

Thiomerosal

Multiple vaccines given simultaneously

CONCLUSIONSImportant to understand the safety profile of commonly used vaccines

Safety profile of vaccines depends on risk factorsof person being vaccinated

AEFI system must identify priority events which need to be reported

Important to understand possible mechanisms, treatment and possible prevention of vaccine reactions