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EbMC Squared CiC Research for Impact

9-Aug-2021

Re:UpdatedReportofUKYellowCarddataforCOVID-19vaccinesupto30thJune2021

Dr.JuneRaine,MedicinesandHealthcareProductsRegulatoryAgency

cc.:Dr.SarahBranch,MHRADirectorofVigilanceandRiskManagementofMedicinescc.:ProfessorAnthonyHarnden,JCVIDeputyChair,UniversityofOxfordcc.:CommitteeonHumanMedicinesChairandCOVID-19VaccinesBenefitRiskExpertWorkingGroupProfessorSirMunirPirmohamedMBChB(Hons)PhDFRCPFRCP(Edin)FBPhS,FFPM(Hon)FMedSci,DavidWeatherallChairofMedicine,UniversityofLiverpool,NHSChairofPharmacogenetics,DirectoroftheWolfsonCentreforPersonalisedMedicine,DirectoroftheMRCCentreforDrugSafetySciencecc.:Chemistry,PharmacyandStandardsExpertAdvisoryGroupChair,ProfessorYvonnePerrieBScHonsMRPharmSFAPSFSBPhDStrathclydeInstituteofPharmacyandBiomedicalSciences,UniversityofStrathclydecc.:ClinicalTrials,BiologicalsandVaccinesExpertAdvisoryGroupChair,andCOVID-19VaccinesSafetySurveillanceMethodologiesExpertWorkingGroupChairDrSirajMisbahMBBS(Hons)MScFRCPFRCPath,ConsultantClinicalImmunologist,LeadforClinicalImmunology,OxfordUniversityHospitals&ChairoftheClinicalTrials,Biologicals&VaccinesExpertAdvisoryGroup(CTBVEAG)&MemberoftheCommissiononHumanMedicines(CHM)cc.:ClinicalTrials,BiologicalsandVaccinesExpertAdvisoryGroupLayRepresentativeandPatientAdvocate,MrsMadeleineWangBA(Hons)cc.:InfectionExpertAdvisoryGroupChairandCOVID-19TherapeuticsExpertWorkingGroupChair,ProfessorJonathanSFriedlandMAPhDFRCPFRCPEFRCPIFESCMIDFMedSciDeputyPrincipal,St.George’s,UniversityofLondoncc.:InfectionExpertAdvisoryGroupLayRepresentative,MsHilaryAShentonCPFA.RetiredSecretarytotheSchoolofMedicine,UniversityofSheffieldcc.:COVID-19TherapeuticsExpertWorkingGroupandCHMLayRepresentative,MsSusanBradfordcc.:Neurology,PainandPsychiatryExpertAdvisoryGroupChair,ProfessorMalcolmRMacleodBScMBChBMRCPPhDFRCP(Edin)ProfessorofNeurologyandTranslationalNeurosciences,UniversityofEdinburghandHonoraryConsultantNeurologist,NHSForthValleycc.:PaediatricMedicinesExpertAdvisoryGroupChair,ProfessorStevenCunninghamMBChBPhDFRCPCHProfessorofPaediatricRespiratoryMedicine,UniversityofEdinburghandHonoraryConsultant,RoyalHospitalforChildrenandYoungPeople,UniversityofEdinburgh,Edinburghcc.:PaediatricMedicinesExpertAdvisoryGroupLayRepresentative,MsSaraPayneBACPELPC,Solicitorcc.:PharmacovigilanceExpertAdvisoryGroupChair,ProfessorJamieColemanMDMA(MedEd)FRCPFBPhSProfessorinMedicalEducation/ConsultantClinicalPharmacologist,UniversityofBirminghamcc.:PharmacovigilanceExpertAdvisoryGroupLayRepresentative–Patientadvocate,MrsMadeleineWang

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EXECUTIVESUMMARY1.TheMHRAhasstatutoryresponsibilityforundertakingpost-authorisationsafetymonitoringintheUKandoperatingatransparentprocess,summarisingsafetydatatothepublic.Itisrequiredtorapidlydetectnewside-effects,achangeinthenatureofknownside-effects,factorsthatincreasethechanceofhavingside-effectsandtakeanynecessaryactiontominimiserisktoindividuals,afterweighingrisksagainstexpectedbenefits.Suchactionscanincludeaddingwarningstoproductinformation,restrictingorsuspendingtheuseofaproductandcommunicatinginformationtohealthcareprovidersandpatients.

2.Bynotprovidingage-andgender-stratifiedsafetyinformation,norreportingdeathsorreactionsoccurringwithincertaintimeframesofvaccination(within12hours,24hours,48hours,1week,2weeks,etc.),theUKGovernment’sYellowCardsystemisnon-transparentandnotfit-for-purposeasanearlywarningsystem.Theseomissionsindatacollectionand/orreportingmeanthatbasicconclusionsaboutsafetycannotbedrawn.Consequently,thepublicandtrialparticipantsarenotfullyinformedofthepotentialrisksoftakingaCOVID-19vaccineandareunabletogivefullyinformedconsent.Thepublic,healthcareworkersandMHRA/CHMcannotrelyonthesystem’sreportingtorevealCOVID-19vaccinemortalityandmorbidity.AcomprehensiveoverhauloftheYellowCardsystemisrequired.

3.ClearsafetysignalscanbediscernedfromdatainsafetysurveillancesystemsintheUSandEU:

• DeathreportsperdoseofCOVID-19vaccinesareapprox.29timeshigherthanforinfluenzavaccines.

• ThehighnumberandrateofdeathreportscoupledwithatighttemporalrelationshiptovaccinationandtheinabilitytoruleoutavaccinereactionlendsweighttoacausalrelationshipbetweenCOVID-19vaccinationanddeath:in>65yearolds,80%ofasampleofdeathreportsoccurredwithin1weekofvaccination.

• At1per100,000injections,ratesofallergicreactionsare10timeshigherwiththePfizerandModernaCOVID-19vaccinesthanwithothertypesof(non-COVID)vaccine.

• Malesbelowtheageof65years,butespeciallyinyoungermalesi.e.12-17yearolds,areatincreasedriskofmyocarditiscomparedwithfemales.

• TheEuropeanMedicinesAgencyhasidentifiedGuillain-BarréSyndromeasapotentialriskfromtheAstraZenecaCOVID-19vaccineandisaddingawarningtotheproductinformationtocommunicatetohealthcareworkersandpatientsthat‘Vaccinatedpersonsneedtoseekimmediatemedicalattentioniftheydevelopweaknessandparalysisintheextremities,possiblyprogressingtothechestandface,aftervaccinationwithVaxzevria,asthesecouldbesignsofGuillain-BarréSyndrome’.

4.FollowingFreedomofInformationrequestsandanalysisofpublicempiricalevidenceintheUKwecandiscern:

• Deathreportratespermilliondosesareapproximately28timeshigherforCOVID-19vaccinesthanforinfluenzavaccinesintheUK.ThisunfortunatelydoesnotsupportMHRAstatementsthatthenumberofsuspectedadversedrugreactionssofarisnotunusualforanimmunisationprogrammeofthisscale.

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• TheCOVID-19vaccinesmayberesponsiblefortheCOVID-labelledmortalitythispastwinter(atleast24,000deaths)inEnglandandthatvaccinesareineffectiveinreducingmortality(weobservemoremortalitynotlesstwoweeksafterfullvaccination).Thisnumberofdeathsisclearlyfarhigherthanthe1,490deathsreportedtotheYellowCardsystem.

• COVID-19deathspermillionpopulationaresignificantlyhigherinthehalfofallcountriesgloballywithaboveaveragepercentageoftheirpopulationvaccinatedforCOVID-19.

• Realworlddata(fromScotlandandIsrael)provideevidenceofthelinkbetweenCOVID-19vaccinationandincreasesinCOVID-19cases.Morecasesareoccurringthanwouldhaveoccurredwithoutvaccinationandmostcasesareoccurringinthevaccinated.Ratherthanvaccinationprotectingthevulnerable,therefore,infact,theoppositeisapparent.Vaccine-associatedenhanceddisease,identifiedbeforerolloutasapotentialriskbyMHRA,appearstobeevidentandneedsfurtherinvestigation.

• Thepeaksindeathswithin28daysofvaccinationinScotlandcorrespondtovaccinationratesinpersons70yearsandoverhavingtheirfirstorseconddose.

• Callsforambulancesforcardiacandrespiratoryarrestandforpeoplefallingunconscious/syncopehaveincreasedabovebaselinesincetheshelflifeforthawedvialsofthePfizerCOVID-19vaccinewasincreasedfrom5to31days,followinganMHRAdecision,andsincerolloutstartedinunder30yearolds.Syncopeisoneofthepre-deathsymptomsnotedbyexaminationofUSAdeathreports.

5.OurreviewofpubliclyreporteddatafromtheUKGovernment’sYellowCardsystemraisesfurtherconcernsasfollows,thatwarrantfurtherinvestigation:

• Ofthe1,490deathreports,thereare482fatalitiesreportedas‘death’or‘suddendeath’withoutaspecificcauseofdeathreported.Suddendeathwouldbemostlikelytooccurfromhaemorrhagic,thrombo-embolicorischaemicevents.Withoutfollow-up,risksofspecificeventsfromtheCOVID-19vaccineswillbeunderestimated.

• RatesofanaphylaxiswithCOVID-19vaccinesintheUK(Pfizer,ModernaandAstra-Zenecavaccines)areestimatedtobe1.5per100,000injections.Thisrateisevenhigherthanthe(alreadyhighcomparedtopreviouslyusedvaccines)estimate(1per100,000)inUSforPfizerandModernavaccinesonly.

• Themanyneurologicalreactionsreportedaresuggestiveofneurodegenerativepathology.• Thenumberandwidespreadlocationofpainreports,thereportsofParoxysmalExtremePain

Disorder(PEPD)(excruciatingpainthatnormallyhasonsetininfancyorinutero,butwhichthroughaFreedomofInformationrequestisidentifiedasoccurringinadults)andlargenumbersofreportsofPEPD-likesymptoms(e.g.lossofconsciousness/syncope,flushing,eyepain,jawpain)maybesuggestiveofspurioussodiumchanneldepolarisation.

• Thereactivationoflatentviruses(e.g.herpeszoster/shingles)isstronglysuggestiveofvaccine-inducedimmunocompromise,asisthehighnumberofimmune-mediatedconditionsreportedincludingGuillain-BarréSyndromeandMultipleSclerosis.Compromisedimmunitypost-vaccinationmayhavecontributedtotheobservedincreasesinSARS-CoV-2infectionspost-vaccination.

• Therehavebeen469reports(and3fatalities)intheUKofinfectiveorinflammatorycardiacconditions,includingmyocarditis,endocarditisandpericarditis.TheUKpublicsafetysummariesdonotindicateinhowmanyoftheseindividualsthereactionhasresolved.Frommyocardititsreports

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totheEUsafetysurveillancesystemweobservethatnearlyaquarterofmyocarditiscasesareunresolved.

• AlthoughbeingidentifiedbyMHRAbeforevaccinerolloutasapotentialriskandbeingpartofpharmacovigilanceplansformonitoring,VaccineAssociatedEnhancedDiseaseandVaccineAssociatedEnhancedRespiratoryDiseaseappearnottohavebeenpubliclyreportedoninsafetysummaries.

6.Risk-benefitbalancedecisionsmayhavebeenbasedoninvalidvaccineimpactdata:avaccineimpactstudyestimatingdeathsavertedbythevaccineswasbasedonkeyassumptionsthatempiricalevidencerefutes.Therisk-benefitbalanceofCOVID-19vaccinesmustbeurgentlyre-assessedbyMHRA/CHM/CHMEAGsusingrealworldempiricalevidenceandassuminguseofknowneffectivetreatmentprotocols.To-date,risksfromCOVID-19vaccinesmaybeunderestimatedandexpectedbenefitsover-estimated.

Pendingfullfollow-upofdeaths,investigationofvaccinesafetyandefficacyandofvaccineimpact,andre-assessmentofrisk-benefitbalance,MHRA/CHM,inlinewithitsstatutoryobligations,mustacttominimiserisktoindividualsby:

• SuspendingtheCOVID-19vaccinesrolloutinallchildrenandadultsandanyplansforboostervaccinations.

• SuspendingenrolmentintrialsinUKofCOVID-19vaccines.• CommunicatingtohealthcareworkersandthepublicthepotentialriskofGuillain-BarréSyndrome

andthesymptomsforwhichpatientsshouldseekimmediatemedicalattention.• CommunicatingtohealthcareworkersandthepublicknowntreatmentprotocolsforCOVID-19

(acuteandlong)andforpost-vaccinationside-effects,includingCovidVaccination(CoVAC)Syndrome,sothatpeoplecanreceivetimelycare.

• ConductingacompleteoverhauloftheYellowCardsystem.

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DearDr.Raine,

Re:UpdatedReportofUKYellowCarddataforCOVID-19vaccinesupto30thJune2021

Thankyouforyourletterof22ndJuly2021,inreplytooururgentreportof9thJune2021regardingtheYellowCarddata.Wehaveupdatedouranalysiswithsuspectedadversereactions(ADRs)to30thJune2021,afternearly45millionpeoplehavereceivedtheirfirstdose,and33millionbothdoses(comparedto39millionand24million,respectively,inourlastreportto26thMay2021).

ThankyoualsoforthelinkstothestrategyfromtheCommissiononHumanMedicines(CHM)ExpertWorkingGrouponhowmonitoringofCOVID-19vaccinesafetyisbeingperformed(1),andfurtherinformationaboutCHM.Inthestrategy,wenote:

• ThatMHRAischargedwithoperatingatransparentprocessandprovidingregularup-to-datesummariesofthesafetyexperiencetothepublic.

• Theneedtoveryquicklybeabletoestablishifseriouseventsthataretemporallyrelatedtovaccinationaremerelycoincidentalassociation.

• ThatamongtheCHMresponsibilitiesare‘advisingontheimpactofnewsafetyissuesonthebalanceofrisksandbenefitsoflicensedmedicines–e.g.addingwarnings,restrictingorsuspendinguseofamedicine’.

• Thattoassesswhetherthereiscontinuedbenefit-riskbalance,inadditiontopost-marketingsafetyofvaccines,keyfurtherinformationisrealworldeffectivenessandpopulationimpactofthevaccines.

• ThatMHRAisrequiredtorapidlydetect,confirm,characteriseandquantifyanynewrisks–newside-effects,achangeinthenatureofknownside-effects,factorsthatincreasethechanceofhavingside-effects-andtakeanynecessaryactiontominimiserisktoindividuals,afterweighingrisksagainstexpectedbenefits.Suchactionmayincludeaddingwarnings,restrictingorsuspendinguseofamedicineorsendingcommunicationstohealthcareprovidersandpatients.

• Thatthemeansbywhichthestrategyiseffectedincludefourmainstrands:1)EnhancedpassivesurveillanceviatheYellowCardsystem,2)Datafroma20%sampleofGPpractices(CPRDAurumDataset),3)YellowCardVaccineMonitorand4)Epidemiologicalstudies.Thelatterthreemeanswouldnothoweverprovideparticularlyrapidinformation:theGPpracticedatareliesontimelyrecordinginGPITsystemsofvaccinationsgivenandofdiagnosesforillness,whicharelikelydelayedwithvaccinationsbeinggivenbyexternalvaccinationcentresandpatientsfindingitdifficulttoobtainappointmentswiththeirGPpreventing/delayingdiagnoses;theYellowCardVaccineMonitor,althoughimportant,isusedinspecificpopulationsunder-representedintrials,andwillnotencompass/generatedataofrelevancetothewholepopulation;andepidemiologicalstudieswillonlybeappliedtoprovideevidenceaboutspecificrisksandwilltaketimetoconduct.Engagingwith

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academia1isnotedasanothermeansofmonitoringsafetybyenablingtherapidconductofepidemiologicalstudiesinOpenSAFELY17:wenotehoweverthattheyasyethavenotpublishedanyvaccinesafetystudiesontheassociatedwebsite2.

Itwouldseemthatfromastrategicviewpoint,therefore,themostrapidsystemavailablecurrentlyistheYellowCardsystem.

Youlinkalsotodataontheimpactofthevaccinationcampaigninreducinginfectionsandmortality.ThereportbyPublicHealthEngland(PHE)andCambridgeUniversity’sMedicalResearchCouncilBiostatisticsUnitcoveringdatato19June2021infersreductioninmortalityof27,200peopleasaresultofthevaccinationcampaign(2).Wenotethatanumberofassumptionshavebeenmadeintheiranalysis:

1)ThatthevaccineisassumedtoreducesusceptibilitytoCOVID-19,andtoreducemortalityonceinfected.Weareunsurewhysuchassumptionshavebeenmadewhenempiricalevidenceisavailable,andinlightoftheCHM’srecognitionofthekeyimportanceofrealworldeffectivenessdata.

2)Thatintheno-vaccinationscenarionootherinterventionsareimplementedtoreduceincidenceandmortality.Weareuncertainwhysuchanassumptionwouldbemadewhentreatmentprotocolsareavailablethatareknowntosignificantlyreducemortalityandthathaveunparalleledsafetyprofile,e.g.ivermectinreducesmortalityby62%comparedtonoivermectin,averageriskratio0.38,95%confidenceinterval0.19–0.73;n=2438;I2=49%;moderate-certaintyevidence(3).

Youindicatedtheimportanceofevaluatingreportsalongsideevidencefromothersources,sowediscusstheupdatedYellowCarddatabyreferencetootherpharmacovigilancesources,literatureandanalyses.

1.DeathratesfollowingCOVID-19vaccinationaresubstantiallyhigherthanwithpreviousvaccines

Asof14thJuly,therehavebeen1,490deathsreportedpost-vaccinationwiththeCOVID-19vaccines.Thisconstitutes237moredeathssinceourlastreportwhenwerequestedahalttotherollout.

WeareawareYellowCardreportsdonotnecessarilyimplycausality,asindicatedinourpreviousreport.TheMHRAitself,however,statesthatthepurposeoftheYellowCardsystemistobean1PHEandtheHealthProtectionResearchUnitinImmunisationattheLondonSchoolofHygieneandTropicalMedicine(LSHTM)2https://www.opensafely.org/

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earlywarningsystemthatamedicine’ssafetymayneedfurtherinvestigation3and,whenurgingdoctorstoreportside-effects,youhavebeenquotedasindicatingthat“Thereisnoneedtoprovethatthemedicinecausedtheadversereaction,justthesuspicionisgoodenough”.4

With1,490deathsnowreportedpost-vaccinationwiththeCOVID-19vaccines,thesevaccinesareclearlylesssafethanvaccineswehavehithertoknown.

Yousuggestinyourletterthat‘someeventsmayhavehappenedcoincidentally’andthatthisis‘particularlythecasewhenmillionsofpeoplearevaccinated’.Thehighnumberofdeathreportscannotunfortunatelybeexplainedbythelargescaleofrollout.IfwecomparedeathreportratesfollowingCOVID-19vaccineswiththosefollowinginfluenzavaccines,datafromtheUSA(VaccineAdverseEventReportingSystem(VAERS)andv-safereports)suggestsdeathspermillionvaccinationswiththeJ&JCOVID-19vaccinein2021were55-110timesgreaterthanwithinfluenzavaccineinthe2016-2019timeperiod(11.0deathspermillionwiththeformer(4)vs0.1-0.2deathspermillionwiththelatter).

TheJ&JvaccineisnotusedintheUKclearly.FollowingaFreedomofInformation(FoI)request,dataforCOVID-19vaccinesusedintheUKarealsoavailable.Fatalitiesreportedpost-COVID-19vaccinetoMHRAareshowntobe169timesmoreinnumberthantheaverageforfatalitiesreportedtoMHRAoverthelast10yearsforallothervaccines5.WhenoneconsidersthatthenumberofseasonalinfluenzavaccinationsgiveninadultsbetweenSeptember2019andMarch2020inEnglandwas11,974,864,i.e.approximatelyonesixthofthenumberofCOVID-19vaccinationsgivento-date,thiswouldimplythattherateoffatalitiesperdoseadministeredintheUKwasintheorderofupto28timeshigherwiththeCOVID-19vaccinesthanwithinfluenzavaccines.6

SimilarevidenceisavailablefromtheUSA:McLachlanetal.2021(5)reportthatvaccinedosesperVAERSdeathreportforinfluenzavaccinationwere7.3milliondosesperdeathreportin2017,reducingto2.3millionperdeathreportin2020,correspondingtoanincreasefrom0.1deathreportspermilliondosesin2017to0.4suchreportspermilliondosesin2020.Bycontrasttherewere7.4deathreportspermilliondosesofCOVID-19vaccinesreportedtoVAERSinthefirstthreemonthsof2021(5).Comparingthisratetoanaverageforinfluenzabetween2017and2020of0.25deathreportspermilliondoses,suggests,againthattherateoffatalitiesperdoseofCOVID-19vaccinesintheUSAisapproximately29timesthatofinfluenzavaccines.Theauthorsestimatedatthetimeofwritingthatifthattrendcontinuedatleast6,500deathscouldbereportedbytheendof2021.Wenotethat6,985deathshadalreadybeenreportedtoVAERSasofJune25th2021.3https://yellowcard.mhra.gov.uk/the-yellow-card-scheme/4https://www.theguardian.com/society/2006/may/12/health.medicineandhealth5Source:JoelSmalleylettertohisMP,appendedtothisletter,followingaFreedomofInformationrequest6Assumingthatfatalityrateswithinfluenzavaccinesaresimilartotheaveragerateforothervaccines.

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Thisseemsnottoconcurunfortunatelywiththestatementinyourletterthat‘thenumber…ofsuspectedADRsreportedsofarisnotunusualforanimmunisationprogrammeofthisscale’.

ComparingratesofdeathreportsfollowingthenewCOVID-19vaccinestoratesofdeathreportedinpreviousvaccinationcampaignsprovidesinformationrelevanttoestablishingasafetysignal.YetinresponsetoanotherFoIrequest7,whenaskedtoprovideevidenceforyourstatementthatthenumberandnatureofYellowCardsreportedwiththenewCOVID-19vaccineswasnotunusual,yourresponsewas,“PriortostartingtheCOVID-19vaccinationprogramme,informationfrompreviousUKvaccinationprogrammeswasusedtohelptheMHRAestimatetheanticipatedvolumeofYellowCardreports.However,theincidentnumbers,includingfatalreportsfrompreviousvaccinationcampaigns,arenotbeingusedasacomparativemeasureforthedatainthesummaryreport."Insoanswering,notonlyhasMHRAnotprovidedthefiguresrequestedinthisparticularFoIrequest,butMHRAhasalsodemonstratedthatitisnotoperatingatransparentsysteminpreparingitssummaryreporttothepublic.

2.ThetighttemporalrelationshipbetweenCOVID-19vaccinationanddeathsuggestscausation

AlthoughtheYellowCardsystemdoesnotappeartosystematicallyrecordthetimesincevaccination,theVAERSintheUSAdoes.Fromthatsystemitisapparentthatsporadiceventreportingishighinnumber,asintheUK,andthatthereisatighttemporalrelationshipbetweenCOVID-19vaccinationanddeaths:15%ofdeathsoccurringwithin24hrs,22%within48hrsandin37%ofdeaths,thepatientbecameunwellwithin48hrsofCOVID-19vaccinationwithaneventthatledtotheirdeath.

FurtherweighttocausalityisprovidedbyadetailedanalysisbyclinicallytrainedreviewersofasampleofVAERSdeathreports(n=250outofthe1644deathsinUSAreportedtoApril2021,themajorityofwhich(67%)werereportedbyhealthcareprofessionals).ThedeathsanalysedfollowedanalmostequalnumberofPfizerandModernaCOVID-19vaccinations,and91%ofdeathsoccurredafteradministrationofthefirstCOVID-19vaccine.Theyreportedthatinonly14%ofthedeathscouldavaccinereactionberuledoutasacontributingfactorinthedeath(5).In203/250deaths(81%)thevaccinemayhavebeenafactorinthedeath,andin13/250deaths(5%)thevaccinewasconsideredthemostlikelycauseofdeathasthedeathoccurredeitheronthesamedayorwithinacoupleofdaysofvaccinationafterastrongreactionsoonaftervaccination(5).Theynotedthatinahighnumberofvaccinerecipientsthedescriptionoftheirpost-vaccineandpre-deathsymptomsincludedsyncope(lossofconsciousness,fainting).Inthoseaged65yearsandover,9%diedwithinonly6hoursofvaccination,18%in<12hours,36%diedbeforethefollowingday,50%diedwithin48hours,80%within1week,90%within2weeksand100%within4weeks(5).Thetimecourseofemergenceofdeathsduetodifferentcauseshasalsobeennoted,withdeathsduetoallergicreactionsoccurringbetween30minutesand4daysofreceiving

7FromStephenFeldman

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vaccination,deathsduetorespiratorydistress+/-pneumoniasymptomsbetweendays2and9,anddeathsduetoacardiacevent(myocardialinfarct,heartattack)occurringbetweendays5and14(5).

Thehighnumberofsporadicreportscoupledwithatighttemporalrelationshipandtheinabilitytoruleoutavaccinereactionlendsweighttoacausalrelationshipandprovidesasafetysignal,warrantingsuspensionoftheCOVID-19vaccinespendinganindependentexpertinvestigation.

• WhyisthisclearsafetysignalnotbeingacteduponbyMHRA?

Evenifonly5%ofthe1,490deathsreportedtoMHRAto-datewerecausallylinkedtovaccination,thiswouldmean74deaths.ThelastemergencyuseauthorisedvaccineintheUK,forswineflu,wassuspendedafter50deaths.

Inassessingtherisk-benefitratio,theMHRAandCHMmayhaveconsideredthatthenumberofdeathsreportedlabelledas‘COVID-19’andtheestimateddeathsavertedfromtherecentvaccineimpactstudy(2)warrantedcontinuationofthevaccinerollout.However,intheUK,thereareseriousconcernsastothevalidityofthecasedefinition,thetestingsystem,theoperationaltestperformancecharacteristics(orlackthereof),theanalysisofPCRtestsregardingcyclethresholdusedandnumberandlocationofprimers/probesandoftherecordingofdeaths(6),alongsideconcernsastothevalidityoftheassumptionsusedinthevaccineimpactstudy.Thisbringsintoquestionthevalidityofthe‘COVID’riskdataand‘deathsavertedbyvaccinesdata’generatedandsubsequentlyusedtoinformrisk-benefitcalculations.

Therisk-benefitratioestimationsneedtobeurgentlyrevisitedbyMHRA/CHM/CHMExpertAdvisoryGroups(EAGs)andindependentexperts.

3.Deathswithin28daysofCOVID-19vaccination

Withregardtoourquestionof‘Howmanypeoplehavediedwithin28daysofvaccination?’,yourletterdidnotrelateanyspecificnumbers.WeappreciatethatthedatareportedtoMHRAwillnotgivethefullpictureofalldeathswithin28daysofCOVID-19vaccinationasnotallreportswillreachMHRA.However,ofthosethatdo,thesystemformonitoringpost-vaccinesafetydatashouldbeabletoindicate,inatimelymanner,time-to-eventdata,asthesearecriticalsafetyindicators,withoutwhichcausalitycannotbegauged.

YouhaveindicatedthatalthoughthetimesincevaccinationisnotalwaysprovidedinYellowCardreports,forreportsoffatalities,wherepermissionisprovided,theMHRAfollowsupinordertoascertainthelengthoftimesincethedeceasedreceivedthevaccine.Wewouldask,therefore,ofthe1,490post-vaccinationdeathsreportedviatheYellowCardsystemto-date;

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• Forhowmanyofthese1,490deathsdoesMHRAhavepermissiontofollowupandhowmanyhasMHRAfollowedup?

• Forhowmanyofthese1,490deathsdoesMHRAhavethedateofvaccinationanddateofdeathordateofonsetoftheeventleadingtodeath?

Youstateinyourletterof22ndJuly2021that‘wehaveinplaceaproactivestrategytocontinuallymonitorthesafetyofCOVID-19vaccines,andthroughthisstrategyweareabletorapidlydetect,confirm,andquantifyanynewrisksandweightheseagainsttheexpectedbenefits.’

• HowcantheriskassociatedwiththeCOVID-19vaccinesberapidlymonitoredbyMHRA–orindeedbytheCHMoritsEAGs-whenthedateofvaccinationisnotreadilyavailabletoenabledeathsandsuspectedADRsoccurringwithincertaintimeframesofvaccinationtobemadepubliclyavailable?

• Eventsoccurringinclosetemporalrelationshiptovaccinationlendweighttocausality.HowcanMHRAassesscausalitywithoutsuchcriticalinformationinatimelyfashion?

• And,subsequently,howcanpeoplemakeaninformeddecisionaboutwhetherornottakingaCOVID-19vaccineisrightforthemortheirdependentswithoutadequate,age-andgender-stratifiedandtimelyinformationaboutthepotentialrisks?Age-andgender-stratifieddataandtime-to-eventdataarenotmadeavailabletothepubliccurrently,asshouldbethecaseinatransparentearlywarningsystem.

WenotethatVAERShasaStandardOperatingProcedure(SOP)formonitoringofADRreportsspecificallyforCOVID-19vaccines(7),whichalsohighlightsAdverseEventsofSpecialInterest(AESIs)forfollow-up.AESIsincludedeath,COVID-19disease,Guillain-BarréSyndrome,seizure,stroke,narcolepsy/cataplexy,anaphylaxis,vaccinationduringpregnancy,acutemyocardialinfarction,myopericarditis,coagulopathy(includingthrombocytopenia,disseminatedintravascularcoagulopathy,anddeepvenousthrombosis),Kawasaki’sdisease,multisystemicinflammatorysyndromeinchildren(MIS-C),multisystemicinflammatorysyndromeinadults(MIS-A),transversemyelitis,BellsPalsy,andappendicitis.Table1indicatesADRsreportedfortheseAESIsintheUK.

Table1-ADRreportstoUKYellowCardsystem(upto21stJuly2021–Week26)forAdverseEventsofSpecialInterestidentifiedinUSVAERSStandardOperatingProcedureforCOVID-19vaccinessafetymonitoring

AESIterm ADRs Fatalities

Death - 1,517Acutemyocardialinfarction 89 13Myocardialinfarction 536 77Anaphylaxis(anaphylacticshock/reaction) 1,194 4Appendicitis(includingappendicitis,noninfectiveappendicitisandappendicitisperforated)

67 0

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AESIterm ADRs Fatalities

Bell’spalsy 879 0Coagulopathy -Deepveinthrombosis(DVT) 1,299 10-Disseminatedintravascularcoagulopathy(DIC) 19 2-Thrombocytopenia(excludingimmunethrombocytopenia) 1,018 7COVID-19disease(excludingasymptomaticCOVID-19andsuspectedCOVID-19)

1,529 79

GuillainBarreSyndrome 407 2Kawasaki’sdisease 0+ 0Multisystemicinflammatorysyndrome(Systemicinflammatoryresponsesyndrome)

7 0

Myocarditis(incl.myocarditis,infectiousmyocarditis,viralmyocarditis) 237 2Pericarditis 281 1Narcolepsy/catolepsy 24 0Seizure(alltypes) 1,948 2Stroke(excl.cerebralvenoussinusthrombosis) 1,713 76-cerebralvenoussinusthrombosis 225 26Transversemyelitis 102 0Vaccinationduringpregnancy(exposurebefore/duringpregancy,foetal/maternal/paternal)*

956 -

Abbreviations:AESI,adverseeventofspecialinterest;excl,excluding;incl.,including+Note,however,thatswollenlymphglands/lymphadenopathy,asymptomofKawasaki’sdisease,wasreportedin12,339ADRreportsandswollentongue,anothersymptom,in996ADRreports.*Spontaneousabortionswerereportedin381reports,ofwhich3werefatal.Therewasalso1haemorrhageinpregnancyreported.

WenotealsothegeneralGuidanceforIndustryfromtheFDAthatdiscussessafetysignals(8).

• PleasecouldyouprovideacopyoftheMHRA’sSOPformonitoringCOVID-19vaccinesuspectedADRs,andindicatehowfollow-upofdeathsand,ifdone,otherAESIs,isconductedandinwhattimeframes?

IftheYellowCardsystemcannotprovidetimely,age-andgender-stratifiedtime-to-eventinformation,astheVAERSinUSAallows(notwithstandingothercallsforVAERStobeimprovedalso),wemustaskourselves,honestlyandopenly,thedifficultquestionofwhethertheUKYellowCardsystemisadequateindesignand/orexecutiontosatisfyitspurpose–asanearlywarningsystem.ThedifferenceintransparencyandcontentbetweentheUSandUKsystemshasbeenhighlightedbyMcLachlanetal.2021(5),whoindicatethatthesparsityofdataintheUKsystemdoesnotsupportmeaningfulresearch,norallowbasicconclusionstobedrawn.

MHRAisnotcurrentlyablethroughtheYellowCardSystem’sset-uptooperateatransparentprocess.Acompleteoverhaulofthesystemisrequired.

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Intheunprecendentedsituationfaced,oflargenumbersofsuspectedADRreportsfromproductswithonlyanEmergencyUseAuthorisation(EUA),itwouldbeunderstandablethatourcountry’ssystemsmightbestrainedbeyondtheirusualcapacity.Acknowledgingthisthreattothesystem’sabilitytoachieveitspurposewouldbebothadmirableandhonourable,alongsideactionthatmitigatedpublicrisk,namelysuspendingtherolloutandEUAspendingfurtherinvestigationandfullfollow-upofalldeathsandAESIs.

Scotland–deathsforanyreasonwithin28daysofCOVID-19vaccination

PublicHealthScotland(PHS),followingFoIrequests,hasreportedthat5,522peoplehavediedforanyreasonwithin28daysofCOVID-19vaccinationinScotlandbetween8thDecember2020and11thJune2021(ModernaCOVID-19vaccine2;Pfizervaccine1877;Astra-Zenecavaccine3643)(9).Althoughprovidingabreakdownbydateofdeath,thepublishedreportandassociatedspreadsheetsstilldonotallowknowledgeofdeathswithindifferenttimeframesofpeoplehavingbeenadministeredavaccine,sotheyprecludecausalityassessment.However,thebelowgraph8showsthatthenumberofdeathswithin28daysofCOVID-19vaccines(n=5522(9)inblue)nowexceedsthosewithin28daysofaPCR+testthatareascribedtoCOVID(n=5,220)(Figure1).

8Source:DataanalystJoelSmalley

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Figure1–COVID-19Deathswithin28daysofPositivePCRTestandwithin28daysofCOVID-19Vaccine,Scotland

Thisgraphelucidatesanumberofotherphenomena:

1)Doctors9arereportingaCOVID-likesicknessemergingafterreceivingvaccine(deathswithin28daysPCR+post-vaccination=3,057intheabovegraph),thedistributionofwhichisverydifferentfromnaturallyoccurringCOVIDinfection(deathswithin28daysPCR+pre-vaccination=2,165).SeealsonextsectiondiscussingcorrelationbetweenvaccinationandoccurrenceofCOVIDcases.

2)Thepeakofdeathswithin28daysofthefirstdoseofCOVID-19vaccines(blueline,4,098deaths)coincideswithalmostallpersons70yearsandoverhavingreceivedtheirfirstdose(Figure1a,page9ofPHS2021b(10)).

3)Thepeakofdeathswithin28daysoftheseconddoseofCOVID-19vaccines(blueline,1,424deaths)correspondstoalmostallpersons70yearsandoverhavingreceivedtheirseconddose(Figure1b,page10ofPHS2021b(10)).

9Forexample,Dr.PeterMcCullough

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Theseobservationssuggestthat,althoughdeathsforanyreasonwithin28daysofCOVID-19vaccinesupto11thJune2021didnotappeartoconstituteexcessmortalitywhencomparedtoexpecteddeathsaccordingtopreviousyearsbyPHScalculations(9),deathswithin28daysofCOVID-19vaccinesdocorrelatewithvaccinesbeingreceivedinthoseaged70yearsandabove,withdeathsincreasingasvaccinationproceedsinthe>70s.

Furthermore,deathsforanyreasonwithin28daysofCOVID-19vaccinesdonotappeartohavebeencomparedtodeathsforanyreasonintheunvaccinatedoverthesametimeperiods(i.e.from8thDecember2021)byPHS.ThelaterPHSreportcomparingvaccinated(1dose,2doses)andunvaccinatedcohortsdidsofrom29thDecember2020onwards,meaningthatdeathsamongthefirst(mostelderlycohortreceivingthefirstdose)vaccinatedbetween8thDecemberand29thDecembermaynothavebeenaccountedforinthisparticularcomparison(10).Theselectionofthe29thDecember2020datewasbasedonefficacygrounds,i.e.withvaccinationeffectexpectedtooccurthreeweeksafterreceiptofvaccination.Theselectionofthisdateisunhelpfulwhenconsideringsafety,however,asweknowfromthesampleofdeathsexaminedbyMcLachlanetal.2021that90%ofdeathreportsinover65yearoldsdiedwithin2weeksofvaccinationand80%within1week(5).

Overall,thislackoftransparencyandlackofinterrogationofthedatabyanumberofdifferentmethodspreventsadequateassessmentofpost-marketingsurveillanceofCOVID-19vaccinesinScotland.

England–deathsforanyreasonwithin28daysofCOVID-19vaccination

WeunderstandthatPublicHealthEngland,inresponsetosimilarFoIrequests,statesthattheydonotholdtheinformationondeathswithin28daysofCOVID-19vaccination.

Again,thisdemonstratesalackoftransparencyandobfuscatesadequateassessmentofpost-marketingsurveillanceofCOVID-19vaccines.

4.IndependentexpertanalysisshowsCOVID-19vaccinesmayberesponsiblefortheCOVID-labelledmortalitythispastwinter,December2020-March2021

MortalityinEnglandandScotlandhas,however,beenextensivelyandcarefullyanalysedbyagecohortbytheindependentdataanalyst,JoelSmalley.Weappendhisanalysis,sentasanopenletterof16thJuly2021tohisMemberofParliamentandprovidekeygraphsbelowshowinghowdeathsin80+yearoldsandcarehomecohortstrackCOVID-19vaccinationratesineachparticularcohort(Figure2forEngland,Figure3forScotland).

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Figure2–COVID-19VaccinationsandDeaths,in80+yearolds,inCareHomes,andOverall,England

Figure3–COVID-19VaccinationsandDeaths,in80+yearoldsandinCareHomes,Scotland

Heindicatesthatthe‘evidenceinthepublicempiricaldatapointstowardsCOVIDvaccinesnotonlybeingineffectiveinreducingmortalitybutalsobeingresponsiblefortheCOVID-labelledmortalitythispastwinter’,andthat,‘InEngland,thedeathsreducedbyCOVIDvaccinesiszero.ThedeathscausedbyCOVIDvaccinesisatleast24,000.’

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Heindicatesthatthemostplausibleexplanationisthat‘vaccinationincreasesthesizeofthesusceptible/vulnerablepopulationandisresponsibleforthemajorityofdeathsinthewinterGompertzdistribution’inEnglandlastwinter.OuranalysisoftheYellowCarddata,withover65,000immunesystemADRsindicativeofimmunosuppression,supportsthisexplanation,asdostudies–includingtheoriginalPfizerstudy-reportingincreasedinfectionsimmediatelypost-vaccination.10Thus,theoccurrenceofantibody-dependentenhancement(ADE)orpathogenicpriming,wherebydiseaseisenhancedinthevaccinated,withtheCOVID-19vaccinesappearsnowtobeevident.

WeunderstandfromMHRA’sProductAssessmentReport(PAR)ofthePfizerCOVID-19vaccine,BTN162b2(11),thatthisvaccine-associatedenhanceddisease(VAED)wasalreadyidentifiedasanimportantpotentialrisk11,alongwithvaccineassociatedenhancedrespiratorydisease(VAERD),andthatVAEDandVAERDwereearmarkedforfurtherinvestigationinthepharmacovigilanceplan.SimilarriskswereidentifiedandpharmacovigilanceplansmadeinthePARfortheAstraZenecaCOVID-19vaccine(12).

• PleaseprovideareportontheinvestigationsperformedandresultsobtainedunderthesepharmacovigilanceplanstomonitorVAEDandVAERDinPfizerandAstraZenecaVaccines.

• HavePfizerandAstraZenecaprovidedfurtherinformationonVAEDandVAERD?Ifnot,whynot,whentheywereidentifiedaspotentialrisksthatshouldbemonitored?

WeunderstandthattheseimportantquestionshavealreadybeenaskedoftheMHRA24-Jun-202112butthat,sixweekson,theMHRAhasstillnotprovidedanswers.Dr.EnglernotesinhisemailtoMHRAthat‘itisofgraveconcernthatwemaybestartingtoseesomesoftsignalsoftheenhancementtheMHRAitselfraisedasaconcern’,as‘double-vaccinatedCovidpatientsarecurrentlyoverrepresentedinICUs’seriouslyillwithCOVIDand‘asmallbutrisingnumberofdeathsarebeingobservedinthosefullyvaccinated’.Dr.Englerfurthernotesthat‘thedataishardtointerpretduetolackofage-stratificationandotherdetails’.Again,thisnon-transparencyintheYellowCardsystemputsthepublicatrisk.

10https://www.bmj.com/content/372/bmj.n783/rr11‘Vaccineassociatedenhanceddisease(VAED)includingVaccineassociatedenhancedrespiratorydisease(VAERD)hasbeenincludedasapotentialrisk.ThisisatheoreticalriskwhichisrelevanttoallCOVID-19vaccinesbasedonVAEDhavingbeenseeninanimalmodelsforvaccinesdevelopedforSARS-CoV-1(asimilarbutnotidenticalvirustoSARS-CoV-2,thevirusresponsibleforCOVID-19)andalsoseeninassociationwithuseofanotherrespiratoryvirusvaccine,theRespiratorysyncytialvirus(RSV)vaccine.Thereiscurrentlynoevidencefromnon-clinicalorclinicaldataofanassociationofVAED/VAERDwithCOVID-19mRNAVaccineBNT162b2;thispotentialriskwillbefurtherinvestigatedaspartofthepharmacovigilanceplanofthisvaccine.’11.MHRA.PublicAssessmentReport.AuthorisationforTemporarySupply.COVID-19mRNAVaccineBNT162b2(BNT162b2RNA)concentrateforsolutionforinjection.;2021aJune.12EmailfromDrJonathanEnglerof24-Jun-2021toMHRACustomerServices@mhra.gov.ukwithSubjectheading‘CSC56062VaccinesforCovid19’,whichwasreportedlypassedontoMHRA’sVigilanceRiskManagementofMedicinesexperts.

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• PleasecouldyouindicatewhyMHRAissilentinrelationtofurtherdata/analysisontheseimportantsafetyissues?

• PleasecouldyouindicatewhyMHRAhasnotactedtosuspendtheCOVID-19vaccines–inlinewithitsstatutoryobligationtominimiserisktoindividuals–whenMHRAknowsthereisapotentialriskofVAEDandVAERD,whentemporaryauthorisationsofCOVID-19vaccinesaredependentuponfurtherriskevaluationunderpharmacoviglanceplans,andsignalsatmacro-andon-the-groundlevelssuggestthattheVAED/VAERDconcernscouldbevalid?

Theevidenceforclaimingthatthevaccinesareineffectiveinreducingmortalityisprovidedbythefactthatwedonotobserve–intheempiricaldata-lowerthanexpectedmortalitytwoweeksafterfullvaccinationandthat,infact,moremortalityisobserved,althoughonasmallerscalethanafterthefirstdose.Fromthisempiricalevidencewecanseetheerrorinthevaccinationimpactreport(2)-thathasnodoubtunderpinnedrisk-benefitcalculations-thatassumedthatthevaccinewouldreducesusceptibilitytoCOVID-19andreducemortalityonceinfected.

Inviewoftheevidenceprovidedbythisanalysis,wewouldagainurgentlyrequestthattheCOVID-19vaccinesbesuspendedpendinginvestigation.

Furthersupportiveevidenceofvaccinationbeinglinkedtohigherdeathratescanbeobservedatthegloballevel.

Figure4showsCOVID-19deathspermillionbeforeandaftervaccinationsaggregatedacrosscountriesgloballyaccordingtothepercentagesoftheirpopulationsvaccinated13.Thebluelineseriesisaggregateddeathratesinthehalfofcountrieshavingaboveaveragevaccinatedpopulations(beforeandaftervaccination),theredlineseriesthatforthosecountrieshavingbelowaveragevaccinatedpopulations(beforeandaftervaccination).AsJoelSmalleypointsout14:

• COVID-19deathratesaresignificantlyhigherinthosecountrieswithaboveaveragevaccinatedpopulations.

• Incountrieswithbelowaveragevaccinatedpopulations(redline)thedeathrateonlyspikeswhenthepercentageofthepopulationvaccinatedexceeds1%(i.e.fromMarch2021).

13Source:JoelSmalley14Source:https://twitter.com/RealJoelSmalley/status/1424019692742656003?s=20

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Figure4–AggregatedCOVID-19deathspermilliongloballyaccordingtothepercentageofthepopulationvaccinatedforCOVID

5.IncreasesinCOVID‘cases’arelinkedtovaccinationrollouts

Scotland

ManycountriesarereportingcorrelationbetweenvaccinationratesandCOVID‘cases’.

IfweexaminethesedataforScotland,thecorrelationbetweenthe‘recentincreaseinvaccinationrateof18-29yearoldsandcasesofallages[orcasesin15-24yearolds]cannotbedismissedascoincidental’15.Figures5and6showthisclosecorrelation16.

Thesedatareflectreportsfromclinicians(e.g.leadingcardiologist,Dr.PeterMcCullough,MD,MPH,ProfessorofMedicine)ofCOVID-likeillnessoccurringinpeopleaftertheirreceivingCOVID-19vaccines.

15Source:JoelSmalley16Source:JoelSmalley

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Figure5–COVID-19‘Cases’inallagegroupsandNumbersVaccinated(18-29yearolds),Scotland

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Figure6–COVID-19‘Cases’in15-24yearoldsandNumbersVaccinated(18-29yearolds),Scotland

Israel–irrefutableevidenceoflinkbetweenvaccinationrolloutandincreaseinCOVID

AllvaccinationinIsraeliswiththePfizer/BioNTechvaccine.ThesedataarefromJoelSmalley,independentdataanalyst17.

Figure7showsCOVID-19casesintheover60sinIsrael.ThemodelledobservedCOVID-19cases(solidblackline)isfittedtotheobserveddatausingasimplemodelassumingexponentialdecay.Thefewestseriesbetween21-Nov-2020and29-May-2021was3(dottedlines).ThefirstoftheserepresentsthemodelledcaseswithnaturalCOVID,thesecondcasesfromthefirstdosewiththe

17https://twitter.com/RealJoelSmalley/status/1422941794476699651?s=20

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Pfizer/BioNTechvaccine(rolloutstarted19-Dec-2021inIsrael)andthethirdseriescasesfromtheseconddose.

Figure7–COVID-19casesinover60yearoldsinIsrael

Figure8belowshowsthemodelledfirstseries(dottedline)andobservedcasedata(solidline)fortheunvaccinated.

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Figure8–ModelledandobservedCOVID-19casesinover60yearoldsinIsraelinunvaccinated

Figure9belowshowsthemodelledsecondandthirdseries(dottedlines)andobservedcasedata(solidline)forthevaccinatedfortheirfirstandseconddoses.

Figure9–ModelledandobservedCOVID-19casesinover60yearoldsinIsraelinthevaccinated

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Figure10belowshowstherehavebeenapproximately19,000morecasesthanwewouldhaveexpectediftherehadbeennovaccinations.

Figure10–ModelledandobservedCOVID-19casesinover60yearoldsinIsraelintheunvaccinated(green)andvaccinateddoses1and2(red)

Figure11belowindicateshowthisincreaseincaseslastwinterfollowingvaccinationhasnotresulted,unfortunately,withfewercaseslateronandthat,comparingtheseriesstartinginJune2021withthesameperiodlastyear,itislikelythattherewillbeapproximately10%morecasesoverallandmostcasesareoccurringinthevaccinated.Thevaccinetrialsneverclaimedtoreducetransmission.18ThedatafromIsraelshowthattherearemore,notfewer,casesoverall,followingvaccination,soratherthanvaccinationprotectingthevulnerable,infact,theoppositeisapparent.

18‘Thevaccinetrialshavenotbeendesignedtomeasurereductionintransmissionriskfrominfectedvaccinatedindividualstosusceptiblecontacts’:https://www.ecdc.europa.eu/sites/default/files/documents/Risk-of-transmission-and-reinfection-of-SARS-CoV-2-following-vaccination.pdf

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Figure11–Modelled(blackline)andobservedCOVID-19cases(blue)inover60yearoldsinIsraelintheunvaccinated(green)andvaccinated(red)intheJune-Octoberperiodin2021vs2020

Overallthecasefatalityrate(CFR)inover60sinIsraelfortheDecember2020-May2021periodis6.6%,slightlyhigherthanthe6.3%observedfromdatapriortoNovember2020.Withtheincreasedcases,however,thissuggestsvaccinesaredirectlyresponsibleforanadditional1,200deathsoutofatotalofapproximately3,000.

6.ImmunesystemreportedADRs(infections,inflammation,immunesystem,allergicresponses)

To30thJune,atotalof65,312ADRsand197fatalitiesfellintothiscategory(Table2),comparedwith54,870ADRsand171fatalitiesasof26thMay.Thisrepresentsafurther10,442immunesystemADRreportsandafurther26fatalitiessinceourlastreport.

Allergicresponsestothevaccinescomprised29,956ADRsand5fatalitiesto30thJune(comparedwith25,270ADRsand4fatalitiesuptoMay26th).Klimeketal.2021(13)havereviewedhowthecontentsofCOVID-19vaccinesdifferfromothertypesofvaccineandhighlightedtheallergicpotentialofliposomes,polyethyleneglycol,tromethamine/trometamol,andmRNA.TheyindicatethatanaphylaxiswiththePfizerandModernavaccinesisoccurringatarateofapproximately1per100,000injectionsandthatthisisapproximately10-foldhigherthanwithothertypesof(non-COVID-19)vaccines(13).IntheUKYellowCarddata,therehavebeen1,194casesofanaphylaxis(4fatalities),equatingtoapproximately1.5casesofanaphylaxisper100,000injections.

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Many‘INFECTION’categoryADRsindicatedtheoccurrenceofre-activationoflatentviruses,includingherpeszosterorshingles(2,499ADRsasofJuly7thvs1,827suchADRsMay26th)andopthalmicherpeszoster(13ADRs).Thisisstronglysuggestiveofvaccine-inducedimmune-compromise.ReactivationofherpeszosterandopthalmicherpeszosterhasalsobeenobservedafterthePfizerCOVID-19vaccineinacaseseriesfromIsrael(14).

Alsosuggestiveofvaccine-inducedimmunocompromiseisthehighnumberofimmune-mediatedconditionsreported,includingGuillain-BarréSyndrome(391ADRs,2fatalities),andMultipleSclerosis(142ADRs,1fatality).

Therehavebeen469reportsofinfectiveorinflammatorycardiacconditions,includingmyocarditis(205ADRs,2fatalities),endocarditis(8ADRs)andpericarditis(256ADRs,1fatality).Aleadingcardiologist,Dr.McCullough,hasvoicedconcernaboutongoingcardiacinjurywithveryhightroponinlevelsinyoungpeoplewithmyocarditis,thatareremaininghighforatleast2months19,suggestiveofongoingcardiacinjury[personalcommunication,meetingofexperts21-Jul-2021].Currently,thegovernmentreport20statesthat‘Thesereportsareextremelyrare,andtheeventsaretypicallymildwithindividualsrecoveringwithinashorttimewithstandardtreatmentandrest.’

• Pleasecanyouconfirmthateachoftheseyellowcardreportsofindividualswithpost-vaccinationmyocarditisandpericarditishavebeenfollowedupandforhowlong?

• Inaddition,pleasecanyouconfirmhowmanyoftheseindividualshaverecoveredfullyandthestatusofthosewhohavenotfullyrecovered?

IntheEudravigilancesafetysurveillancesystem,therehavebeen1034reportsofmyocarditisalonewiththePfizerCOVID-19vaccine,23(2.2%)ofwhichhavebeenfataland244ofwhich(23.6%)havenotresolved.Inthe12-17yearagegroup,95%ofreports(88/93)havebeeninmales;in18-64yearolds70%(539/774)aremalesandin65yearsandover54%(60/112)aremales.Fromthesedataitisclearthatmales(<65yearsbutparticularlyinthe<18yearagegroup)areparticularlyaffectedbymyocarditis,andthiscouldbeduetohigherexpressionlevelsofACE2receptorsinmenthaninwomen(15).

AnincreaseincardiacorrespiratoryarrestscanbeobservedfromNationalAmbulanceSyndromicSurveillance(NASS)systemreportsofdailycalls(Figure12)(16).TheCOVID-19vaccinerolloutstarted8thDecember2020.Callsforcardiacorrespiratoryarreststarttoincreaseapproximately1weekafterrolloutbegins,reflectingMcLachlan’sobservationsofdeathsduetoacardiacevent(myocardialinfarct,heartattack)occurringbetweendays5and14followingafirstdose(5).A

19Troponinlevels40-50ng/mLandnotcomingdownforprolongedperiod(e.g.2months)inyoungpeoplewithmyocarditis(UpperLimitofNormalis0.5ng/mLatDr.McCullough’slaboratory).20https://www.gov.uk/government/publications/coronavirus-covid-19-vaccine-adverse-reactions/coronavirus-vaccine-summary-of-yellow-card-reporting

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furtherconcerningriseincardiacorrespiratoryarrestcallsabovebaselinelevelshasbeenongoingsinceMay21st2021approximately(Figure12).

Figure12–NationalAmbulanceSyndromicSurveillance(NASS)systemreportsofdailycallsforcardiacorrespiratoryarrest,England

ThishappenstocorrespondtotheissuancebyNHSEnglandon20May2021ofthenotificationofthechangetoshelflifeofthePfizerCOVID-19vaccine,allowingthethawedvialtobestoredat2-8°Cfor31days,ratherthanthe5dayslimitthathaduptothatdatebeenapplied(17).ThisfollowedMHRA’samendmenttotheConditionsofAuthorisationofthePfizervaccine.Thisalsocorrespondstotherolloutstartinginyoungeradults,agedunder30yearsold.Itwould,therefore,beofrelevancetoexaminetheage-andgender-distributionofboththeNASScardiacorrespiratoryarrestcallsdata(16)andofADRreportstotheYellowCardsystem,asiftheincreasesincelateMayismainlyinyoungermales(asopposedtofemales)itcouldbesuggestiveofanACE2receptormediatedeffect.Iftherewerenodifferenceintheproportionofcalls/reportstoyoungmenandwomen,itmightbemoreindicativeofablanketeffectduetothechangeinshelf-lifeamendment.

Thattheage-andgender-stratifieddataarenotreadilyavailablefromtheYellowCardsystemhighlightstherisktothepublicthatanon-transparentsystemrepresents.

Therollout,particularlytoyoungeragegroupsshouldbehaltedandthePfizerCOVID-19vaccineshelf-lifeamendmentreversedpendinginvestigation.

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7.Bleeding,clottingandischaemicreportedADRs

To30thJune2021,atotalof25,253bleeding,clottingandischaemicsuspectedADRshavebeenreported,ofwhich964werefatal(Table3).Inthe5weekssinceourlastreporttherehavebeen11,487suchreportsand108fatalities.

Bleeding,clottingandischaemicADRswerethemostcommoncauseofpost-vaccinationfatalities.

ThemostcommonYellowCardcategoriesaffectedbythesesortsofADRsweregeneraldisorders(deathforunspecifiedreason482),thenervoussystem(183fatalities,mainlyfrombrainbleedsandclots),respiratory(with115fatalities,mainlyfrompulmonarythromboembolism)andcardiaccategories(104fatalities).

• Themostcommoncauseofsuddendeathisacardiovascularevent.Havethesedeathswithunspecifiedreasonbeenfolloweduptoestablishthelikelycause?

8.PainreportedADRs

To30thJune2021therehavebeen291,159painADRs(6fatalities),includingmuscleandtissuedisorders,nervoussystemdisorders,migraineandheadache(Table4).

9.NeurologicalsuspectedADRs

To30thJune2021reportsincluded12,727suspectedneurologicalADRs,including2,485ADRs(2fatalities)involvingseizuresand2,926ADRsinvolvingsomeformofparalysis,palsyincludingBell’spalsyorotherneuropathyorGuillain-BarréSyndrome.Sensorydisturbanceswerereportedin6,604ADRs,includinghighnumbersofeye(4,858ADRs)andeardisorders.Therehavebeen438reportsofblindness21.Searchesforencephalopathy,dementia,ataxia,spinalmuscularatrophy,delirium,Parkinsonordystoniaresultedin706reports,thevastmajorityinthepsychiatricdisordersYellowCardcategory(Table5).

Crossingoftheblood-brainbarrierandneurodegenerativepathologyissuggestedbythereactionsreported.Preclinicaldatademonstratethecrossingoftheblood-brainbarrierbytheS1subunitofthespikeproteinwheninjectedintravenously(18).

TheEuropeanMedicinesAgencyhasrecentlypublishedasafetyupdatereportfromthePharmacovigilanceRiskAssessmentCommittee(PRAC)ontheAstraZenecaCOVID-19vaccine(19),inwhichtheystate‘Vaccinatedpersonsneedtoseekimmediatemedicalattentioniftheydevelop

21ToJuly21st2021

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weaknessandparalysisintheextremities,possiblyprogressingtothechestandface,aftervaccinationwithVaxzevria,asthesecouldbesignsofGuillain-BarréSyndrome’,andtheyindicatetheproductinformationwillbeupdatedintheWarningsandPrecautionssectiontoalerthealthcareprofessionalsandpeopletakingthevaccineofthispotentialrisk.

• WillMHRAtakeactiontowarnhealthcareprovidersandpeopleintheUKofthepotentialriskofGuillain-BarréSyndromewiththeAstraZenecaCOVID-19vaccine?

OnefurthercaseofParoxysmalExtremePainDisorder(PEPD)hasbeenreportedsinceourlastreport,bringingthetotalto12cases,allfollowingtheAstra-ZenecaCOVID-19vaccine.

PEPDresultsfromagenemutationcausingsodiumchannelabnormalitiesandexcruciatingpainepisodes.Itisanextremelyrareinheritedneuropathiccondition,havingbeendefinitivelydescribedinonly77patientsfrom15familiesworldwide(20,21).Inlightofthis,12casesbeingreportedsincetheCOVID-19vaccinerolloutstartedintheUKand12fortheAstra-ZenecaCOVID-19vaccineintheEuropeanMedicinesAgency’sEudravigilancedatabase(anadditional2casescomparedtothetimeofourlastreport)wouldappearhighlyunusual.TheonsetofPEPDisreportednormallytobeinearlyinfancy,oftenonthefirstdayoflifeorinutero(21),yettheEuropeanCOVID-19vaccinepharmacovigilancedatashowsthatthePEPDcasesbeingreportedareoccurringinadults(9/12cases–fortheother3casestheagewasnotspecified).

PEPDmay,however,beunderdiagnosednormallyduetoitsabilitytomimicothersyndromesandsyncopes(22).CommonsymptomsofPEPDincludetransientlossofconsciousnesswithasystole,vasodilatation(flushing)andcyanosis(22).Othersignsandsymptomsincludelimbswelling,apnoeaandpupillarychanges,andeyeandjawpain(23)aswellasnon-epileptictonicseizuresandconstipation,thelatterbroughtonbyfearofthepain(21).Wewouldliketodrawyourattentiontothefrequencywithwhichthesesymptomshavebeenreportedpost-COVID-19vaccination22:lossofconsciousness1,465;syncope4,104;vasodilatation133;flushing1,033;cyanosis137(including1neonatal);limbswelling9;apnoea53(including1infantileapnoea);pupillarydeformity1;periorbitaloreyepain3,986;jawpain847;constipation624.Furthermore,thefrequencywithwhichpainingeneralhasbeenreported(291,159painADRs)maysuggestthattheCOVID-19vaccinesarespuriouslyaffectingsodiumchanneldepolarisation,asoccursinthisraregeneticdisorderofPEPD.InaFoIrequesttotheMHRA,itwasconfirmedthatthecasesreportedtotheYellowCardsysteminUKhavealsooccurredinadults.

• SincedrawingtheseunusualreportstotheattentionoftheMHRA,havetheseindividualsbeenfollowedup?

Thelargenumbersofsyncope/lossofconsciousnessreportedtoMHRAreflectthediscussionofMcLachlanetal.2021(5)alreadymentioned,inwhichtheyobservedfromtheirdetailedanalysis22Upto14-Jul-2021

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ofVAERSdeathreportsthatdescriptionsofpatients’post-vaccineandpre-deathsymptomsincludedsyncope.TheNASSbulletin(16)alsolists‘Unconscious/passingout’asoneofthesyndromicindicatorswith11,335callsintheweekandthattheseareabovebaselinelevels.Theirdataalsoshowsthat‘Unconscious/passingout’callshaveincreasedalarminglysinceMay21st,2021(Figure13):

Figure13–NationalAmbulanceSyndromicSurveillance(NASS)systemreportsofdailycallsforpeoplebeing‘UnconsciousorPassingout’,England

TheverylargenumberofneurologicalADRs,adult-occurringcasesoftheusuallyveryrareandinfancy-onsetPEPDandthereportsofPEPD-likesymptomsprovidesasafetysignalwarrantingsuspensionofCOVID-19vaccinespendinginvestigation.

10.Reproductivesystemdisorders

Upto30thJune2021,therewereahighnumberofReproductiveSystemADRs(9,184,Table6),including258ADRsreportedrelatedtothemalereproductivesystemand8,926ADRsforthefemalereproductivesystem,mainlyinthe‘reproductiveandbreastdisorders’category.Thiswillbethesubjectofaseparatereport.

Conclusion

AsnotedintheCHM’sExpertWorkingGroupreportonCOVID-19vaccinesafetysurveillance(1),MHRAhasstatutoryresponsibilityforundertakingpost-authorisationsafetymonitoringintheUK.WeasktheMHRAtotakeactionasfollows,inlinewithitsstatutoryobligationtominimise

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risktoindividuals,pendingfullinvestigationofvaccinesafetyandefficacyandre-assessmentofrisk-benefitratiosbyMHRA/CHM/CHMEAGsandindependentexpertsusingrealworldempiricalevidenceandassuminguseofknowneffectivetreatmentprotocols:

• SuspendtheCOVID-19vaccinesimmediatelyinallchildrensoplanstovaccinatechildrenaged12&overarecancelled,incl.imminentplansinthoseathigherriskofCOVID-19,whowouldbemostvulnerabletovaccineside-effects,andplansin16-17yearolds.

• SuspendtheuseofCOVID-19vaccinesinalladults• SuspendenrolmentintrialsinUKofCOVID-19vaccines• CommunicatetohealthcareworkersandvaccinerecipientsthepotentialriskofGuillain-

BarréSyndromewiththeAstraZenecaCOVID-19vaccineandthat‘Vaccinatedpersonsneedtoseekimmediatemedicalattentioniftheydevelopweaknessandparalysisintheextremities,possiblyprogressingtothechestandface,aftervaccination,asthesecouldbesignsofGuillain-BarréSyndrome’.

• CommunicatetohealthcareworkersandvaccinerecipientsknowntreatmentprotocolsforCOVID-19(acuteandlong)andforpost-vaccinationside-effects,includingCovidVaccination(CoVAC)Syndrome,sothatpeoplecanreceivetimelycare.Wehavecollatedhealthguidancefrominternationalclinicalexpertgroupsonmanagingtheseconditions,whichwecansharewithyoufordistribution.

• PostponeanyEUAassessmentofboostervaccinations• ConductacomprehensiveoverhauloftheUK’sYellowCardsystem

WethanktheUKFreedomProject23fortheirassistancewithdataextraction,JoelSmalleyforsharinghisgraphsandanalysesandDr.JonathanEnglerandDr.StephenFeldmanforsharingthecorrespondencetheyhavehadwithMHRA.Weremainatyourservicetoassistfurther.

Yourssincerely,

Dr.TessLawrie(MBBCh,PhD) KatherineS.MacGilchrist(MSc)Director,Evidence-basedMedicineConsultancyLtd CEO/SystematicReviewDirectorandEbMCSquaredCiC24,Bath,UK EpidemicaLtd.,UK23www.ukfreedomproject.org24PleasenotethatEbMCSquaredCiCisaCommunityInterestCompanythatconductsresearchmandatedbythepublicandfundedbypublicdonations.Wehavenoconflictsofinterestanddonotengageinindustry-fundedwork.

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References1. CHM.ReportoftheCommissiononHumanMedicinesExpertWorkingGrouponCOVID-19vaccinesafetysurveillance.20215February.2. PHE.DirectandindirectimpactofthevaccinationprogrammeonCOVID-19infectionsandmortality.2021b.3. BryantA,LawrieTA,DowswellT,FordhamEJ,MitchellS,HillSR,etal.IvermectinforPreventionandTreatmentofCOVID-19Infection:ASystematicReview,Meta-analysis,andTrialSequentialAnalysistoInformClinicalGuidelines.AmericanJournalofTherapeutics.2021;28(4).4. ShayDK,GeeJ,SuJR,al.e.SafetyMonitoringoftheJanssen(Johnson&Johnson)COVID-19Vaccine—UnitedStates,March–April2021.MMWRMorbMortalWklyRep.2021;70:680-4.5. MclachlanS,OsmanM,DubeK,ChiketeroPP,ChoiY,FentonN.AnalysisofCOVID-19vaccinedeathreportsfromtheVaccineAdverseEventsReportingSystem(VAERS)DatabaseInterimResultsandAnalysis.London,UK:QueenMaryUniversityofLondon;2021.6. CraigC,LeeJ.AnopenletterfromDrClarreCraigandDrJohnLeetoMattHancockre.CovidDeathsRecording2021Availablefrom:https://www.covid19assembly.org/2021/06/an-open-letter-from-dr-clare-craig-and-dr-john-lee-to-matt-hancock/[accessed28-Jul-2021].7. VAERS.VaccineAdverseEventReportingSystem(VAERS)StandardOperatingProceduresforCOVID-19(asof29January2021).USA:CDC;2021.ContractNo.:v2.8. FDA.GuidanceforIndustry.GoodPharmacovigilancePracticesandPharmacoepidemiologicAssessment.USDHHS,FDA,CDER,CBER;2005March2005.9. PHS.PublicHealthScotland.COVID-19StatisticalReportasat21June2021.Publicationdate:23June2021.;2021a.10. PHS.PublicHealthScotland.COVID-19StatisticalReportasat19July2021.Publicationdate:21July2021.;2021b.11. MHRA.PublicAssessmentReport.AuthorisationforTemporarySupply.COVID-19mRNAVaccineBNT162b2(BNT162b2RNA)concentrateforsolutionforinjection.;2021aJune.12. MHRA.PublicAssessmentReport.Nationalprocedure.Vaxzevria(previouslyCOVID-19VaccineAstraZeneca,suspensionforinjection).COVID-19Vaccine(ChAdOx1-S[recombinant]).PLGB17901/0355.;2021bJuly.13. KlimekL,EckrichJ,HagemannJ,CasperI,HuppertzJ.[AllergicreactionstoCOVID-19vaccines:evidenceandpractice-orientedapproach].DerInternist.2021;62(3):326-32.14. FurerV,ZismanD,KibariA,RimarD,ParanY,ElkayamO.HerpeszosterfollowingBNT162b2mRNACovid-19vaccinationinpatientswithautoimmuneinflammatoryrheumaticdiseases:acaseseries.Rheumatology(Oxford,England).2021.15. BwireGM.Coronavirus:WhyMenareMoreVulnerabletoCovid-19ThanWomen?SNComprClinMed.2020:1-3.16. PHE.NationalAmbulanceSyndromicSurvillanceSystem:England.Datato25July2021.;2021a.17. NHSEngland.COVID-19VaccinePfizer-BioNTech:changetoshelflifewhenstoredinrefrigeratorsat2-8C.2021.18. RheaEM,LogsdonAF,HansenKM,WilliamsLM,ReedMJ,BaumannKK,etal.TheS1proteinofSARS-CoV-2crossestheblood–brainbarrierinmice.NatureNeuroscience.2021;24(3):368-78.19. EMA.COVID-19vaccinesafetyupdate.VaxzevriaAstraZenecaAB.202114July.20. EsmyotMLI,Katimada-AnnaiahT,GrosuL.Paroxysmalextremepaindisorder-anobstetricsperspective.BJOG:AnInternationalJournalofObstetricsandGynaecology.2014;121:168.21. FerrieCD.Paroxysmalextremepaindisorder.JournalofPediatricNeurology.2010;8(1):15-7.

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AppendixI–UpdatedanalysisofYellowCarddata(methods)Inthislatestupdateto30thJune2021,wehaveagainsearchedtheYellowCardreportsusingpathology-specifickeywordstogroupthedataaccordingtothefollowingfivebroad,clinicallyrelevantcategories.Afterrunningeachsearch,weenteredtheresultsintoanExcelspreadsheet,excludingADRsthatwereclearlyirrelevantorappearedinduplicate.

A. ImmuneSystemADRsB. Bleeding,ClottingandIschaemicADRsC. ‘Pain’ADRsD. NeurologicalADRsE. ReproductiveSystemADRs

A.ImmuneSystemAdverseDrugReactions(Infection,Inflammation,Autoimmune,Allergic)(Table2)WeusedthefollowingSEARCHTERMStoidentifyimmunesystemADRs:INFECTION(category),immunesystem(category),-itis;immun,multiplesclerosis,lupus,myasthenia,pernicious,diabetes,Addison,Crohn’s,Coeliac,Graves,alopecia,amyloidosis,antiphospholipid,angioedema,Behcet's,pemphigoid,psoriasis,aplasia,sarcoidosis,scleroderma,thrombocytopenia,vitiligo,MillerFisher,Guillain-Barre;allerg*,urticaria,rash,eczema,asthma,anaphylac*.

B.Bleeding,ClottingandIschaemicAdverseDrugReactions(Table3)WeusedthefollowingSEARCHTERMStoidentifybleeding,clottingandischaemicADRs.Termsnotsearchedinourlastreportareinbold:haemorrhage,bleed,haemo*,epistaxis,thrombo*,emboli*,coag*,death,occlus,ischaem*,infarct*,angina,stroke,cerebrovascular,CVA.Aspreviously,weincludedtheterm‘death’inthissearchgroup,asthistermaccountedformanyreportedfatalities(482)withoutspecificdetails.Giventhelargenumberoffatalitieswithoutaspecificcauseofdeath,weconsideredthatADRsreportedinthisway,inparticularas‘suddendeath’,wouldbemostlikelytooccurfromhaemorrhagic,thrombo-embolicorischaemicevents.GiventheseriousnessofthisADR,weconsidereditjustifiabletodothispendingclarificationofthecauseofdeathinthese482people.

C.‘Pain’AdverseDrugReactions(Table4)WeusedthefollowingSEARCHTERMStoidentifypainADRs:pain,-algia,headache,migraine.

D.NeurologicalAdverseDrugReactions(Table5)InadditiontoexaminingADRsintheNERVOUSSYSTEMDISORDERS(category),weusedthefollowingSEARCHTERMStoidentifyneurologicalADRsspecificallyinvolvingparalysis,neurologicaldegeneration,andconvulsiveADRsasfollows:(paralysis),palsy,paresis,neuropathy,incontinence,Guillain-Barre,MillerFisher,multiplesclerosis;(neurodegeneration)encephalopathy,dementia,ataxia,spinalmuscularatrophy,delirium,Parkinson;(seizure),convuls,seizure,fit,-lepsy

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E.ReproductiveSystemAdverseDrugReactions(Table6)Searchtermsincludedthoseforthemalereproductivesystem-Testic,testes,scrotal,penile,epididym,prostate,‘breastcancermale’,balanitis,sperm,‘infertilitymale’,erection,semen(excludingbasement),gynaecomastia,‘malesexualdysfunction’–andforthefemalereproductivesystemandpregnancy-Breastcancer(excludingmale),lactation,mastitis,breastabcess,genitalherpes,genitalabscess,endometritis,Infertility(excludingmale),oophoritis,menopaus*,menstrua*,vaginal,vulval,vulvo,cervix,ovarian,pelvis,genital,sexualdysfunctionexcludingmale,uterine,fallopian,exposuresassociatedwithpregnancy,deliveryandlactation(Category).

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Table2.ImmuneSystemAdverseDrugReactions(upto30thJune2021–Week23)

SEARCHtermsInflammation

(-itis),infectionImmun,immune

system+

Allerg,asthma,eczema,urticaria,rash,anaphylac

YellowCardCategory AllADRs(Fatal) AllADRs(Fatal) AllADRs(Fatal)

TotalWeek23AllADRs(Fatal)

Blooddisorders 132(0) 1272(12) 1404(12)Cardiacdisorders 297(2) 1(0) 298(2)Congenitaldisorders 2(0) 5(0)

7(0)

Eardisorders 13(0) 1(0) 14(0)Endocrinedisorders 28(0) 20(0)

48(0)

Eyedisorders 234(0) 6(0) 69(0) 309(0)Gastrointestinaldisorders 746(4) 142(0)

888(4)

Generaldisorders 1161(0)

976(0) 2137(0)Hepaticdisorders 57(1) 9(0) 66(1)Immunesystemdisorders

2580(0) 1612(4)

4192(4)

Infections 22823(158) 7(0) 163(0) 22993(158)

Injuries 41(0) 5(0) 1(0) 47(0)Investigations 1(0) 29(0) 2(0) 32(0)Metabolicdisorders 204(1)

204(1)

Muscle&tissuedisorders 1985(0) 65(0)

2050(0)

Neoplasms 1(0)

1(0)Nervoussystemdisorders 255(0) 572(6)

827(6)

Pregnancyconditions 11(0)

11(0)

Psychiatricdisorders 2(0)

2(0)

Renal&urinarydisorders 42(1) 3(0)

45(1)

Reproductive&breastdisorders 29(0)

9(0)

38(0)

Respiratorydisorders 84(2) 5(0) 834(0)

923(2)

Skindisorders 566(0) 1338(0) 26287(1) 28191(1)Surgical&medicalprocedures 269(2) 3(0)

272(2)

Vasculardisorders 306(3) 7(0) 313(3)GrandTotal 28803(171) 6553(21) 29956(5) 65312(197)Abbreviations:ADR,adversedrugreaction

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+Multiplesclerosis,lupus,myasthenia,pernicious,diabetes,Addison,Coeliac,Graves,alopecia,amyloidosis,antiphospholipid,angioedema,Behcet's,pemphigoid,psoriasis,aplasia,sarcoidosis,scleroderma,thrombocytopenia,vitiligo,MillerFisher,Guillain-Barre,Crohn

Table3.Bleeding,ClottingandIschaemicAdverseDrugReactions(upto30thJune2021–Week23)

SEARCHterms Death

Haemorrhage,bleed,haemo,

epistaxis

Ischaem,infarct,angina,stroke,

cerebrovascular,CVA

Thrombo,emboli,

coag Occlus

YellowCardCategory

AllADRs(Fatal)

AllADRs(Fatal) AllADRs(Fatal)

AllADRs(Fatal)

AllADRs(Fatal)

TotalWeek23

AllADRs(Fatal)

Blooddisorders 40(0) 13(0) 166(4) 219(4)Cardiacdisorders 9(5) 863(94) 27(5) 2(0) 901(104)Congenitaldisorders 2(0) 2(0)Eardisorders 22(0) 22(0)Endocrinedisorders 13(0) 1(0) 14(0)Eyedisorders 298(0) 15(0) 19(0) 120(0) 452(0)Gastrointestinaldisorders 671(5) 47(4) 40(1) 1(0) 759(10)Generaldisorders 484(482) 61(0) 3(0) 1(0) 549(482)Hepaticdisorders 3(0) 3(1) 87(5) 0(0) 93(6)Infections 1(0) 11(0) 12(0)Injuries 28(1) 14(0) 4(0) 1(0) 47(1)Investigations 44(0) 3(0) 197(0) 244(0)Metabolicdisorders 1(0) 1(0)Muscle&tissuedisorders 6(0) 6(0)Neoplasms 1(0) 3(0) 4(0)Nervoussystemdisorders 434(81) 2196(67) 385(35) 11(0) 3026(183)Pregnancyconditions 6(1) 2(0) 54(0) 62(1)Psychiatricdisorders 18(0) 18(0)Renal&urinarydisorders 80(1) 15(1) 13(0) 4(0) 112(2)Reproductive&breastdisorders 8625(0) 2(0) 8627(0)

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SEARCHterms Death

Haemorrhage,bleed,haemo,

epistaxis

Ischaem,infarct,angina,stroke,

cerebrovascular,CVA

Thrombo,emboli,

coag OcclusRespiratory

disorders 2931(1) 17(1)1701(113) 1(0) 4650(115)

Skindisorders 80(0) 80(0)Socialcircumstances 1(0) 1(0)Surgical&medicalprocedures 7(0) 7(0)Vasculardisorders 1627(3) 76(2) 3607(51) 35(0) 5345(56)

GrandTotal 509(483) 14979(97) 3262(170)6327(214) 176(0) 25253(964)

Abbreviations:ADR,adversedrugreaction;CVA,cerebrovascularaccident

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Table4.PainAdverseDrugReactions(upto30thJune2021–Week23)

SEARCHterms

Pain,-algia,headache,migraine

YellowCardCategory Total(Fatal)Blooddisorders 1546(0)Congenitaldisorders 17(0)Eardisorders 2558(0)Endocrinedisorders 15(0)Eyedisorders 3894(0)Gastrointestinaldisorders 13271(0)Generaldisorders 41296(2)Hepaticdisorders 79(0)Injuries 23(0)Muscle&tissuedisorders 105566(0)Neoplasms 2(0)Nervoussystemdisorders 111984(4)Pregnancyconditions 3(0)Psychiatricdisorders 1(0)Renal&urinarydisorders 1162(0)Reproductive&breastdisorders 1407(0)Respiratorydisorders 7085(0)Skindisorders 1118(0)Vasculardisorders 132(0)GrandTotal 291159(6)

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Table5.NeurologicalAdverseDrugReactions(upto30thJune2021–Week23)

SEARCHterms

Convuls,seizure,fit,-

lepsy

Paralysis,palsy,paresis,

neuropathy,incontinence,Guillain-Barre,MillerFisher,

multiplesclerosis

Speech,taste,smell,

olfactory,blind,sight,visual,vision,deaf,

hearing

Encephalopathy,dementia,

ataxia,spinalmuscularatrophy,delirium,

Parkinson,dystonia

YellowCardCategory

AllADRs(Fatal) AllADRs(Fatal) AllADRs(Fatal) AllADRs(Fatal)

TotalWeek23

AllADRs(Fatal)

Congenitaldisorders 1(0) 6(0) 3(0) 2(0) 12(0)Eardisorders 698(0) 698(0)Eyedisorders 22(0) 4858(0) 4880(0)Gastrointestinaldisorders 59(0) 59(0)Investigations 2(0) 3(0) 5(0)Nervoussystemdisorders 2479(2) 2588(0) 877(0) 165(0) 6109(2)Pregnancyconditions 15(0) 15(0)Psychiatricdisorders 120(0) 539(0) 659(0)Renal&urinarydisorders 249(0) 249(0)Socialcircumstances 30(0) 30(0)Surgical&medicalprocedures 5(0) 5(0)GrandTotal 2485(2) 2926(0) 6604(0) 706(0) 12721(2)Abbreviations:ADR,adversedrugreaction

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Table6.ReproductiveSystemAdverseDrugReactions(upto30thJune2021–Week23)

SEARCHterms

Testic,testes,scrotal,penile,epididym,prostate,‘breastcancermale’,balanitis,sperm,‘infertilitymale’,erection,semen(excludingbasement),gynaecomastia,‘malesexualdysfunction’

Breastcancer(excludingmale),lactation,mastitis,breastabcess,genitalherpes,genitalabscess,endometritis,Infertility(excludingmale),oophoritis,menopaus*,menstrua*,vaginal,vulval,vulvo,cervix,ovarian,pelvis,genital,sexualdysfunctionexcludingmale,uterine,fallopian,exposuresassociatedwithpregnancy,deliveryandlactation(Category)

YellowCardCategory AllADRs(Fatal) AllADRs(Fatal) Total(Fatal)Congenitaldisorders 2(0) 24(0) 26(0)Injuries 2(0) 2(0) 4(0)Investigations 4(0) 9(0) 13(0)Neoplasms 15(0) 119(0) 134(0)Nervoussystemdisorders 2(0) 2(0)Pregnancyconditions 9(0) 9(0)Psychiatricdisorders 2(0) 2(0)Renal&urinarydisorders 1(0) 1(0)Reproductive&breastdisorders 127(0) 8676(0) 8803(0)Skindisorders 106(0) 106(0)Socialcircumstances 76(0) 76(0)Surgical&medicalprocedures 1(0) 7(0) 8(0)GrandTotal 258(0) 8926(0) 9184(0)Abbreviations:ADR,adversedrugreaction

AppendixII–LetterfromJoelSmalleytohisMPPleaseseetheattachment