Vaccine safety

Vaccines

1. Vaccine Safety
Department of Pharmacology

2. What is vaccination?
•Vaccinationistheadministrationofantigenicmaterial(thevaccine)to
produceimmunitytoadisease.
•Vaccinescanpreventoramelioratetheeffectsofinfectionbya
pathogen.
•Vaccinationisconsideredtobethemostessentialandcost-effective
methodofpreventinginfectiousdiseases.

3. Where the vaccination is needed?
•Morbidityandmortalityattributabletovaccine-preventablediseases
aredeclined.
•Highratesofvaccination,lowincidenceofvaccinepreventable
diseaseandadverseeventsafterimmunizationhasbeenthematter
ofconcern.

4. Safety of Vaccines
•AnextensivereviewofvaccinesafetybyInstituteofmedicine(IOM)
foundthatknowledge&researchcapacityhasbeenlimiteddueto:
Inadequateunderstandingofbiologicmechanismsunderlying
adverseevent
Insufficientinformationfromcasereportsandcaseseries
Inadequatesizeandlengthoffollow-upmanypopulation
basedepidemiologicstudies
Limitationsofexistingsurveillancesystemstoprovide
persuasiveevidenceofcausation
•TheIOMconcludedifresearchcapacityandaccomplishmentsarenot
improved,futurereviewsofvaccinesafetywillbehandicapped

5. Clinical Problems in
PharmacoepidemiologicalResearch
PolicyIssues
•Physico-chemicalproperties
•Lowerrisktoleranceofvaccines
e.g.theeventthatoccurat~1/1000000-1/10000000doses,suchas
acuteencephalopathyafterwholecellpertussisvaccine,GBS
(Group-BStreptococcal)afterswineinfluenzavaccine.
•Exposureofvaccinestolargenumberofpeoplebypublichealth
authorities-Mandatoryvaccination
•Herdimmunity.
•Exposuretovaccineuniversally“firstdonoharm”,itappliesmore
inpublichealththaninclinicalmedicine
•Eg:Cutterincident-theadministrationofinactivatedpoliovaccine
toabout4lakhpersonsresultedin260poliocases.

6. Error in production
•Eg:poliovaccinecontaminatedbysimianvirus40
•Exposureofhighlevelsofethylmercuryfromthimerosalpreservative
invaccine–highlightstheimportanceofsafetyconcernsthebasisof
strictregulatorycontrolbyFDA&WHO.
•Vaccinesafetystudieshavenarrowmarginsforerror-highstandards
ofaccuracy&timelinessareneeded
•Vaccinesgenerallyhavefewalternativestrainsortypes-decisionto
withdrawavaccineorswitchbetweenstrainsdependsonriskbenefit
perspective
•Eg:thedecisionoflicensewithdrawalofMumpsvaccinescontaining
theUrabestrainduetotheriskofvaccineassociatedMeningitis
withoutanalternativeinUK.

7. •Certaincountrieshavecompensationprogrammeforpersonsinjured
byvaccination
•Eg:InUSvaccineinjurytablecontainsvaccinewhichcontainsdata
necessaryfortheassessmentofadverseeventscausedbyspecific
vaccines
•Periodicrevisionofvaccineinjurytableleadstothemanufacturersthe
importanceofimprovingthequalityofvaccines
•Recommendationsfortheuseofvaccinesdependsonthebalanceof
risk&benefits
•Researchinvaccinessafetyhelptodistinguishtruevaccinereactions
fromcoincidentalevents
•Ithelpstomaintainpublicconfidenceinimmunization

8. Clinical Issues
•Evaluationofsafety&efficacyinlaboratoryforvaccinesisequally
importantasotherpharmaceuticalproductsbeforelicensure.
Phase1trial
•Requiresubjectsintens
•Detectextremelycommonadverseevents
Phase2trial
•Enrollhundredsofsubjects
•Helpsinconcluding
•Therelationshipsbetweenconcentrationofantigen
•Noofvaccinecomponents

9. Phase 3 trial
•Samplesize-larger.
•Basedonefficacyconsiderations.
•Inferencesonsafetydependsonsamplesizes&durationofobservation.
•Formulationtechniques
•Effectofsuccessivedoses
•Profilesofcommonreactions
Management,preventionortreatmentofvaccineadverseevent-
rudimentarystage.
Subspecialtieswithadequatereferralbase&researchfundsare
needed

10. Methodological Problems
1.SignalDetection
•Surveillancesystemshelpindetectingtheadverseeventsof
vaccinesintimelymanner.
•VaccinesafetySurveillancesystemshouldexaminemultiple
exposuresandmultiplediseaseoutcome
•Thesensitivityandspecificitydependsonthegoalof
surveillance.
•Sensitivity-detectionofapreviouslyunknownillnessor
syndrome
•Specificity-trackingaknowndisease

11. 2)StandardDefinitionsandEvaluativeProtocols
–CaseDefinitionsareusedatthetimeofreportingoratthetimeofanalysis
toimprovespecificity.
•Applicationofdefinitionsatthetimeofreporting:
oReducesthenoofreportsprocessed
oLowerstheoperatingcost.
oSensitivityofsurveillance–low.
•Ifthereportingformisopenended-
osensitivityofsurveillancegreater.
oCostwillbehigher.
•Advancementofscientificknowledgewillbehinderedin
immunizationsafetyduetolackofstandardcasedefinitions

12. 3)Assessmentofcausality
Assessmentofvaccineassociatedadverseeventsisnot
possibleunless…
oAvaccinespecificclinicalsyndromeisobserved
oRecurrenceuponrechallenge
oVaccinespecificlaboratoryfinding
•Epidemiologicstudiesarenecessarytoassesswhether
vaccinatedpersonsareathigherriskthanunvaccinated
personsifadverseeventoccurinabsenceofvaccination.

13. 4)EXPOSURE
•Documentationofexposurestatusisimportantto
preventmisclassification
•Poordocumentationdueto
oSubstantialmobilitybetweenhealthcareproviders
oSubstantialdifficultymaybeencounteredinascertaining
vaccinationstatus-Inolderpersons
•Immunizationcardrecorder

14. 5)OUTCOME
•Assessingtherareeventsduetovaccinationismajorchallenge
•AccordingtoInstituteofMedicinecommitteeastudymaybe
technicallyfeasiblebutlogisticallyinfeasible
•Theotherdifficultyinassessingtherareeventsinpopulations
lessfrequentlyexposedisinadequatestudypower.

15. 6)Analysis,ConfoundingandBias
•Childhoodvaccinesareadministeredonschedule,hereageis
theconfoundingfactor.
•Factorswhicharedifficulttocontrolleadstodelayed
vaccinationornonvaccination.
•eg:lowsocioeconomicstatus.

16. Currently Available Solutions
Pre-licensure
•Separate,largescale,longterm,randomisedexperimental
trials-neededtobetterassessmentofseriousvaccinerisks.
•Broadeningtheassessmentofpreandpostlicensureis
necessary.
•Data&safetymonitoringboards(DSMBs)represents
anotherareaofpotentialimprovementsinthepre-licensure
process.

17. Post Licensure
1.SpontaneousReportingSystems(SRS):
•InformalorformalpassivesurveillanceorSRShavebeenthe
cornerstoneofmostvaccinesafetymonitoringsystemdueto
lowcostofoperations.
•VaccinemanufacturersalsomaintainSRSfortheirproducts,
whichareusuallyforwardedtoappropriatenational
regulatoryauthorities.

18. •Administrationofvaccines→healthcareproviders+surveillance
system/regulatoryagency→developsvaccineadverseevent
reportingsystem(VAERS).
•ToincreasesensitivityVAERSformisdesigned&computerizedto
permitnarrativedescriptionsofadverseevents.
•Reportingformscontainingcheck-offboxesforspecificeventswith
accompanyingcasedefinitionshavebeendevelopedincertain
countries.
•Afieldguidelinesforimplementationofmonitoringofadverse
eventsfollowingimmunization(AEFI)hasrecentlybeendeveloped
byWHO.

19. 2) Classifications & Case Definitions
•Vaccine adverse events can be classified into :
•Frequency (common, rare)
•Extend (local or systemic)
•Severity
•Causality
•Preventability

20. Recentclassificationdividesadverseeventsaftervaccinations
into:
1.Vaccine-induced
2.Vaccine-potentiated
3.Programmaticerror
4.Coincidental
Dutchsystem-classificationofreports:
1.Simple-asinglevaccineinjection&asinglemajorreaction
2.compound-asinglevaccineinjection&morethanonemajorreaction
3.Multiple->1vaccineinjectioninthesameperson&1majorreaction
4.Compoundmultiple->1vaccineinjectioninthesameperson&>1
majorreaction

21. 3) Standardized Clinical Assessment Protocols &
Centers:
4 Assessment of Causality:
Depends on :
1.Strength of association
2.Analytic bias
3.Biologic gradient /dose response
4.Statistical significance
5.Consistency
6.Biologic plausibility/coherence

22. 5) Signal Detection
•Identifyingapotentialnewvaccinesafetyproblem(signal)requiresamixof
clinicalintuition&epidemiologicexpertise.
•VAERSisoneofthelargestregistriesforrarevaccineadverseeventsinthe
world.
•Eg;bell’spalsywasdetectedinrecipientsofanewSwissintranasalinfluenza
vaccine.
•Duetoitseaseofimplementation&interpretation,theproperreportingrate
ratio(PRR)methodisthemostwidelyuseddisproportionalitymeasuresin
VAERSforprospectiveandretrospectivesignalgeneration.

23. 6)MassImmunizationCampaigns
•Wheneveraverylargenumberofvaccinedosesareadministeredoverawell
definedshorttimeinterval,resultsinmoreprominentclustersofvaccine
adverseevents.
•Surveillanceofvaccineadverseeventsaroundthetimeofmassimmunization
campaignshavebeenextremelyusefulingeneratingsignals,eitherpositive(eg
:GBSafterpoliovaccine)ornegative(eg:GBSaftermeals)
•VAERStypeofdatahashelpstoidentifypotentialriskfactorsforvaccine
adverseevents.

24. 7)ClinicalTrials
A)Post-licensureclinicaltrials
•Optimizationofvaccineuseisdonebyclinicaltrialsafterlicensure
toassesstheeffectofchangesin
•Vaccineformulation
•Vaccinestrain
•Ageatvaccination
•Thenumberandtimingofvaccinedoses
•Simultaneousadministration
•Interchangeabilityofvaccinesfromdifferentmanufacturers

25. B)Phase4SurveillanceStudies
•Improvestheabilitytodetectadverseeventsthatarenotdetected
duringpre-licensuretrials
C)Ad-HocEpidemiologicStudies
•Assesssignalsofpotentialadverseeventsgeneratedbyspontaneousreporting
systems,themedicalliteratureorothermechanisms
•Egofad-hocfollowupstudiestosignalsofvaccinesafetyissuesareSIDS
afterDTPvaccination.
D)AutomatedLarge-linkedDatabases
•Developmentofautomatedlargelinkdatabasesmaypermitimprovedability
tomonitorthesafetyofsuchpost-licensurechangesinvaccinewithout
conductingsuchclinicaltrials

26. Methodological Approaches
1.Exposures
•Vaccinationrecords:helpstofindouttheexposureofvaccineineach
individual.
•Thedatacanbeeasilyretrieved&reviewedforanystudydesign.
•Automatedvaccinationrecords:
•Easethelogisticsoforganizingthestudies.
•Assesstheaccuracyofautomateddataineachstudy

27. •Whenpersonsreceivethevaccinationfromavarietyofproviders,their
exposurestatusmaybemisclassified.Thiserrorcouldbeminimizedifa
CentralizedNationalVaccinationRegistrywereimplementedtotrackall
vaccinationfrombirth.
•VaccineIdentificationStandardsInitiative(VISI)–organizedbyCDCto
improvetheaccuracyandefficiencyoftransferofvaccineidentification
information.
2.Outcomes
•Toensurebothhighsensitivity&specificity,asequentialapproachis
required.
•E.g.forastudyofneurologicillnessfollowingDTPimmunization-
medicalrecordsofthesepatientsreviewedtoseeiftheymetthecase
definition.Foroutcomeswithinsidiousonsetlikemultiplesclerosis
sourcesofinformationneedtobecollected&analyzed.

28. 3)Analysis
•Thecasecrossoverorcaseseriesapproachesaregainingpopularity
invaccinesafetystudies
4)Bias
•Tominimizeitisbesttorelyondatasourcesthatgatherinformation
onoutcomesandvaccinesexposureindependently.

29. Thank You