Vacunación contra el SARS-CoV-2 y miocarditis en un estudio de cohorte nórdico de 23 millones

JAMACardiology| OriginalInvestigation

SARS-CoV-2VaccinationandMyocarditisinaNordicCohortStudy of23MillionResidents

ØysteinKarlstad,MScPharm,PhD;PetteriHovi,MD,PhD;AndersHusby,MD,PhD;TommiHärkänen,PhD;RandiMarieSelmer,MSc,PhD; NicklasPihlström,MSc;JørgenVinsløvHansen,MSc,PhD;HannaNohynek,MD,PhD;NinaGunnes,MSc,PhD;AndersSundström,BA,PhD; JanWohlfahrt,MSc,DMSC;TuomoA.Nieminen,MSocSc;MariaGrünewald,MSc,PhD;HanneLøvdalGulseth,MD,PhD;AndersHviid,MSc,DMSC; RickardLjung,MD,PhD,MPH

IMPORTANCE ReportsofmyocarditisafterSARS-CoV-2messengerRNA(mRNA)vaccination haveemerged.

OBJECTIVE ToevaluatetherisksofmyocarditisandpericarditisfollowingSARS-CoV-2 vaccinationbyvaccineproduct,vaccinationdosenumber,sex,andage.

DESIGN,SETTING,ANDPARTICIPANTS Fourcohortstudieswereconductedaccordingtoa commonprotocol,andtheresultswerecombinedusingmeta-analysis.Participantswere 23122522residentsaged12yearsorolder.TheywerefollowedupfromDecember27,2020, untilincidentmyocarditisorpericarditis,censoring,orstudyend(October5,2021).Dataon SARS-CoV-2vaccinations,hospitaldiagnosesofmyocarditisorpericarditis,andcovariatesfor theparticipantswereobtainedfromlinkednationwidehealthregistersinDenmark,Finland, Norway,andSweden.

Editor'sNote page612

Supplementalcontent

EXPOSURES

The28-dayriskperiodsafteradministrationdateofthefirstandseconddosesof aSARS-CoV-2vaccine,includingBNT162b2,mRNA-1273,andAZD1222orcombinations thereof.Ahomologousschedulewasdefinedasreceivingthesamevaccinetypefordoses1 and2.

MAINOUTCOMESANDMEASURES

Incidentoutcomeeventsweredefinedasthedateoffirst inpatienthospitaladmissionbasedonprimaryorsecondarydischargediagnosisfor myocarditisorpericarditisfromDecember27,2020,onward.Secondaryoutcomewas myocarditisorpericarditiscombinedfromeitherinpatientoroutpatienthospitalcare. Poissonregressionyieldedadjustedincidencerateratios(IRRs)andexcessrateswith95% CIs,comparingratesofmyocarditisorpericarditisinthe28-dayperiodfollowingvaccination withratesamongunvaccinatedindividuals.

RESULTS Among23122522Nordicresidents(81%vaccinatedbystudyend;50.2%female), 1077incidentmyocarditiseventsand1149incidentpericarditiseventswereidentified.Within the28-dayperiod,formalesandfemales12yearsoroldercombinedwhoreceiveda homologousschedule,theseconddosewasassociatedwithhigherriskofmyocarditis,with adjustedIRRsof1.75(95%CI,1.43-2.14)forBNT162b2and6.57(95%CI,4.64-9.28)for mRNA-1273.Amongmales16to24yearsofage,adjustedIRRswere5.31(95%CI,3.68-7.68) foraseconddoseofBNT162b2and13.83(95%CI,8.08-23.68)foraseconddoseof mRNA-1273,andnumbersofexcesseventswere5.55(95%CI,3.70-7.39)eventsper 100000vaccineesaftertheseconddoseofBNT162b2and18.39(9.05-27.72)eventsper 100000vaccineesaftertheseconddoseofmRNA-1273.Estimatesforpericarditiswere similar.

CONCLUSIONSANDRELEVANCE Resultsofthislargecohortstudyindicatedthatbothfirstand seconddosesofmRNAvaccineswereassociatedwithincreasedriskofmyocarditisand pericarditis.Forindividualsreceiving2dosesofthesamevaccine,riskofmyocarditiswas highestamongyoungmales(aged16-24years)aftertheseconddose.Thesefindingsare compatiblewithbetween4and7excesseventsin28daysper100000vaccineesafter BNT162b2,andbetween9and28excesseventsper100000vaccineesaftermRNA-1273. ThisriskshouldbebalancedagainstthebenefitsofprotectingagainstsevereCOVID-19 disease.

JAMACardiol.2022;7(6):600-612.doi:10.1001/jamacardio.2022.0583

PublishedonlineApril20,2022.

AuthorAffiliations: Author affiliationsarelistedattheendofthis article.

CorrespondingAuthor:Rickard Ljung,MD,PhD,MPH,DivisionofUse andInformation,SwedishMedical ProductsAgency,POBox26,SE-751 03Uppsala,Sweden(rickard.ljung@ lakemedelsverket.se).

TheEuropeanMedicinesAgencyandEuropeanCommissionhave,byOctober2021,approved4vaccinesagainst SARS-CoV-2:BNT162b2(Pfizer-BioNTech),mRNA1273(Moderna),AZD1222(AstraZeneca),andAd26.COV2.S (Janssen).TheNordiccountrieshaveprimarilyusedthe2messengerRNA(mRNA)vaccinesBNT162b2andmRNA-1273. Thesevaccineshavebeenshowntobeefficientandsafe,althoughcasesofmyocarditisorpericarditisduringthefirst weeksaftervaccinationhavebeenreported.1

Casereports,surveillancedata,andotherreportsfromthe US,Israel,andCanadaindicateanincreasedriskofmyocarditis aftervaccinationwithSARS-CoV-2mRNAvaccines,higherafter theseconddose,especiallyinyoungermen.2-9 DatafromCanada andFranceindicatemorecasesofmyocarditisaftermRNA-1273 thanafterBNT162b2,butthisremainstobeelucidated.10,11

InnationwidecohortstudiesinDenmark,Finland,Norway, andSweden,weevaluatedtherisksofmyocarditisandpericarditisfollowingSARS-CoV-2vaccinationinacombinedpopulationof23.1millionindividuals.High-qualitynationwideregistersenabledustoevaluatetheriskbyvaccineproduct, vaccinationdosenumber,sex,andage.

Methods

SettingandDataSources

Weconductedpopulation-basedcohortstudiesin4Nordiccountries(Denmark,Finland,Norway,andSweden)usinglinkeddata fromnationwidehealthregistersonSARS-CoV-2vaccination, myocarditisandpericarditisdiagnoses,andothercovariates (eMethodsinthe Supplement).AllNordicresidentsareassigned auniquepersonalidentifieratbirthorimmigration,enablingdeterministiclinkagebetweenregisters.Thesecountrieshaveuniversalandtax-financedhealthcaresystems,andreportingtonationalregistersismandatory,providingnear-completefollow-up ofallresidentsovertime.12,13 Eachcohortstudywasanalyzed separatelyaccordingtoacommonprotocol,andtheresultswere combinedbymeta-analyses.Onthebasisofcurrentlawineach ofthecountries,thisregister-basedresearchwasconductedaccordingtothelaws,regulations,andauthoritypermits,andinformedconsentfromindividualswasnotapplicable(eMethods inthe Supplement).14 Therequirementforobtaininginformed consentwaswaivedbecausealldataarepubliclyavailable.This studyfollowedtheStrengtheningtheReportingofObservational StudiesinEpidemiology(STROBE)reportingguideline.

StudyPopulation

Weincludedallpersonswhoturned12yearsorolderin2021, wereresidentsonJanuary1,2017,andwerealiveandstillresidingwithinthecountryonDecember27,2020.Weexcluded20211personswithanymyocarditisorpericarditisin inpatientoroutpatienthospitalcarefromJanuary1,2017,to December26,2020(eMethodsinthe Supplement).

SARS-CoV-2Vaccination

TheNordiccountriesimplementednationalvaccinationcampaignsagainstSARS-CoV-2fromDecember27,2020,provid-

KeyPoints

Question IsSARS-CoV-2messengerRNA(mRNA)vaccination associatedwithriskofmyocarditis?

Findings Inacohortstudyof23.1millionresidentsacross4Nordic countries,riskofmyocarditisafterthefirstandseconddosesof SARS-CoV-2mRNAvaccineswashighestinyoungmalesaged16to 24yearsaftertheseconddose.Foryoungmalesreceiving2doses ofthesamevaccine,datawerecompatiblewithbetween4and7 excesseventsin28daysper100000vaccineesafter second-doseBNT162b2,andbetween9and28per100000 vaccineesaftersecond-dosemRNA-1273.

Meaning Theriskofmyocarditisinthislargecohortstudywas highestinyoungmalesafterthesecondSARS-CoV-2vaccinedose, andthisriskshouldbebalancedagainstthebenefitsofprotecting againstsevereCOVID-19disease.

ingfreevaccinationstoallresidents.Phaseddistributionplans wereimplemented,prioritizingvaccinationofindividualsat highestriskofCOVID-19complications(ie,nursinghomeresidents,healthcareworkers,andolderadults).Denmark, Finland,andNorwayalmostexclusivelyusedmRNAvaccinesafterfullorpartialdiscontinuationofAZD1222inMarch 2021becauseofseriousbutrareeventsofthrombosiswith thrombocytopenia.15,16 SwedenusedAZD1222foramajority ofthepopulationolderthan64yearsandmRNAvaccinesin otheragegroups.ThevaccineAd26.COV2.Shadverylimited use.TheNordiccountriesvaccinatedapproximately6times moreindividualswithBNT162b2thanwithmRNA-1273becauseofhigheravailabilityoftheformervaccine.Westudied riskofmyocarditisandpericarditisin28-dayriskperiodsaftertheadministrationdateofthefirstandseconddosewith BNT162b2,mRNA-1273,andAZD1222(Figure1).Ahomologousschedulewasdefinedasreceivingthesamevaccinetype fordoses1and2.

MyocarditisandPericarditis

WedefinedincidentoutcomeeventsasthedateoffirsthospitaladmissionformyocarditisorpericarditisfromDecember27,2020,onward.Theprimaryoutcomewasamainorsecondarydiagnosisofmyocarditisatdischargefrominpatient hospitalcare.Secondaryoutcomeswereamainorsecondary diagnosisofpericarditis(inpatienthospitalcare)andamain orsecondarydiagnosisofeithercondition(myocarditisorpericarditis)combinedfromeitherinpatientoroutpatienthospitalcare(eTable1inthe Supplement).

Covariates

Weusedthefollowingcovariatesforadjustmentandstratification:sex,age,calendarperiod,healthcareworkerstatus, nursinghomeresident,and5comorbidities(pulmonarydisease,kidneydisease,autoimmunedisease,cardiovasculardiseaseordiabetes,andcancer)definedbydiagnosesbeforethe startoffollow-up(eTable2inthe Supplement).WealsoadjustedforverifiedSARS-CoV-2infectionbeforeDecember27, 2020,whereasinfectionafterthisdatewasacensoringevent.

WedefinedhavingSARS-CoV-2asthesampledateofapositivereversetranscriptase–polymerasechainreactionorlateralflowtest.

StatisticalAnalysis

Wetookadvantageofthelongitudinalinformationinour nationalcohortstocalculateexactunvaccinatedandvaccinatedperson-timeatriskforeachindividual(Figure1).We startedfollow-uponDecember27,2020.Eachindividual wasfollowedupuntilfirstoutcomeeventofinterestora censoringevent,definedasfirstoccurrenceofapositive testresultforSARS-CoV-2infection,receivingAd26.COV2.S vaccine,receivingathirddoseofanySARS-CoV-2vaccine, emigration,death,orcountry-specificstudyend(latest October5,2021).Individualscontributedperson-timeas unvaccinateduntilthefirstvaccination.Aftereachfirstor seconddose,individualscontributedperson-timeinamain riskperiodofinterestdefinedasday0uptoandincluding day28(Figure1).Theresultingfollow-upperiodsandnumbersofmyocarditisandpericarditiscaseswereaggregated forallindividualsaccordingtovaccinationstatus(ie,unvaccinated,riskperiodafterfirstdose,andriskperiodafterseconddose).

WeusedPoissonregressionforthenumberofeventsto estimateincidencerateratios(IRRs)with95%CIs,comparingratesintheriskperiodsaftervaccinationwithratesinunvaccinatedperiods.Wetookpotentialconfoundingfactorsinto accountbyadjustmentin3models.Model1includedadjustmentforsexandagegroup(12-15,16-19,20-24,25-29,30-39, 40-64,and≥65years).Model2includedadjustmentasin model1andforhealthcareworkerstatus,nursinghomeresident,andtheaforementionedcomorbidities.Model3includedadjustmentasinmodel2andforcalendarperiods(DecemberthroughMarch,AprilthroughJune,andJulytothe studyend).Weusedmodel2inthemainanalyses,whereas models1and3wereusedforsensitivityanalyses.Wein-

A,Exampleofanindividualwhowas vaccinatedwithafirstdoseonMay 20,2021,andfollowedup0to28 daysfromfirstdose,andvaccinated withaseconddoseonJune25,2021, andfollowedup0to28daysaftera seconddose.B,Exampleofan individualwhowasnotvaccinated andwasfollowedupuntiltheendof follow-uponOctober5,2021.

cludedsubgroupresultsaccordingtosexandage(12-15, 16-24,25-39,and≥40years).Analyseswereconductedin DenmarkandSwedenwithSAS,version9.4(SASInstituteInc), inFinlandwithR,version3.6.3(RFoundationforStatistical Computing),andinNorwaywithStata,version16.0(StataCorpLLC).

Meta-analyses

Meta-analysesoftheIRRestimateswerebasedonrandomeffectsmodelsimplementedusingthemixmetapackage17 of R.18 Wetestedthehomogeneityofcountry-specificestimates usingtheCochran Q test,19 calculatedthepooledincidence ratesusingthesumofeventsandperson-yearsinthecountries,andcalculatedthepooledexcessratesusingthepooled incidenceratesandIRRestimates.FortheCIs,weusedthedelta method,assumingindependenceoftheincidenceratesand IRRestimates.

SupplementaryAnalyses

Inacomplementaryanalysis,westudiedincidentmyocarditiswithin28daysfollowingSARS-CoV-2infectionfromAugust1,2020,toendofstudy.Wealsostudiedriskofmyocarditisorpericarditisinashorter7-dayriskperiod.Furthermore, amongmyocarditiscases,weestimatedtheproportionofpatientsdischargedonday4orlaterandtheproportionofcases inwhichthepatientdiedwithin28daysoftheadmissiondate, usingtheKaplan-Meierestimator.Amongmyocarditiscases aftervaccination,wecalculatedthemediantimefromvaccinationtooutcome(hospitaladmissiondate).

Results

Across4Nordiccountries,23122522residents(49.8%maleand 50.2%female)werefollowedupfromDecember27,2020,to October5,2021,atthelatest.Bystudyend,17129982resi-

Figure1.SchematicIllustrationsofFollow-upTimeWindowsintheCohortStudy

Table1.NumberofIndividualsContributingtoUnexposedandExposedPerson-Time byVaccineTypeandVaccineSchedulea

≥12y12-15y16-24y25-39y≥40y

Populationatstartoffollow-up,No.2312252212380042675558504616414162796

OnlyfirstdoseAZD1222,No.178447831248345240120641

dents(74%)hadreceived2dosesand1681930residents(7%) hadreceived1doseofSARS-CoV-2vaccines.Bystudyend, 487751of1238004persons(39%)aged12to15years, 2009995of2675558persons(75%)aged16to24yearsofage, 3736517of5046164persons(74%)aged25to39years,and 12579805of14162796persons(89%)aged40yearsorolder hadreceivedatleast1doseofaSARS-CoV-2vaccine(Table1; eTable3inthe Supplement).

MyocarditisandPericarditisDuringFollow-up

Duringthe28-dayriskperiodsfollowingvaccinationandduringunvaccinatedperiods(13millionperson-yearsintotal),we observed1077incidentmyocarditiscasesand1149incident pericarditiscases.Incidenceratesofmyocarditisduringthe unvaccinatedperiodwere9.7per100000person-yearsfor malesand4.3per100000person-yearsforfemales(Table2). Amongindividualsaged16to24years,incidencerateswere 18.8per100000person-yearsformalesand4.4per100000 person-yearsforfemales.Incidenceratesofpericarditisincreasedwithage(eTable4inthe Supplement).

VaccinationandMyocarditis

Duringthe28-dayriskperiod,weobserved105myocarditis casesfollowingadministrationofthefirstdoseofBNT162b2 and115myocarditiscasesfollowingtheseconddose.Wealso observed15myocarditiscasesfollowingadministrationofthe firstdoseofmRNA-1273and60myocarditiscasesfollowing theseconddose.

AdjustedIRRscomparingthe28-dayriskperiodsfollowingfirstandseconddosescomparedwithunvaccinatedperiodswere1.38(95%CI,1.12-1.69)forthefirstdoseofBNT162b2

Abbreviation:mRNA,messenger RNA.

a Nordiccountriescombined (Denmark,Finland,Norway,and Sweden).

b Vaccinationsincludedfrom December27,2020,toOctober5, 2021,withmalesandfemales combined;vaccineusedforthefirst dosegivenfirst,andvaccineused fortheseconddosegivensecond.

and1.75(95%CI,1.43-2.14)fortheseconddose,and1.16(95% CI,0.69-1.93)forthefirstdoseofmRNA-1273and6.57 (95%CI,4.64-9.28)fortheseconddose.Amongmales,after thefirstandseconddoses,adjustedIRRswere1.40(95%CI, 1.09-1.80)forthefirstdoseofBNT162b2and2.04(95%CI,1.612.58)fortheseconddose,and1.45(95%CI,0.84-2.52)forthe firstdoseofmRNA-1273and8.55(95%CI,6.40-11.41)forthe seconddose.Amongfemales,followingthefirstandsecond doses,adjustedIRRswere1.46(95%CI,1.01-2.11)forthefirst doseofBNT162b2and1.25(95%CI,0.77-2.05)forthesecond dose,and1.45(95%CI,0.35-5.97)forthefirstdoseofmRNA1273and2.73(95%CI,1.27-5.87)fortheseconddose.

Amongmales16to24yearsofage,theadjustedIRRsfor myocarditiswere5.31(95%CI,3.68-7.68)foraseconddoseof BNT162b2and13.83(95%CI,8.08-23.68)foraseconddose ofmRNA-1273.Forfemales,thecomparativeadjustedIRRs werelower(Table2, Figure2 , Figure3 ;eFigure1inthe Supplement).

Wealsoestimatedtheexcessnumbersofmyocarditis eventsper100000vaccineesinthe28-dayriskperiods.Among allmales,thesenumberswere0.27(95%CI,0.09-0.46)events afterthefirstdoseofBNT162b2and0.67(95%CI,0.46-0.88) eventsaftertheseconddose,and0.33(95%CI,−0.11to0.78) eventsafterthefirstdoseofmRNA-1273and4.97(95%CI,3.626.32)eventsaftertheseconddose.Amongallfemales,theexcessnumbersofeventsper100000vaccineesinthe28-day riskperiodswere0.15(95%CI,0.02-0.28)eventsafterthefirst doseofBNT162b2and0.09(95%CI,−0.09to0.26)eventsaftertheseconddose,and0.05(95%CI,−0.13to0.23)events afterthefirstdoseofmRNA-1273and0.48(95%CI,0.070.89)eventsaftertheseconddose(Table2).

Subgroup,exposureb

Males,ages≥12y

No.of eventsc

Follow-up, 1000 personyears

Crude incidence rateper 1000 person-years offollow-upd IRR(95%CI)

No.ofexcessevents in28dper100000 vaccinees(95%CI)

Unvaccinated5205340.60.0971[Reference]0[Reference]

AZD1222643.00.1392.39(1.04to5.48)0.62(0.00to1.24)

AZD1222/AZD1222≤529.2ND1.29(0.31to5.33)0.12(−0.48to0.72)

BNT162b270560.90.1251.40(1.09to1.80)0.27(0.09to0.46)

BNT162b2/BNT162b285495.00.1722.04(1.61to2.58)0.67(0.46to0.88)

BNT162b2/mRNA-12733423.71.43316.99(11.51to 25.07) 10.34(6.86to13.83)

mRNA-12731393.20.1391.45(0.84to2.52)0.33(−0.11to0.78)

mRNA-1273/mRNA-12735372.30.7338.55(6.40to11.41)4.97(3.62to6.32)

Males,ages16-24y

Unvaccinated149794.60.1881[Reference]0[Reference]

AZD122200.70NDNDND

AZD1222/AZD122200.10NDNDND

BNT162b22463.90.3762.16(1.40to3.33)1.55(0.70to2.39)

BNT162b2/BNT162b23741.50.8915.31(3.68to7.68)5.55(3.70to7.39)

BNT162b2/mRNA-1273174.63.68735.62(18.87to 67.25) 27.49(14.41to40.56)

mRNA-1273≤511.5ND2.90(1.05to7.97)1.75(−0.20to3.71)

mRNA-1273/mRNA-1273155.82.58413.83(8.08to23.68)18.39(9.05to27.72)

Males,ages25-39y

Unvaccinated1461440.60.1011[Reference]0[Reference]

AZD122203.1NDNDND

AZD1222/AZD122200.5NDNDND

BNT162b217109.20.1561.62(0.94to2.80)0.46(0.00to0.92)

BNT162b2/BNT162b21583.90.1791.75(1.03to2.99)0.59(0.07to1.10)

BNT162b2/mRNA-1273159.71.54323.16(12.60to 42.59) 11.33(5.59to17.07)

mRNA-1273≤530.6ND1.27(0.40to3.99)0.16(−0.55to0.86)

mRNA-1273/mRNA-12732623.01.13212.96(8.23to20.42)8.01(4.92to11.11)

Males,ages≥40

Unvaccinated2062657.60.0781[Reference]0[Reference]

AZD1222639.30.1532.30(0.99to5.33)0.66(−0.02to1.34)

AZD1222/AZD1222≤528.6ND1.24(0.30to5.18)0.10(−0.53to0.74)

BNT162b227375.80.0720.93(0.62to1.40)−0.04(−0.28to0.20)

BNT162b2/BNT162b231363.60.0851.08(0.74to1.57)0.05(−0.19to0.28)

BNT162b2/mRNA-1273≤59.4ND3.54(0.85to14.79)1.17(−0.58to2.93)

mRNA-12736480.1251.89(0.84to4.28)0.45(−0.10to1.00)

mRNA-1273/mRNA-12731143.30.2543.45(1.87to6.35)1.38(0.50to2.27)

Females,ages≥12y

Unvaccinated2114942.20.0431[Reference]0[Reference]

AZD1222≤564.1ND1.87(0.58to6.03)0.17(−0.13to0.46)

AZD1222/AZD1222≤531.6ND1.67(0.40to6.97)0.19(−0.30to0.69)

BNT162b235572.30.0611.46(1.01to2.11)0.15(0.02to0.28)

BNT162b2/BNT162b230522.70.0571.25(0.77to2.05)0.09(−0.09to0.26)

BNT162b2/mRNA-1273≤519.1ND9.62(3.11to29.77)1.44(0.02to2.87)

mRNA-1273≤590ND1.45(0.35to5.97)0.05(−0.13to0.23)

mRNA-1273/mRNA-1273771.60.0982.73(1.27to5.87)0.48(0.07to0.89)

Females,ages16-24y

Unvaccinated31707.10.0441[Reference]0[Reference]

AZD122202.4NDNDND

AZD1222/AZD122200.3NDNDND

Table2.MyocarditisWithin28DaysAfteraDoseofSARS-CoV-2Vaccinea

Subgroup,exposureb

No.ofexcessevents in28dper100000 vaccinees(95%CI)

BNT162b2≤563.2ND1.98(0.56to7.01)0.18(−0.13to0.49)

BNT162b2/BNT162b2≤543.9ND2.86(1.10to7.48)0.57(−0.01to1.15)

BNT162b2/mRNA-1273≤54ND71.70(15.10to 340.36) 3.74(−1.45to8.93)

mRNA-1273010.7NDNDND

mRNA-1273/mRNA-127306NDNDND

Females,ages25-39y

Unvaccinated421269.70.0331[Reference]0[Reference]

AZD122208.8NDNDND

AZD1222/AZD122201.3NDNDND

BNT162b2≤5105ND2.35(0.90to6.12)0.21(−0.03to0.45)

BNT162b2/BNT162b2≤585ND2.35(0.89to6.25)0.26(−0.04to0.55)

BNT162b2/mRNA-127307.5NDNDND

mRNA-1273027.7NDNDND

mRNA-1273/mRNA-1273≤521ND7.31(2.16to24.78)0.95(−0.14to2.03)

Females,ages≥40y

Unvaccinated1372541.60.0541[Reference]0[Reference]

AZD1222≤552.9NDNDND

AZD1222/AZD1222≤530NDNDND

BNT162b227392.50.0691.37(0.90to2.08)0.14(−0.03to0.31)

BNT162b2/BNT162b220388.10.0521.02(0.63to1.65)0.01(−0.18to0.20)

BNT162b2/mRNA-1273≤57.5ND8.12(1.83to36.00)1.79(−0.72to4.29)

mRNA-1273≤548.5ND4.68(0.60to36.45)0.12(−0.13to0.38)

mRNA-1273/mRNA-1273≤544.4ND3.03(1.10to8.31)0.46(−0.05to0.97)

Amongmales16to24yearsofage,theexcessnumberof myocarditiseventsper100000vaccineesinthe28-dayrisk periodsafterthefirstdoseofBNT162b2was1.55(95%CI,0.702.39)eventsandaftertheseconddosewas5.55(95%CI,3.707.39)events,anditwas1.75(95%CI,−0.20to3.71)eventsafterthefirstdoseofmRNA-1273and18.39(95%CI,9.0527.72)eventsaftertheseconddose(Table2).

Foraheterologousschedule(1dosewithBNT162b2and theotherdosewithmRNA-1273),38myocarditiscases(34 males)occurredfollowingtheseconddose,withanexcess numberofeventsinmalesof10.34(95%CI,6.86-13.83)events. Inmalesaged16to24years,17myocarditiscasesoccurred, withanexcessnumberofeventsof27.49(95%CI,14.4140.56)events(Table2).

VaccinationandPericarditis

PericarditisinmalesfollowedapatternsimilartomyocarditisbyvaccineproductandagebutwithlowerIRRs.Pericarditiswasrareinfemalesaged12to39years.Amongmalesaged 16to24yearsofage,theexcessnumberofpericarditisevents withinthe28-dayriskperiodwas7.39per100000vaccinees (95%CI,1.46-13.32)eventsfortheseconddoseofmRNA-1273 (eTables4and5inthe Supplement).

VaccinationandMyocarditisorPericarditisCombined TheIRRsofmyocarditisorpericarditiscombinedamongmales aged16to24yearswereslightlyhigherthanthoseofmyocar-

Abbreviations:IRR,adjusted incidencerateratio;mRNA, messengerRNA;ND,notdetermined. a TheIRRsandexcesseventsin28 daysper100000vaccinees, accordingtosexandage.TheIRRs formodel2,adjustedforagegroup, sex,previousSARS-CoV-2infection, healthcareworkerstatus,nursing homeresident,andcomorbidity variables;forothermodelssee eFigure2andeTable5inthe Supplement

b Vaccinedoseslistedinsequential order.

c Onrowswithoutcases,only follow-updataareshown.

d Onrowswith5orfewercases, incidentrateisnotgiven.

ditis(Table3).Inmalesaged25to39years,theIRRswere generallylower.Amongfemalesaged16to24years,theIRRs weresimilartothoseformalesbutwithfewerevents.Among malesaged12to15years,thecrudeIRRwasbasedonveryfew eventsamongthevaccinatedpopulation(eTable6inthe Supplement).

SARS-CoV-2InfectionandMyocarditis

Duringthe28-dayriskperiodafterapositiveSARS-CoV-2test, therewere73myocarditiscases.Excesseventsofmyocarditiswere3.26(95%CI,1.90-4.61)eventsper100000individualswithapositivetestresultamongallmales,and1.37(95% CI,−0.14to2.87)eventsper100000individualswithapositivetestresultamongmalesaged16to24years(eTable7in the Supplement).

SupplementaryAnalyses

TheIRRsandexcessrateswereslightlyattenuatedwhenmodel 1wascomplementedbyothercovariates(model2)andfurtherattenuatedwhencalendarperiodwasadded(model3) (eFigure2andeTable5inthe Supplement).Amongmalesaged 16to24years,adjustmentforcalendarperiod(model3)yielded unstablepointestimateswithwideCIsfortheseconddoseof mRNA-1273.Heterogeneityoftheanalysesacrosscountrieswas notstatisticallysignificant(eFigure2inthe Supplement);thus, wepresenttheresultsaspooled4-countryestimatesofIRRs andexcessrates.

Table2.MyocarditisWithin28DaysAfteraDoseofSARS-CoV-2Vaccinea (continued)

Malesaged16-24y

2.69(1.08-6.69)

2.03(0.86-4.80)

1.89(0.55-6.44)

2.07(1.04-4.13)

2.16(1.40-3.33)

9.63(1.28-72.40)

4.50(0.59-34.02)

1.29(0.32-5.26)

2.90(1.05-7.97)

5.02(2.40-10.48)

4.70(1.98-11.14)

7.25(2.65-19.86)

5.25(3.01-9.18)

5.31(3.68-7.68)

BNT162b2/mRNA-1273

32.76(7.90-135.91)

36.38(17.88-74.00)

35.62(18.87-67.25)

10.47(1.39-78.75)

17.38(4.18-72.35)

24.96(7.18-86.70)

11.28(5.64-22.57)

13.83(8.08-23.68)

Squaresrepresentincidencerateratios(IRRs)with95%CIs;squaresize, countryweight;anddiamonds,pooledestimateswith95%CIs.Asinglevaccine nameindicatesfirstdoseofthatvaccine(eg,BNT162b2)andtheriskofthe outcomeafterthefirstdose.Vaccinenamesincombinationindicateavaccine scheduleoffirstdoseofthefirstvaccineandaseconddoseofthesecond

Ofthe213myocarditiscasesinthe28-dayriskwindowafteraseconddoseofSARS-CoV-2mRNAvaccination,135events occurredwithinthefirstweek,yieldinghigherIRRsinthe7-day riskperiod(Table2;eTable8inthe Supplement).Amongmales aged16to24years,theadjustedIRRswere12.50(8.24-18.96) foraseconddoseofBNT162b2and38.29(21.95-66.80)fora seconddoseofmRNA-1273.

Formalesaged12to39years,country-specificmediantime tohospitaladmissionformyocarditiscaseswas3to7days (eTable9inthe Supplement).Comorbidconditionsdidnotdiffermarkedlybetweenvaccinatedandunvaccinatedmyocarditiscases(eTable10inthe Supplement).Medianhospital lengthofstaywas4to5daysforbothvaccinatedandunvaccinatedcases(eTable11inthe Supplement).Forallagegroups, the28-daymortalityoftheunvaccinatedcaseswithmyocarditiswas0.8%(95%CI,0.3%-2.0%)andrangedfrom0.2% (95%CI,0.0%-0.4%)aftertheseconddoseofBNT162b2to 4.5%(95%CI,0.0%-13.2%)aftertheseconddoseof mRNA-1273;therewerenodeathsamongcasesforpatients youngerthan40years(eTable11inthe Supplement).

Malesaged25-39y B

0.85(0.11-6.29)

1.08(0.39-3.00)

3.48(1.40-8.68)

1.28(0.55-2.95)

1.62(0.94-2.80)

1.30(0.18-9.70)

1.76(0.24-12.79)

0.89(0.12-6.40)

1.27(0.40-3.99)

1.65(0.39-7.04)

2.25(0.95-5.30)

2.16(0.50-9.30)

1.25(0.50-3.10)

1.75(1.03-2.99)

BNT162b2/mRNA-1273

32.03(7.75-132.38)

20.19(9.86-41.37)

35.02(4.86-252.53)

23.16(12.60-42.59)

16.36(8.04-33.30)

7.65(1.85-31.65)

22.19(8.90-55.32)

7.23(3.13-16.70)

12.96(8.23-20.42)

vaccine(eg,BNT162b2,BNT162b2)andtheriskoftheoutcomeafterthe seconddose.Model2adjustedforagegroupandsex,previousSARS-CoV-2 infection,healthcareworkerstatus,nursinghomeresident,andcomorbidity variables.

Discussion

Thiscohortstudyof23.1millionresidentsacross4Nordiccountriesshowedhigherratesofmyocarditisandpericarditiswithin 28daysafterbeingvaccinatedwithSARS-CoV-2mRNAvaccinescomparedwithbeingunvaccinated.Therisksofmyocarditisandpericarditiswerehighestwithinthefirst7daysof beingvaccinated,wereincreasedforallcombinationsofmRNA vaccines,andweremorepronouncedaftertheseconddose. AseconddoseofmRNA-1273hadthehighestriskofmyocarditisandpericarditis,withyoungmalesaged16to24yearshavingthehighestrisk.

MyocarditisaftermRNAvaccinationwasrareinthisstudy cohortandevenamongyoungmales.Theriskofmyocarditis followingthemRNAvaccineshasbeenevaluatedbytheUS FoodandDrugAdministration,whichconcludedthatthebenefitsofvaccinationoutweightherisksandfullyauthorizedthe useofmRNA-1273inpersons18yearsorolderandBNT162b2 inpersons16yearsorolder.Inaddition,BNT162b2isautho-

Figure2.MyocarditisWithin28DaysAfterSARS-CoV-2Vaccinationin4NordicCountriesAmongMalesAged16to39Years,WithPooledEstimates

SARS-CoV-2VaccinationandMyocarditisinaNordicCohortStudyof23MillionResidents

Femalesaged≥12y B

1.14(0.59-2.21)

1.50(0.93-2.40)

1.41(0.78-2.54)

1.43(0.95-2.13)

1.40(1.09-1.80)

1.51(0.37-6.20)

0.90(0.22-3.64)

2.05(0.65-6.51)

1.42(0.63-3.20)

1.45(0.84-2.52)

2.19(1.33-3.61)

1.97(1.21-3.21)

1.86(1.00-3.46)

2.07(1.43-2.99)

2.04(1.61-2.58)

21.61(7.99-54.48)

16.99(11.51-25.07)

11.78(6.65-20.87)

5.63(2.47-12.84)

10.76(5.71-20.28)

7.07(4.51-11.08)

8.55(6.40-11.41)

Squaresrepresentincidencerateratios(IRRs)with95%CIs;squaresize, countryweight;anddiamonds,pooledestimateswith95%CIs.Asinglevaccine nameindicatesfirstdoseofthatvaccine(eg,BNT162b2)andtheriskofthe outcomeafterthefirstdose.Vaccinenamesincombinationindicateavaccine scheduleoffirstdoseofthefirstvaccineandaseconddoseofthesecond

rizedforemergencyuseinchildren5yearsorolder.20,21 The EuropeanMedicinesAgencyconcludedthatthebenefitsofvaccinationoutweightherisksandapprovedmRNA-1273foruse inpersons12yearsorolderandBNT162b2forthose5yearsor older.22,23 Inaddition,acommentpublishedbytheAmerican CollegeofCardiology24 evaluatedvaccine-associatedmyocarditisriskandconcludedthatthebenefitsofvaccination outweightherisks.AsofJanuary2022,therehavebeennearly 5.8milliondeathsassociatedwithCOVID-19worldwide sincethestartofthepandemic. 25 Allcurrentlyavailable SARS-CoV-2mRNAvaccinesarehighlyeffectiveagainstsevereCOVID-19andprovidesomeprotectionagainsttransmissionandinfection. 26-28 Thereissomeevidencethatthe mRNA-1273vaccine,possiblyowingtoitshigherconcentrationofmRNA,isassociatedwithincreasedimmunogenicity andeffectiveness. 29,30 Thismoreprofoundimmuneresponsecouldbeonereasonforthehigherriskofmyocarditis, butthishypothesisneedstobeinvestigatedfurther.

1.72(0.64-4.62)

0.36(0.11-1.41)

2.20(1.11-4.36)

1.46(0.86-2.49)

1.46(1.01-2.11)

2.48(0.33-18.69)

0.87(0.12-6.30)

1.45(0.35-5.97)

2.86(1.29-6.34)

0.84(0.36-1.94)

0.70(0.21-2.30)

1.14(0.62-2.10)

1.25(0.77-2.05)

11.03(1.53-79.73)

3.77(0.90-15.81)

39.56(5.50-284.58)

9.62(3.11-29.77)

5.13(1.18-22.32)

2.52(0.61-10.38)

3.53(0.85-14.72)

0.63(0.09-4.53)

2.73(1.27-5.87)

vaccine(eg,BNT162b2,BNT162b2)andtheriskoftheoutcomeafterthe seconddose.Model2adjustedforagegroupandsex,previousSARS-CoV-2 infection,healthcareworkerstatus,nursinghomeresident,andcomorbidity variables.

Ourfindingsareconsistentwithhigherriskaftertheseconddoseandhigherriskinyoungmales.2,3,10,11,31-36 Excess eventswithin28daysinmalesaged16to24yearsof5.55events per100000vaccineesaftertheseconddosewithBNT162b2 and18.39eventsper100000vaccineesaftertheseconddose withmRNA-1273areamongthehighestreported.3,4,32,33 Our findingofahigherriskofmyocarditisaftermRNA-1273than afterBNT162b2inthisgroupisinlinewithdatafromtheUS, Canada,France,andEngland.5,10,11,33,35 Incomparisonwithpreviousstudies,wehadtheadvantageofdataanalyzedaccordingtoacommonprotocolfrom4differentcountries,andthat showedsimilardirectionsofassociations,despiteconsiderabledifferencesinpriorSARS-CoV-2infectionlevelsandlockdownpolicies.

StrengthsandLimitations

Themainstrengthsofourstudyincludethepopulationbasedcohortdesignin4Nordiccountries,largesamplesize,

Figure3.MyocarditisWithin28DaysAfterSARS-CoV-2Vaccinationin4NordicCountries AmongMalesandFemalesAged12YearsorOlder,WithPooledEstimates

Malesaged≥12y A

Table3.MyocarditisorPericarditisCombinedWithin28Days AfteraDoseofSARS-CoV-2Vaccine,AccordingtoSexandAgea

Subgroup,exposureb

Males,aged≥12y

No.of eventsc

Follow-up, 1000 personyears

Crude incidence rateper 1000 personyearsof follow-upd IRR(95%CI)

No.ofexcessevents in28dper100000 vaccinees(95%CI)

Unvaccinated13945340.40.2611[Reference]0[Reference]

AZD122218430.4181.47(0.91to2.36)1.02(−0.12to2.16)

AZD1222/AZD12221029.20.3421.22(0.64to2.30)0.47(−0.93to1.87)

BNT162b2213560.80.3801.38(1.19to1.60)0.80(0.48to1.13)

BNT162b2/BNT162b22274950.4591.65(1.43to1.91)1.39(1.04to1.74)

BNT162b2/mRNA-12735723.72.4028.21(6.20to10.88)16.18(11.94to20.43)

mRNA-12733093.20.3221.17(0.82to1.68)0.36(−0.41to1.14)

mRNA-1273/mRNA-12739372.31.2874.63(3.75to5.72)7.74(6.10to9.37)

Males,aged16-24y

Unvaccinated271794.50.3411[Reference]0[Reference]

AZD1222≤50.7ND8.69(0.98to77.17)10.34(−10.14to30.81)

AZD1222/AZD122200.1NDNDND

BNT162b24163.90.6421.94(1.39to2.70)2.38(1.27to3.49)

BNT162b2/BNT162b25941.51.4204.20(3.15to5.58)8.30(6.05to10.54)

BNT162b2/mRNA-1273244.65.20620.04(12.29to32.69)37.94(22.73to53.14)

mRNA-1273711.50.6112.20(1.03to4.67)2.55(0.07to5.03)

mRNA-1273/mRNA-1273225.83.79011.36(7.32to17.65)26.51(15.38to37.64)

Males,aged25-39y

Unvaccinated3441440.50.2391[Reference]0[Reference]

AZD1222≤53.1ND2.62(0.35to19.35)1.54(−2.03to5.10)

AZD1222/AZD122200.5NDNDND

BNT162b243109.20.3941.62(1.02to2.56)1.15(0.23to2.08)

BNT162b2/BNT162b24183.90.4892.10(1.49to2.97)1.96(1.10to2.83)

BNT162b2/mRNA-1273279.72.77811.47(7.50to17.55)19.45(12.07to26.83)

mRNA-12731230.60.3921.64(0.92to2.93)1.17(−0.08to2.43)

mRNA-1273/mRNA-127342231.8297.33(5.27to10.19)12.11(8.40to15.83)

Males,aged≥40y

Unvaccinated7482657.50.2821[Reference]0[Reference]

AZD12221639.30.4071.30(0.78to2.15)0.72(−0.55to1.98)

AZD1222/AZD12221028.60.3501.13(0.59to2.13)0.30(−1.23to1.83)

BNT162b2125375.70.3331.10(0.91to1.33)0.23(−0.22to0.67)

BNT162b2/BNT162b2122363.60.3361.09(0.90to1.32)0.22(−0.24to0.67)

BNT162b2/mRNA-127369.40.6402.30(1.02to5.20)2.77(−0.05to5.59)

mRNA-127310480.2080.74(0.40to1.38)−0.56(−1.95to0.83)

mRNA-1273/mRNA-12732843.30.6472.25(1.54to3.29)2.76(1.44to4.08)

Females,aged≥12y

Unvaccinated6194942.10.1251[Reference]0[Reference]

AZD12221064.10.1561.24(0.66to2.35)0.23(−0.40to0.87)

AZD1222/AZD1222≤531.6ND0.74(0.27to2.00)−0.34(−1.68to1.01)

BNT162b296572.30.1681.15(0.93to1.43)0.17(−0.07to0.42)

BNT162b2/BNT162b2102522.70.1951.26(0.95to1.68)0.31(−0.03to0.66)

BNT162b2/mRNA-12731519.10.7876.64(3.90to11.30)5.13(2.49to7.77)

mRNA-127322900.2441.96(1.28to3.00)0.92(0.36to1.48)

mRNA-1273/mRNA-12732871.60.3912.88(1.87to4.45)1.96(1.10to2.81)

Females,aged16-24y

Unvaccinated63330.0181[Reference]0[Reference]

AZD122200NDNDND

AZD1222/AZD122200NDNDND

Table3.MyocarditisorPericarditisCombinedWithin28Days

AfteraDoseofSARS-CoV-2Vaccine,AccordingtoSexandAgea

(continued)

No.ofexcessevents in28dper100000 vaccinees(95%CI)

BNT162b208.5NDNDND

BNT162b2/BNT162b205.6NDNDND

BNT162b2/mRNA-127300NDNDND

mRNA-1273≤53.2ND13.12(1.19to144.65)2.24(−2.17to6.65)

mRNA-1273/mRNA-127300.2NDNDND

Females,aged25-39y

Unvaccinated66707.10.0931[Reference]0[Reference]

AZD122202.4NDNDND

AZD1222/AZD122200.3NDNDND

BNT162b2763.20.1111.20(0.55to2.63)0.14(−0.42to0.71)

BNT162b2/BNT162b21043.90.2282.49(1.27to4.88)1.05(0.24to1.85)

BNT162b2/mRNA-1273≤54ND21.19(7.85to57.19)9.05(1.10to16.99)

mRNA-1273≤510.7ND6.34(2.26to17.77)2.41(0.00to4.82)

mRNA-1273/mRNA-1273661.00124.26(10.03to58.68)7.36(1.46to13.26)

Females,aged≥40y

Unvaccinated931269.70.0731[Reference]0[Reference]

AZD122208.8NDNDND

AZD1222/AZD122201.3NDNDND

BNT162b2121050.1142.09(1.13to3.88)0.46(0.09to0.82)

BNT162b2/BNT162b216850.1882.84(1.11to7.25)0.94(0.27to1.60)

BNT162b2/mRNA-1273≤57.5ND12.33(4.51to33.67)4.71(0.56to8.87)

mRNA-1273627.70.2176.50(2.71to15.56)1.41(0.26to2.56)

mRNA-1273/mRNA-12738210.3816.48(3.12to13.45)2.47(0.73to4.21)

near-completefollow-up,andindependentascertainmentof vaccinationsanddiagnosesfromnationwideregisterswith mandatoryreporting.Thefindingsinthemeta-analyseswere supportedbyconsistentfindingsacrossall4countries,despitesomecountry-specificdifferencesindatasources, SARS-CoV-2transmission,testingactivities,andvaccination schedules.

Therearealsosomelimitationsofthestudy.Wedefined eventsasaninpatienthospitaladmissionwithacorresponding mainorsecondarydischargediagnosisofmyocarditisorpericarditis.Diagnosticcodeshavebeenshowntohave85%positivepredictivevalueamongpatientsyoungerthan60years.37 Thus,withoutaccesstodataonclinicalmeasures,suchastroponinlevels,diagnosticimagingresults,andendomyocardialbiopsy,westudiedmyocarditisasdiagnosedinclinicalpracticeand couldthereforenotassesshowmanyofthesepatientsfulfilled allcriteriaforreceivingamyocarditisdiagnosis.38 However,the medianhospitallengthofstaywas4to5daysforbothunvaccinatedandvaccinatedpatients,enablingsufficienttimeforadequatediagnosticproceduresandindicativeofnodifferencein diseaseseveritybetweenvaccinatedandunvaccinatedcases. Deathswererare,withnodeathsofpersonsyoungerthan40 years.Ourfindingsinchildrenaged12to15yearswerelimited torelativelyfewexposedindividualsbecausevaccinationinthis agegrouponlyrecentlystartedinmostcountries.

Surveillancebias,wherebyincreasedfocusandmediaattentiononmyocarditisasanadverseeventaftervaccination39

Abbreviations:IRR,adjusted incidencerateratio;mRNA, messengerRNA;ND,notdetermined. a TheIRRsandexcesseventsin28 daysper100000vaccinees, accordingtosexandage.TheIRRs formodel2adjustedforagegroup, sex,previousSARS-CoV-2infection, healthcareworkerstatus,nursing homeresident,andcomorbidity variables;forothermodelssee eTable5inthe Supplement

b Vaccinedoseslistedinsequential order.

c Onrowswithoutcases,only follow-updataareshown.

d Onrowswith5orfewercases, incidencerateisnotgiven.

resultedinmoresubclinicalcasesbeingdiagnosed,cannot beruledout.Hence,allstudiesincludingdataonvaccinationandmyocarditisafterApril25,2021,arelikelyproneto thispotentialsurveillancebias. However,inour study,surveillancebiasisunlikelytofullyexplainthedifferences betweenthefirstandseconddose,betweenthe2mRNA vaccines,andbetweenagegroups.DenmarkandNorway hadlowerbackgroundincidenceratesofmyocarditisthan FinlandandSweden.

Westudiedratesofmyocarditisafterapositivetestresult forSARS-CoV-2infection. However,SARS-CoV-2infectionis associatedwithacuteandpostacuteeventsotherthanmyocarditis,includinghospitalizations,intensivecareunitadmissions,anddeath.40 Thepresentstudyshowedincreasedrisk ofmyocarditisafterapositivetestresultforSARS-CoV-2infection,andtheriskwashighestintheolderagegroups, whereastheriskofmyocarditisaftervaccinationwashighest intheyoungeragegroups. However,the estimatedriskofany outcomeafterSARS-CoV-2infectionwillbedependentonthe testingstrategy.IfonlysevereCOVID-19casesaretested,the associationwithothereventswillbestrengthenedowingto selectionbias.Therefore,toreduceselectionbiasinouranalysesofmyocarditisafterSARS-CoV-2infection,weincludedonly theperiodfromAugust2020onward,whentestingwaswidely availableintheNordiccountries.

The2mRNAvaccineswereusedintheNordiccountries accordingtoavailabilityduring2021,andsupplywaslimited

duringthefirstmonthsof2021.Furthermore,vaccinationwas firstprovidedforolderadults.Theavailabilityhasthusvariedacrossage,calendarmonths,andcountries.Thebackgroundincidencerateofmyocarditisfluctuateswithinfectiousdiseaseburden,beingtypicallyhigherduringthefalland winter.41 Moreover,differencesinlockdownmeasuresaffectingthespreadofSARS-CoV-2andothervirusescouldalsoaffect thebackgroundincidencerateinbothunvaccinatedandvaccinatedpersons.MostoftheyoungeragegroupswerevaccinatedfromJulytoSeptember2021,andveryfewduringthe spring. However,our supplementarymodel3withadjustmentforcalendarperiodresultedinwiderCIsbutdidnotsubstantiallychangethepointestimates.

TheobservedrisksofmyocarditisandpericarditisareapplicabletothecurrentSARS-CoV-2pandemicsituationinthe Nordiccountries.Inothersettings,thebackgroundincidenceofmyocarditisandpericarditisandrisksfollowingvaccinationmaydiffer.Furthermore,wecannotdrawconclusionsfromthestudyresultstopredictmyocarditisand pericarditisafterathirddoseorforchildrenyoungerthan12 years.WecapturedallhospitalizationsformyocarditisandpericarditisintheNordiccountriesduringthestudyperiod;however,withoutaccesstodataonclinicalmeasuresanddiagnosticimagingresults,futureadjudicationmustassesshowmany

ARTICLEINFORMATION

AcceptedforPublication: February23,2022.

PublishedOnline: April20,2022. doi:10.1001/jamacardio.2022.0583

OpenAccess: Thisisanopenaccessarticle distributedunderthetermsofthe CC-BYLicense ©2022KarlstadØetal. JAMACardiology

AuthorAffiliations: DepartmentofChronic Diseases,NorwegianInstituteofPublicHealth, Oslo,Norway(Karlstad,Selmer,Gunnes,Gulseth);

DepartmentofPublicHealthandWelfare,Finnish InstituteforHealthandWelfare,Helsinki,Finland (Hovi,Härkänen);DepartmentofEpidemiology Research,StatensSerumInstitut,Copenhagen, Denmark(Husby,Hansen,Wohlfahrt,Hviid); DepartmentofEpidemiologyandBiostatistics, ImperialCollegeLondon,London,UnitedKingdom (Husby);DivisionofLicensing,SwedishMedical ProductsAgency,Uppsala,Sweden(Pihlström, Grünewald);HealthSecurity,FinnishInstitutefor HealthandWelfare,Helsinki,Finland(Nohynek); NorwegianResearchCentreforWomen’sHealth, OsloUniversityHospital,Oslo,Norway(Gunnes); DivisionofUseandInformation,SwedishMedical ProductsAgency,Uppsala,Sweden(Sundström, Ljung);InformationServices,FinnishInstitutefor HealthandWelfare,Helsinki,Finland(Nieminen); DepartmentofDrugDesignandPharmacology, PharmacovigilanceResearchCenter,Universityof Copenhagen,Copenhagen,Denmark(Hviid); InstituteofEnvironmentalMedicine,Karolinska Institutet,Stockholm,Sweden(Ljung).

AuthorContributions:DrsKarlstadandLjunghad fullaccesstoallofthedatainthestudyandtake responsibilityfortheintegrityofthedataandthe accuracyofthedataanalysis.DrsKarlstad,Hovi, andHusbycontributedequallytothisstudyandare consideredco–firstauthors;DrsHviidandLjung

ofthesepatientsfulfillallcriteriaforamyocarditisdiagnosis. Althoughstudiesonthelong-termprognosisofvaccineassociatedcasesofmyocarditisarelackingandareurgently needed,someevidencesuggeststhatthe28-dayriskofdeath, hospitalreadmissionrates,anddevelopmentofheartfailure appearlow,especiallyintheyoungeragegroups.34

Conclusions

Inthiscohortstudyof23.1millionNordicresidentsaged12 yearsorolder,theriskofmyocarditiswashigherwithin28days ofvaccinationwithbothBNT162b2andmRNA-1273comparedwithbeingunvaccinated,andhigherafterthesecond doseofvaccinethanthefirstdose.TheriskwasmorepronouncedaftertheseconddoseofmRNA-1273thanafterthe seconddoseofBNT162b2,andtheriskwashighestamong malesaged16to24years.Ourdataarecompatiblewith4to7 excesseventswithin28daysper100000vaccineesafteraseconddoseofBNT162b2,and9to28excesseventswithin28days per100000vaccineesafteraseconddoseofmRNA-1273.The riskofmyocarditisassociatedwithvaccinationagainst SARS-CoV-2mustbebalancedagainstthebenefitsofthese vaccines.

contributedequallyandareconsideredco–senior authors.

Conceptanddesign: Karlstad,Hovi,Husby,Selmer, Nohynek,Sundström,Grünewald,Gulseth, Hviid,Ljung.

Acquisition,analysis,orinterpretationofdata: Karlstad,Hovi,Husby,Härkänen,Selmer,Pihlström, Hansen,Gunnes,Sundström,Wohlfahrt,Nieminen, Grünewald,Gulseth,Hviid,Ljung.

Draftingofthemanuscript: Karlstad,Husby, Härkänen,Nohynek,Ljung.

Criticalrevisionofthemanuscriptforimportant intellectualcontent: Karlstad,Hovi,Husby, Härkänen,Selmer,Pihlström,Hansen,Nohynek, Gunnes,Sundström,Wohlfahrt,Nieminen, Grünewald,Gulseth,Hviid.

Statisticalanalysis: Karlstad,Härkänen,Selmer, Pihlström,Hansen,Gunnes,Sundström, Grünewald,Ljung.

Obtainedfunding: Gulseth,Hviid. Administrative,technical,ormaterialsupport: Karlstad,Nohynek,Gulseth.

Supervision: Hovi,Husby,Nohynek,Wohlfahrt, Hviid,Ljung.

ConflictofInterestDisclosures: DrKarlstad reportedparticipatinginresearchprojectsfunded byNovoNordiskandLEOPharma,all regulator-mandatedphase4studieswithfunds paidtohisinstitutionandoutsidethesubmitted work.DrHovireportedbeingaffiliatedwiththe FinnishInstituteforHealthandWelfareandwas thusobligatedbylegislationtoinvestigatethe potentialpostmarketingharmfuleffectsofvaccines duringtheconductofthestudy.DrHusbyreported receivingfundingfromtheLundbeckFoundation. DrNohynekreportedreceivingnonfinancial supportfromWHOSAGE(StrategicAdvisoryGroup ofExperts)andtheGlobalAdvisoryCommitteeon VaccineSafetyduringtheconductofthestudy;and beingemployedbytheFinnishInstituteforHealth andWelfare(THL),whichreceivesresearchfunding

fromSanofiPasteur,GlaxoSmithKline,andPfizerfor researchstudiesnotrelatedtothecurrentstudy nortoCOVID-19.DrSundströmreported participatinginresearchfundedbygovernmental agencies,universities,AstellasPharma,Janssen Biotech,AstraZeneca,Pfizer,Roche,(then)Abbott Laboratories,(then)Schering-Plough,UCBNordic, andSobi,withallfundspaidtoKarolinskaInstitutet, outsidethesubmittedwork.DrNieminenreported receivinggrantsfromSanofiPasteuroutsidethe submittedwork;andbeingemployedbyTHL. DrGrünewaldreportedbeinginvolvedinthe EuropeanMedicinesAgencyregulatoryassessment ofComirnaty;beingpreviouslyemployedatadrug developmentconsultancyfirmwithcross-product responsibilities;andbeinginvolvedonaprojectfor pertussisvaccinesfundedbySanofiPasteur,Merck Sharp&DohmeCorp,andGlaxoSmithKlineatthe SwedishAgencyofInfectiousDiseaseControl. DrGulsethreportedparticipatinginresearch projectsandclinicaltrialsfundedbyNovoNordisk, GlaxoSmithKline,AstraZeneca,and Boehringer-IngelheimpaidtoOsloUniversity Hospital;andreceivingpersonalfeesfrom Sanofi-Aventis.DrHviidreportedreceivinggrants fromTheLundbeckFoundationduringtheconduct ofthestudy.DrLjungreportedreceivinggrants fromSanofiAventispaidtohisinstitutionoutside thesubmittedwork;andreceivingpersonalfees fromPfizeroutsidethesubmittedwork.Noother disclosureswerereported.

AdditionalInformation: Amongus,DrHviidhad fullaccesstoalltheDanishdata,DrHovihadfull accesstoalltheFinnishdata,DrKarlstadhadfull accesstoalltheNorwegiandata,DrLjunghad fullaccesstoalltheSwedishdata,andDrHärkänen hadfullaccesstoallthemeta-analysesdatainthe study,andeachinvestigatortakesresponsibilityfor theintegrityofthedataandtheaccuracyofthe respectiveanalyses.Inaddition,DrsHusby, Hansen,andWohlfahrt,oftheStatensSerum

Institut,analyzedtheDanishdataandare responsibleforthoseanalyses;DrsKarlstad, Selmer,andGunnes,oftheNorwegianInstituteof PublicHealth,conductedandareresponsiblefor theanalysesoftheNorwegiandata;DrsHoviand Härkänen,oftheFinnishInstituteforHealthand Welfare,conductedandareresponsibleforthe analysesoftheFinnishdata;andDrsPihlström, Sundström,Grünewald,andLjung,oftheSwedish MedicalProductsAgency,conductedandare responsiblefortheanalysesoftheSwedishdata.

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SARS-CoV-2VaccinationandMyocarditisinaNordicCohortStudyof23MillionResidents

OriginalInvestigation Research

people-who-received-pfizer-covid-shot-202104-25

40.LongB,CariusBM,ChavezS,etal.Clinical updateonCOVID-19fortheemergencyclinician:

SARS-CoV-2VaccinationandMyocarditisinaNordicCohortStudyof23MillionResidents

presentationandevaluation. AmJEmergMed 2022;54:46-57.doi:10.1016/j.ajem.2022.01.028

41.ArolaA,PikkarainenE,SipiläJO,PykäriJ, RautavaP,KytöV.Occurrenceandfeaturesof

Editor'sNote

childhoodmyocarditis:anationwidestudyin Finland. JAmHeartAssoc.2017;6(11):e005306. doi:10.1161/JAHA.116.005306

CommunicatingtheBenefitsofVaccinationinLightofPotentialRisks

AnnMarieNavar,MD,PhD;RobertO.Bonow,MD

Sincetheinitialcasereports ofmyocarditisfollowingCOVID-19 vaccination,severalpopulation-basedstudieshavedemonstratedanincreasedriskofmyocarditisfollowingvaccination,includingnationwidestudiesinEnglandandIsrael.1,2 In thisissueof JAMACardiology,Karlstadandcolleagues3 usednationwidepopulation immunizationandhospitalizationregisterdatafromDenmark,Finland,Sweden,andNorwaytoevaluatetherelative incidenceofmyocarditisandpericarditisafterimmunization againstSARS-CoV-2.Withdatafrommorethan23millionpersons,thestudyredemonstrateswhathasbeenshownpreviously:theriskofvaccine-associatedmyocarditisisnothomogeneous,asyoungmenandadolescentboysappeartobeat thehighestrisk,norisitconsistentbetweenvaccines,withthe risktodateappearingtobemuchhigherafterreceiptof mRNA-1273(Moderna)thanBNT162b2(Pfizer-BioNTech).

efitsofimmunizationinthoseolderthan40yearsclearlyoutweightherisks.

Relatedarticle page600

Howmightthesedatainformhowhealthcareprofessionalscommunicatewiththeirpatientsaboutvaccination?First, thegoodnews:olderadults,whoareatthehighestriskof COVID-19complications,appeartobeatextremelylowriskof vaccine-associatedmyocarditis.Forbothmenandwomen olderthan40years,theexcessnumberofcasesofmyocarditisfollowingvaccinationwasfewerthan2in100000vaccineesacrossallvaccinesstudied(Moderna,Pfizer-BioNTech,and AstraZeneca).3 Forreference,thedeathtollfromCOVID-19in theUSasofMarch2022wasmorethan200per100000 population.4 Giventhehighratesofmorbidityandmortality fromCOVID-19infectioninolderadultsandtheefficacyofthe vaccineinpreventingsevereinfectionanddeath,theben-

AuthorAffiliations: DivisionofCardiology, DepartmentofInternalMedicine,Universityof TexasSouthwesternMedicalCenter,Dallas(Navar);

Editor, JAMACardiology (Navar);Divisionof Cardiology,DepartmentofMedicine,Northwestern UniversityFeinbergSchoolofMedicine,Chicago, Illinois(Bonow);DeputyEditor,Diversity,Equity, andInclusion, JAMACardiology (Bonow).

CorrespondingAuthor: AnnMarieNavar,MD,PhD, UTSouthwesternMedicalCenter,ClinicalHeartand VascularCenter,WestCampusBldg3,2001Inwood Rd,FifthFloor,Dallas,TX75390(ann.navar@ utsouthwestern.edu).

PublishedOnline: April20,2022. doi:10.1001/jamacardio.2022.0590

Inyoungermen,however,theriskofmyocarditisismuch higher,withupto28excesscasesper100000vaccinees(1in 3571)amongyoungmenwhoreceiveaseconddoseofCOVID-19 vaccinewithmRNA-1273.3 Fortunately,thisriskappearsmuch loweramongyoungmenwhoreceivedBNT162b2(6excess casesper100000vaccinees,orapproximately1in17000vaccinees),andnoneofthecasesofmyocarditisfollowing immunizationinpersonsyoungerthan40yearswasfatal. Giventhesedata,youngmenmaychooseBNT162b2over mRNA-1273topotentiallylowertheirriskofmyocarditis,and healthcareprofessionalsmayconsiderrecommending BNT162b2overmRNA-1273forcertainpopulations,includingyoungmenandotherindividualsforwhomconcernsabout myocarditispresentabarriertoimmunization. However,the lowerriskofmyocarditiswithBNT162b2shouldbebalanced againstthepotentialthatmRNA-1273maybemoreeffective inpreventingsevereSARS-CoV-2infectionthanBNT162b2owingtoitsgreaterimmunogenicity.5

TheriskofmyocarditisfollowingCOVID-19immunizationisreal,butthislowriskmustbeconsideredincontextof theoverallbenefitofvaccine.Attheindividuallevel,immunizationpreventsnotonlyCOVID-19–relatedmyocarditisbut alsoseveredisease,hospitalization,long-termcomplications afterCOVID-19infection,anddeath.Atthepopulationlevel, immunizationhelpstodecreasecommunityspread,decreasethechancesofnewvariantsemerging,protectpeople whoareimmunocompromised,andensureourhealthcaresystemcancontinuetoprovideforourcommunities.

ConflictofInterestDisclosures: DrNavarreported receivingpersonalfeesfromPfizerand AstraZeneca,outsidethescopeofthiswork.No otherdisclosureswerereported.

1.HusbyA,HansenJV,FosbølE,etal.SARS-CoV-2 vaccinationandmyocarditisormyopericarditis: populationbasedcohortstudy. BMJ.2021;375: e068665.doi:10.1136/bmj-2021-068665

2.BardaN,DaganN,Ben-ShlomoY,etal.Safetyof theBNT162b2mRNACovid-19vaccineina nationwidesetting. NEnglJMed.2021;385(12): 1078-1090.doi:10.1056/NEJMoa2110475

3.KarlstadØ,HoviP,HusbyA,etal.SARS-CoV-2 vaccinationandmyocarditisinaNordiccohort

studyof23millionresidents. JAMACardiol.Published onlineApril20,2022.doi:10.1001/jamacardio.2022. 0583

4.MuellerB,LutzE.UShasfarhigherCoviddeath ratethanotherwealthycountries. TheNewYork Times.February1,2022.AccessedMarch2,2022. https://www.nytimes.com/interactive/2022/02/ 01/science/covid-deaths-united-states.html

5.DickermanBA,GerlovinH,MadenciAL,etal. ComparativeeffectivenessofBNT162b2and mRNA-1273vaccinesinU.S.veterans. NEnglJMed 2022;386(2):105-115.doi:10.1056/NEJMoa2115463