Zurich Open Repository andArchiveUniversity of ZurichMain LibraryStrickhofstrasse 39CH-8057 Zurichwww.zora.uzh.ch

Year: 2017

Safety of live vaccinations on immunosuppressive therapy in patients withimmune-mediated inflammatory diseases, solid organ transplantation or after

bone-marrow transplantation - A systematic review of randomized trials,observational studies and case reports

Croce, Evelina ; Hatz, Christoph ; Jonker, Emile F ; Visser, L G ; Jaeger, Veronika K ; Bühler, Silja

Abstract: BACKGROUND: Live vaccines are generally contraindicated on immunosuppressive therapydue to safety concerns. However, data are limited to corroborate this practice. OBJECTIVES: To esti-mate the safety of live vaccinations in patients with immune-mediated inflammatory diseases (IMID) orsolid organ transplantation (SOT) on immunosuppressive treatment and in patients after bone-marrowtransplantation (BMT). DATA SOURCES: A search was conducted in electronic databases (Cochrane,Pubmed, Embase) and additional literature was identified by targeted searches. ELIGIBILITY CRITE-RIA: Randomized trials, observational studies and case reports. POPULATION: Patients with IMID orSOT on immunosuppressive treatment and BMT patients <2years after transplantation. INTERVEN-TION/VACCINATIONS LOOKED AT Live vaccinations: mumps, measles, rubella (MMR), yellow fever(YF), varicella vaccine (VV), herpes zoster (HZ), oral typhoid, oral polio, rotavirus, Bacillus Calmette-Guérin (BCG), smallpox. DATA EXTRACTION: One author performed the data extraction using pre-defined data fields. It was cross-checked by two other authors. RESULTS: 7305 articles were identifiedand 64 articles were included: 40 on IMID, 16 on SOT and 8 on BMT patients. In most studies, the ad-ministration of live vaccines was safe. However, some serious vaccine-related adverse events occurred. 32participants developed an infection with the vaccine strain; in most cases the infection was mild. However,in two patients fatal infections were reported: a patient with RA/SLE overlap who started MTX/dex-amethasone treatment four days after the YFV developed a yellow fever vaccine-associated viscerotropicdisease (YEL-AVD) and died. The particular vaccine lot was found to be associated with a more than20 times risk of YEL-AVD. One infant whose mother was under infliximab treatment during pregnancyreceived the BCG vaccine at the age of three months and developed disseminated BCG infection anddied. An immunogenicity assessment was performed in 43 studies. In most cases the patients developedsatisfactory seroprotection rates. In the IMID group, YFV and VV demonstrated high seroconversionrates. MTX and tumor necrosis factor inhibitory therapy appeared to reduce immune responses to VVand HZ vaccine, but not to MMR and YF-revaccination. Seroconversion in SOT and BMT patientsshowed mostly higher rates for rubella than for measles, mumps and varicella. LIMITATIONS: Risk ofbias was high in the majority of studies since 39 of them were observational and 17 were case series/casereports. Only eight studies were randomized trials. BMT patient numbers included in this review werelow. CONCLUSIONS: Although live vaccinations were safe and sufficiently immunogenic in most studies,some serious reactions and vaccine-related infections were reported in immunosuppressed IMID and SOTpatients. Apart from mild vaccine-related infections MMR and VV vaccines were safe when administeredless than two years after BMT. IMPLICATIONS OF KEY FINDINGS: Until further data are available,live vaccinations under most immunosuppressive treatments should only be administered after a carefulrisk benefit assessment of medications and dosages. FUNDING: None.

DOI: https://doi.org/10.1016/j.vaccine.2017.01.048

Posted at the Zurich Open Repository and Archive, University of ZurichZORA URL: https://doi.org/10.5167/uzh-143879Journal ArticleAccepted Version

Originally published at:Croce, Evelina; Hatz, Christoph; Jonker, Emile F; Visser, L G; Jaeger, Veronika K; Bühler, Silja (2017).Safety of live vaccinations on immunosuppressive therapy in patients with immune-mediated inflammatorydiseases, solid organ transplantation or after bone-marrow transplantation - A systematic review ofrandomized trials, observational studies and case reports. Vaccine, 35(9):1216-1226.DOI: https://doi.org/10.1016/j.vaccine.2017.01.048

2

1

Title1

Safety of live vaccinations on immunosuppressive therapy in patients with immune-mediated2

inflammatory diseases, solid organ transplantation or after bone-marrow transplantation – a3

systematicreviewofrandomizedtrials,observationalstudiesandcasereports4

5

Authors6

EvelinaCrocea7

ChristophHatza,b,c8

EmileF.Jonkerd9

L.G.Visserd10

VeronikaK.Jaegere11

SiljaBühlera,*12

13

aDepartmentofPublicHealth,DivisionofInfectiousDiseases/TravelClinic,Epidemiology,14

BiostatisticsandPreventionInstitute,Hirschengraben84,8001Zurich,Switzerland.Phone:+414415

6344631,Fax:+4144634498416

bDepartmentofMedicineandDiagnostics,SwissTropicalandPublicHealthInstitute,Socinstrasse17

57,4051Basel,Switzerland.Phone:+41612848111,Fax:+4161284810118

cUniversityofBasel,Switzerland,Petersplatz1,4003Basel,Switzerland,Phone:+41612848111,19

Fax:+4161284810120

2

cDepartmentofInfectiousDiseases,LeidenUniversityMedicalCenter,Leiden,TheNetherlands,1

Phone:+31715262613,Fax:+317152667582

eDepartmentofRheumatology,BaselUniversityHospital,Petersgraben4,4031Basel,Switzerland.3

Phone:+41615565018,Fax:+416126590214

5

*Correspondingauthor6

7

891011121314151617181920212223242526272829303132 33

3

Abstract1

Background: Live vaccines are generally contraindicated on immunosuppressive therapy due to2

safetyconcerns.However,dataarelimitedtocorroboratethispractice.3

Objectives: To estimate the safety of live vaccinations in patients with immune-mediated4

inflammatorydiseases(IMID)orsolidorgantransplantation(SOT)onimmunosuppressivetreatment5

andinpatientsafterbone-marrowtransplantation(BMT).6

Data Sources: A search was conducted in electronic databases (Cochrane, Pubmed, Embase) and7

additionalliteraturewasidentifiedbytargetedsearches.8

Eligibilitycriteria:Randomizedtrials,observationalstudiesandcasereports.9

Population:PatientswithIMIDorSOTonimmunosuppressivetreatmentandBMTpatients<2years10

aftertransplantation.11

Intervention/vaccinationslookedat:Livevaccinations:mumps,measles,rubella(MMR),yellowfever12

(YF),varicellavaccine(VV),herpeszoster(HZ),oraltyphoid,oralpolio,rotavirus,BacillusCalmette–13

Guérin(BCG),smallpox.14

Dataextraction:Oneauthorperformedthedataextractionusingpredefineddatafields.Itwascross-15

checkedbytwootherauthors.16

Results:7,305articleswereidentifiedand64articleswereincluded:40onIMID,16onSOTand8on17

BMTpatients. Inmoststudies,theadministrationof livevaccineswassafe.However,someserious18

vaccine-related adverse events occurred. 32 participants developed an infection with the vaccine19

strain;inmostcasestheinfectionwasmild.However,intwopatientsfatalinfectionswerereported:20

apatientwithRA/SLEoverlapwhostartedMTX/dexamethasonetretamentfourdaysaftertheYFV21

developedayellowfevervaccine-associatedviscerotropicdisease(YEL-AVD)anddied.Theparticular22

vaccinelotwasfoundtobeassociatedwithamorethan20timesriskofYEL-AVD.Oneinfantwhose23

motherwas under infliximab treatment during pregnancy received the BCG vaccine at the age of24

threemonthsanddevelopeddisseminatedBCG infectionanddied.An immunogenicityassessment25

4

wasperformedin43studies.Inmostcasesthepatientsdevelopedsatisfactoryseroprotectionrates.1

In the IMID group, YFV andVV demonstrated high seroconversion rates.MTX and tumor necrosis2

factor inhibitory therapy appeared to reduce immune responses toVVandHZ vaccine, butnot to3

MMRandYF-revaccination.SeroconversioninSOTandBMTpatientsshowedmostlyhigherratesfor4

rubellathanformeasles,mumpsandvaricella.5

Limitations:Riskofbiaswashighinthemajorityofstudiessince39ofthemwereobservationaland6

17werecaseseries/casereports.Onlyeightstudieswererandomizedtrials.BMTpatientnumbers7

includedinthisreviewwerelow.8

Conclusions: Although live vaccinations were safe and sufficiently immunogenic in most studies,9

someseriousreactionsandvaccine-relatedinfectionswerereportedinimmunosuppressedIMIDand10

SOT patients. Apart from mild vaccine-related infections MMR and VV vaccines were safe when11

administeredlessthantwoyearsafterBMT.12

Implications of key findings: Until further data are available, live vaccinations under most13

immunosuppressivetreatmentsshouldonlybeadministeredafteracarefulriskbenefitassessment14

ofmedicationsanddosages.15

Funding:None.16

Keywords17

Immunosuppressivemedication, live vaccine, immune-mediated inflammatory disease, solid organ18

transplantation,bone-marrowtransplantation19

Abbreviations20

AEs–adverseevents,BCG-BacillusCalmette–Guérin,BMT-bonemarrowtransplantation,CSA-cyclosporineA,GvHD–21graft versus host disease, HZ - herpes zoster, HZV - herpes zoster vaccine, IBD - inflammatory bowel disease, IFX –22infliximab, IMID - immune-mediated inflammatory disease, INF – interferon, IVIG – intravenous immunoglobulin, JIA -23juvenileidiopathicarthritis,MMF-mycophenolate-mofetil,MMR-mumps;measles;rubella,MS–multiplesclerosis,MTX–24methotrexate,RA–rheumatoidarthritis,RCT–randomizedcontrolledtrial,RTX–rituximab,SAE–seriousadverseevent,25SLE–systemiclupuserythematosus,SOT–solidorgantransplantation,TAC–tacrolimus,TCZ–tocilizumab,TNFi–tumor26necrosis factor inhibitor, VV – varicella vaccine, VZV – varicella zoster virus, YEL-AVD - yellow fever vaccine-associated27viscerotropicdisease,YF–yellowfever,YFV–yellowfevervaccine28

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5

Introduction1

2

Immunizationsareanimportantmeansforpreventinginfectiousdiseasesinhealthyindividualsand3

especially in vulnerable patient groups with immunocompromising conditions. However, live4

vaccinationscontainanattenuatedvaccinestrain,whichhasthetheoreticalpotentialtoreverttothe5

original pathogenic form and to induce infection by the vaccine strain, particularly in6

immunocompromised individuals. Serious infectionswith the vaccine strain and even deaths have7

occurredinHIVpatients,leukemiapatientsandpatientswithinheritedimmunodeficiencies[1–4].8

Thenumberof individuals treatedwith immunosuppressivemedicationsdue to immune-mediated9

inflammatory diseases (IMID), solid organ transplantation (SOT) or patients after bone-marrow10

transplantation(BMT)hasgrownoverthelastdecades[5].Cliniciansareincreasinglyexposedtothe11

dilemma on whether an immunosuppressed patient can receive a live vaccine – which is very12

importantassevereinfectionswithinfectionspreventablebylivevaccinationssuchasmeaslesand13

varicella canoccuron immunosuppressive therapy [6,7].On theotherhand, the live vaccine itself14

may impose a danger to the immunosuppressed individual. Furthermore, vaccines may be less15

effectivewhenadministeredtoanimpairedimmunesystem[8].16

Todate,livevaccinesarecontraindicatedundermostimmunosuppressivetherapies.However,data17

aregenerallyscarce.Overthelastfewyearseffortshavebeenmadetoevaluatethesafetyofsome18

live vaccines in selected immunosuppressed individuals by conducting both, retrospective and19

prospective studies. Further data have become available as live vaccines were occasionally20

administeredinadvertentlyorafteracarefulrisk-benefitassessmenttoindividualpatients.21

In this systematic review,we aim to provide an overview on the results of published randomized22

trials,observational studiesandcase reportson livevaccinations inpatientswith IMIDsorSOTon23

immunosuppressivetherapyaswellasBMTpatientswhoreceivedalivevaccinelessthantwoyears24

after receiving theBMT. Live vaccinesaregenerally acceptedafter this 2 year timeperiod inBMT25

6

patientsifnoimmunosuppressivetherapyisgivenandnoGvHDispresent[9].Ourprimaryobjective1

istoexaminethesafetyofthelivevaccinations(mumps,measles,rubella(MMR),yellowfever(YF),2

varicellavaccine(VV),herpeszoster(HZ),oraltyphoid,oralpolio,rotavirus,BacillusCalmette–Guérin3

(BCG), smallpox) in patients on immunosuppressive treatment with an IMID or SOT as well as4

patientslessthantwoyearsafterBMT.Thisincludestheassessment(i)ofsystemicorlocalvaccine5

reactions (ii) of the risk of infection with the attenuated vaccine strain, and (iii) on whether live6

vaccinations are associated with relapses/worsening of the underlying disease or organ rejection.7

Our secondary objectives are to examine the immunogenicity and the clinical protection of live8

vaccinationsinthesepatients.9

10

11

7

Methods1

Eligibilitycriteriaforstudyinclusion2

Population:PatientsofanyagewithanIMIDorSOTwhowereonimmunosuppressivetreatmentat3

the timeof vaccinationaswell aspatients less than twoyearsafterBMTwereconsidered.As live4

vaccinesaregenerallyacceptedtwoyearsafterBMTifnoimmunosuppressivetherapyisgivenand5

no GvHD is present publications on live vaccines more than two years after BMT were not6

considered.7

Studied Vaccinations: Live attenuated vaccinations (MMR, YF, VV, HZ, oral typhoid, oral polio,8

rotavirus,BCG,smallpox).9

Outcomes: Our primary outcome measure is the safety of live vaccinations; this includes the10

assessment(i)ofsystemicor localvaccinereactions(ii)oftheriskof infectionwiththeattenuated11

vaccine strain,and (iii)onwhether livevaccinationsareassociatedwith relapses/worseningof the12

underlyingdiseaseororganrejection.Thesecondaryoutcomemeasuresaretheimmunogenicityand13

clinical protection of live vaccinations in patients with the conditions defined above. To assess14

immunogenicitywe includedhumoral immuneresponses (antibodyconcentrations, seroconversion15

rates) and cellular responses, depending on the available information in the studies. As often no16

controlgroupwasstudiedwefocusedonclinicalprotectionandnotonefficacyoreffectivenessof17

vaccinations.18

IncludedStudyDesigns:Randomizedtrials,observationalstudiesandcasereports.19

InformationSources20

The Cochrane, Pubmed, Embase databases were searched without applying time restrictions.21

Unpublished (grey) literature (unpublished reports, conference abstracts) was retrieved through22

targeted website searches of relevant organizations and international conferences dealing with23

vaccination, infectious diseases, IMIDs, SOT and BMT, i.e. European League Against Rheumatism,24

8

CentersforDiseaseControlandPrevention,InfectiousDiseasesSocietyofAmerica,AmericanCollege1

ofRheumatology,EuropeanSocietyforOrganTransplantation,AmericanSocietyofTransplantation,2

European Society for Blood and Marrow Transplantation, American Society for Bone Marrow3

Transplantation. Additional articleswere identified through reference lists of selected papers. The4

searchwasrunonMarch23rd2014.AlimitedupdatesearchwasrunonJanuary22nd2016.5

Search termswere peer reviewed during the development process. The search terms in Figure 16

were used in combination to search the databases. CorrespondingMedical Subject Headings and7

Embasesubjectheadingsweresearchedfor.8

Studyselection9

Two review authors performed eligibility assessment based on titles, key words, and abstracts10

independently (SB and VKJ). Disagreements between review authorswere resolved by consensus.11

One review author conducted the eligibility assessment (EC) based on the full article; this was12

checkedbytwootherreviewauthors(SBandVKJ).Ifauthorspublishedseveralstudiesonthesame13

subject(e.g.varicellavaccinationinstemcelltransplantation)wecomparedsamplesizes,outcomes14

andtimeframesofstudyconducttoavoiddoublecounting.15

Datacollectionprocess16

Adataextractionsheetwaspilotedonfiverandomly-selectedstudiesandwasrefinedaccordingly.17

Dataextractionwasperformedbyoneauthor(EC)andcheckedbytwootherauthors(SBandVKJ).In18

caseofdisagreement,aconsensuswassoughtbydiscussionbetweenthethreeauthors.In10cases,19

studyauthorswerecontactedtoreceivefurther/clarifyinginformation.Sevenauthorsansweredand20

insixcases the relevant informationcouldbe retrieved. In threecases theauthordidnot respond21

and it could not be clarifiedwhether the patients were treatedwith immunosuppressive therapy22

duringtheimmunization.Thesethreearticleswereexcluded.23

Dataitems24

9

Informationfromeachrecordwasextractedonyearofpublication,yearofstudyconduct,country,1

study design, number of participants, enrolment of controls, number of vaccine doses, underlying2

disease, immunosuppressivemedication, primary vaccine dose or secondary/revaccination vaccine3

doses, vaccine reaction (local or systemic), infection through vaccine strain, flare of underlying4

disease (IMID) or transplant rejection (SOT/BMT), immunogenicity assessment performed, test for5

immunogenicityassessment, timepoint for immunogenicityassessment, resultsof immunogenicity6

assessment,clinicalprotectionassessmentperformed,durationof follow-up forclinicalprotection,7

results of clinical protection assessment, conclusion (see supplementary file). If a live vaccinewas8

administered to a seronegative patient it was defined as a “primary vaccination”. If a second9

vaccinationwasgivenor ifpatientswereknown tobe seropositiveat the timeof vaccination, the10

vaccinationwasdefinedas“secondaryvaccination”or“re-immunization”.11

12

13

10

Results1

Studyselection2

7,290 articles were identified through database searching and 15 articles were identified through3

othersources.Afterremovalofduplicates,7,187articlesremained.550articleswereleftaftertitle4

andkeywordscreeningand105 (IMIDn=64,BMTn=20,SOTn=21)articleswere leftafterabstract5

screening(Figure2).Thefull-textofthesearticleswereassessedforeligibilityandfinally64articles6

wereincludedinthissystematicreview(seesupplementaryfilefordetailsonincludedstudies).7

Of these, 40 (YF n=9 (n=8 in adults, n=1 in children and adults),MMR n=6 (n=1 in adults, n=5 in8

children), varicella n=12 (n=3 in adults, n=9 in children, n=1 in children and adults), HZ n=8 (all in9

adults),polion=1(adult),BCGn=4(n=2inadults,n=2inchildren),livetyphoidn=1(adult),smallpox10

n=1(adult))wereconductedinIMIDpatients.16studies(YFn=2(n=1inadults,n=1inchildrenand11

adults),MMRn=7(allinchildren),varicellan=11(n=2inadults,n=9inchildren),BCGn=1(children))12

were identified in SOTpatients and eight (MMRn=4 (n=2 in children, n=2 in children and adults),13

varicella n=5 (n=1 in adults, n=2 in children, n=2 in children and adults)) in BMT patients. Some14

studiesevaluatedseverallivevaccines.Nostudyonrotavirusvaccinationwasidentified.Inonestudy15

the participants (IMID patients)were vaccinated simultaneously against YF,MMR and varicella. In16

five studies (SOT patients) the participants were vaccinated against MMR and varicella17

simultaneously.41full-textarticleswereexcludedbecausepatientswerenotonimmunosuppressive18

therapyattimepointofvaccination(IMIDorSOT,n=15),administrationoflivevaccinelaterthantwo19

yearsafterBMT(n=11),nooriginalwork(n=12),theresultswerealreadypresentedinotherarticles20

(n=2),orbecauseofanadditionalinheritedimmunodeficiencyofthevaccinatedpatient(n=1).Outof21

the64includedarticles,eightwererandomizedcontrolledtrials(RCTs),39observationalstudiesand22

17case series/reports.RCTswereonly identified in the IMIDgroup (varicellan=5,HZn=1,YFn=1,23

MMRn=1).24

Studycharacteristics25

11

Atotalof21,082patientsreceivedalivevaccineinthestudies,whichwerepublishedbetween19771

and2016.Studieswereconductedin18differentcountriesincludingUSA(n=18),Brazil(n=13),Japan2

(n=6) and Germany (n=4). As some patients received several live vaccines concomitantly the3

presentednumbersmaynotaddup.4

Immunemediatedinflammatorydiseases5

Mostofthepatients(n=20,556)hadanIMID.Ofthese,19,630patientsreceivedanHZ,474anMMR,6

233aYF,202avaricella,10anoral typhoid,5aBCG,onea livepoliomyelitis andonea smallpox7

vaccination.8

Themost frequently representeddisease categories in the IMIDgroupare summarized inTable1.9

The participants in the IMID groupwere under 22 different immunosuppressivemedications. The10

most commonmedication in this groupwas glucocorticoids (n=384)with a prednisone-equivalent11

dosage rangeof2.5-35mg/day, followedbymethotrexate (MTX,n=268)withadosage rangeof5-12

27mg/m2/week. 98 patients in the IMID group were treated with a combination therapy; 21813

receivedamonotherapywithabiological,39receivedacombinationtherapywithabiological.63314

patientsreceivedherpeszostervaccine(HZV)underbiologicaltherapy. Itwasunclearwhetherthis15

was a mono- or a combination therapy. In this study the medication was only reported in16

7,780/18,683patients.SonumbersofpatientswithHZVon immunosuppressive therapymayhave17

been higher [10]. In the IMID group, in 18 studies primary vaccinations were administered, in 1318

studies secondary doses were given. In six studies a primary and a secondary vaccination were19

administeredandinthreestudiesitwasunknownwhetheraprimaryorasecondaryvaccinationwas20

given.21

22

SOT23

339SOTpatientswith livevaccinationswere identified;192werevaccinatedagainstvaricella,17224

againstMMR,20againstYF,and24receivedtheBCGvaccine.25

12

Ofthe339SOTs,271werelivertransplants,62kidneytransplants,fourhearttransplants,onesmall1

boweltransplant,andoneliverandsmallboweltransplant.TheSOTpatientsweretreatedwitheight2

different immunosuppressive medications. The most frequently used medication was tacrolimus3

(TAC,n=134,2.4-10ng/ml in serum), followedbycyclosporineA (CSA,n=56)withadosage range4

from30-120ug/l;70 transplantedparticipantswereunderacombination therapy. In sevenstudies5

patients received a primary vaccination, in one study only revaccinationswere given and in eight6

studiesthepatientsreceivedaprimaryvaccinationaswellasasecondaryvaccination.7

BMT8

Only a small part of the participantswerepatientswithBMT (n=187). Of these, 152 received an9

MMR vaccination and 38 received a VV. The underlying diseases of BMT patients are specified in10

Table2.AllBMTpatients(n=38)whoreceivedVV,werenotoncurrentimmunosuppressivetherapy.11

27patientswhoreceivedanMMRimmunizationweretreatedwithanimmunosuppressivetherapy12

at vaccination (CSA n=12, CSA/prednisone n=11; prednisone n=2, mycophenolate-mofetil (MMF)13

n=2). Inonestudy,sevenBMTpatients(MMRvaccinationn=7,VVn=3)tookacalcineurin inhibitor14

and MMF as graft versus host disease (GvHD) prophylaxis [11]. In five studies only primary15

vaccinationswereadministeredandinthreestudiesthepatientsreceivedaprimaryandasecondary16

immunization.17

Resultsofindividualstudies18

Safety19

Localorsystemicvaccinereactions20

Outofthe21,082involvedparticipants,localorsystemicvaccine-associatedadversereactionswere21

observed in 280 patients (1.3%): 207/20,556 (1.0%) in the IMID group, 61/339 (18.0%) in the SOT22

groupand12/187intheBMTgroup(6.4%).Mostfrequentadversereactions(n=269)weremildsuch23

as injection-site pain, headache, fatigue, myalgia, fever, arthralgia, and nausea. Serious adverse24

13

events(SAEs)werereportedby11participants(Table3).1

InonestudySAEswerereportedin11IMIDpatientsunderprednisonetreatmentwhoreceivedHZV2

[12].However,SAEsintheplacebogroupwereasfrequentasintheHZ-vaccinatedgroup(6.6%vs.3

5.7%).OneoftheSAEsintheHZgroupwasvaccine-relatedbuttheexactreasonwasnotmentioned.4

Sixdeathsoccurred(threeinplacebogroupandthreeinHZgroup),ofwhichnonewasjudgedtobe5

vaccine-related. The most frequently reported SAEs were respiratory, thoracic and mediastinal6

disorders[12].7

After receivingMMR,poliomyelitis, smallpox, live typhoidandBCGvaccination in the IMIDgroup,8

therewereno reportedSAEs. Similarly, in theSOTandBMTgroupnoSAEswere reported.Across9

IMID,SOTandBMTpatients,17articlesdidnotdocumentwhetheradverseeventswereobserved.10

Pathologythroughunrestrictedproliferationoftheattenuatedstrain11

12

32 participants developed an infection through the vaccine strain. Overall, one infection occurred13

afterYFV, threeafterMMRvaccination,20afterVV, fiveafterHZV,oneafter livepolio, oneafter14

BCG,andoneaftersmallpoxvaccination.15

16

IMID17

In12of20,556(0.06%)IMIDpatientsavaccine-strain-relatedinfectionwasreported(Table3).One18

49-year old female patientwith rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE)19

whostartedMTXanddexamethasone(dosageunknown)fourdaysaftertheYFVdevelopedayellow20

fever vaccine-associated viscerotropic disease (YEL-AVD) and died [13,14]. She received the21

vaccinationduring a YF vaccination campaign in Peru, duringwhichoneparticular vaccine lotwas22

found to be associated with a more than 20 times risk of YEL-AVD. Among 42,742 persons who23

receivedavaccinefromthislot,fivedevelopedaYEL-AVD.24

Onejuvenileidiopathicarthritis(JIA)patientwithMTXexperiencedarashandfever20daysaftera25

14

primary MMR vaccination [15]. However, the rash was interpreted as disease-related [personal1

communicationwithauthors].2

One patient with muco-cutaneous lymphnode syndrome under steroid therapy developed mild3

varicella11daysafter immunizationwithVV[16],oneSLEpatientexperienceda localizedrash(<54

vesicles)afterVV[17].5

HZandvaricella zostervirus (VZV)-like rasheswereseen in fivepatientsafter immunizationwitha6

HZV [10,12,18].One of themexperienced a serious ophthalmic herpes zoster infectionwhichwas7

determinedtobevaccine-relatedbytheinvestigator;howeverwildtypevirusandnotvaccinestrain8

viruswas identifiedbyPCR [12].Anotherpatientwho receiveda15-daysupplyofprednisone two9

monthsbeforebeingvaccinated,developedHZsevendaysaftervaccination[18].Onepatientwith10

reactivearthritisunder50mgetanercepthadapositivestoolcultureforpoliovirusSabin1-likeRNA11

butwithout any symptoms after oral polio vaccination [19]. One infantwhosemotherwas under12

infliximab(IFX)treatmentduringpregnancyreceivedtheBCGvaccineattheageofthreemonthsand13

developeddisseminatedBCGinfectionanddied[20].Onepatientwithatopiceczemaundertopical14

fluocinolone or betamethasone therapy developed smallpox-like vesicles after the smallpox15

immunizationandimprovedrapidlyafterreceivinghyperimmuneserumagainstvaccinia[21].16

SOT17

16/339(4.7%)SOTpatientshadavaccine-relatedinfection(Table3);14patientsdevelopedvaricella18

afterVVwithintwotoeightweeks.Inall14patientsitwasonlyamoderateformofvaricellawithout19

complications [22–24]. Two patients had transient swelling of the parotid glands after mumps20

immunization[25,26].21

BMT22

IntheBMTgrouponepatientdevelopedHZsevendaysafterreceivingthevaricellavaccine(Table3)23

[27].Symptomsresolvedwithtreatment.Inanotherstudythreepatientsdevelopedadisseminated24

rashwithin2.5weeksafterVV[28].Therashresolvedwithouttreatment.Inallfourcasestherewas25

15

notclearwhetherthereactionhadoccurredinpatientsvaccinatedlessthanormorethantwoyears1

afterBMT.2

Flareofunderlyingdisease/transplantrejectionaftervaccination3

IMID4

Inaself-controlledcase-seriesstudy,a12.8times(95%CI4.28-38.13,p<0.001)higherexacerbation5

ratewasreportedinmultiplesclerosis(MS)patientswhoreceivedYFVunderglatirameracetateand6

interferontreatmentcomparedtotimeperiodswhenthesepatientshadnotreceivedYFV(“not-at-7

risk-periods”) [29]. Ina retrospectivecohort studybyHeijsteketal [30],noaggravationofdisease8

wasregisteredintheMMRvaccinatedJIApatients.InanotherstudybyHeijstekandcolleagues[31],9

the mean number of flares per patient did also not differ significantly between the vaccinated10

patientsandthecontrolgroup.Aboywithatopicdermatitisexperiencedanexacerbationoftheskin11

disease one week after BCG vaccination [32]. The exacerbation of the skin lesions resolved 3.512

months later after treatment. While 1/10 patients with inflammatory bowel disease (IBD) under13

prednisolone 10mg had a flare 15 days after live typhoid immunization, 8/10 patients reported14

improvementof abdominal symptomsafter 90days [33]. In three further studies improvementof15

the basic diseases were reported. Two randomized controlled studies mentioned a significant16

improvementof thepsoriaticarea in83%ofpsoriasispatientsafter fourdosesofVV [34,35]. Less17

patients in thecontrolgroupshowedasignificant improvement. Inacasereport, twoSLEpatients18

experiencedimprovementoftheirextrarenalmanifestationsafterBCGvaccination[36].19

SOT20

IntheSOTgroup,threecasesoforganrejectionswerereported.Onepatientdevelopedanepisode21

ofacuterejectionthreeweeksaftermeaslesvaccination.Theotherpatientshowedchronicrejection22

at the time of vaccination and remained unchanged for one year [37]. Another single rejection23

episodeoftheliverwasreported,whichoccurredmorethanoneyearafteraVVandwasconsidered24

asunassociatedtoimmunization[38].25

16

BMT1

OnechildafterautologousBMThadarelapseofhermalignancyafterMMRimmunization,thetime2

pointwasunknown[39].3

Immunogenicity4

In43studiesanimmunogenicityassessmentwasperformed:23(YFn=6,MMRn=3,VVn=9,HZn=5)5

intheIMIDgroup,12(YFn=1,MMRn=7,VVn=4)intheSOTgroupandinalleightstudies(MMRn=3,6

VVn=5) in theBMTgroup. In themajority, an immunogenicity assessmentwas performedbefore7

vaccination;thetimepointsfortheimmunogenicityassessmentvariedfrom15daysto13yearsafter8

vaccination.9

10

IMID11

In19articles thehumoral immuneresponseand in twoarticles thehumoralandcellular response12

wasassessed.Intwoarticlesthetestmethodwasnotdocumented.13

YF-vaccinated IMIDpatientsshowedhighseroconversionrates in fourarticles,whichdidnotdiffer14

between patients and controls [29,40–42]. Patients under therapy with short-term high dose15

corticosteroids,long-termlow-dosecorticosteroids,glatirameracetate,interferongamma(INF-y)or16

MTX received a primary YFV. Only in one of these studies, patientswho received transcutaneous17

vaccinationinsteadofsubcutaneousvaccinationdemonstratedsignificantlylowerYFV-specificT-cell18

responses[40].AfterYFrevaccinationunder IFX(±MTX),1/17patientsand1/15controlsremained19

seronegative[8].Inanotherstudyonrheumaticpatientsundervarioustreatmentsaseropositivityof20

87%wasachievedafterYFrevaccination.Patientsshowedlowertitersofneutralizingantibodiesthan21

healthy individuals [43]. The patient with the lowest antibody titer had been administered 2mg22

rituximab(RTX)fourmonthsbeforeYFrevaccination.23

24

In one study,MMR-vaccinated JIA patients treated with low-doseMTX had lower levels of virus-25

specificantibodiesandIFN-yproducingTmemorycellsthanhealthychildren[44].Thepatientswho26

17

additionally receivedetanercept showedadeclineof virus-specific IFN-yproducing T cells and IgG1

antibodies were slightly increased. Kawasaki patients vaccinated against MMR within six months2

after administration of intravenous immunoglobulin (IVIG) had lower IgG concentrations against3

measles,mumpsandrubellacomparedtocontrols[45].Patientsvaccinatedlaterthanninemonths4

after IVIG administration did not show any difference to controls. No significant differences in5

humoralresponseswereobservedbetweenpatientswithandwithoutMTXorbiologicsafterMMR6

vaccination[31].7

8

Inthreestudieswithalimitedsamplesize,VVshowedgoodimmunogenicityresultsinIMIDpatients9

[16,46,47]. In two studies, SLE patients developed comparable VZV-specific antibody levels to10

controls[17,48].HoweverthecellularresponseswerelowerinSLEpatients[17].11

In three studies JIA showed lower seroconversion rates than controls [49–51]. In one study all 1012

non-converters were under sole MTX therapy or received additional prednisone [49]. In another13

study all four non-converters were under tumor necrosis factor inhibitor (TNFi) therapy [49]. In14

contrary to tocilizumab (TCZ) treated patients, patients under IFX/MTX and etanercept had15

insufficientresponses[51]. Inareportofsixcasesundertreatmentwithmesalamine,olsalazine,6-16

mercaptopurine,and/orIFXextremelyvaryingresultswereobserved[52].17

18

InthreestudiesHZVshowedaworse immuneresponse in immunosuppressedpatients than inthe19

immunocompetent group [53–55]. In a case report a patientwithMS under fingolimod remained20

seronegativeafteradministrationofHZV,evendespitehehadtwoclinicalepisodesofHZ infection21

[54].22

In a study 10 SLE patients under prednisone, hydroxychloroquine orMTX showed similar cellular23

immune responses as controls, but the increase of antibody levelswas lower [55]. In two studies24

patients under treatmentwith steroids and furthermodifying agents achieved adequate antibody25

levelsafterHZV[12,56].26

18

SOT1

In10studies thehumoraland in twostudiescellularandhumoral testswereperformed.Akidney2

transplant recipient under CSA and mycophenolic acid vaccinated against YFV 19 years post-3

transplantreachedantibodytiterswithinthelowerrangeofthoseofcontrols[57].4

The seroconversion after post-transplant vaccination showed generally higher rates for rubella5

(range 70-100%) than formeasles (44-100%),mumps (48-100%) and varicella (71%) [25,26,37,58–6

61].PatientswereundervarioustherapiesincludingCSA,prednisone,azathioprineandTAC.Intwo7

studies, the patients were also tested after a second or a third vaccination and showed higher8

seroconversionratesafterwards[58,59].9

10

TheseroconversionrateafterVVinSOTpatientsvariedfrom25to87%[22,25,26,58–60,62,63].Ina11

studywithpatientsundertripletherapywithprednisone,CSAandazathioprine,59%developedanti-12

varicellaantibodieswithinthefirstfourtoeightweeksafteraprimaryvaccinedose[62].Bythreeto13

sixmonthsafterimmunization,85%wereseropositiveandat24months76%oftheantibodytiters14

remainedpositive. In twostudies,patientsunderMMF,prednisone,CSA,TACorsirolimusreached15

similar seroconversion rates of 64-67% [60,63]. 87%of patients under CSA and TAC receiving one16

doseofVVseroconvertedand86%hadpositivecellularresponses[22].17

PatientsunderTACandCSAreceivingavaricella revaccinationoneyearafter liver transplantation,18

hadseroconversionratesbetween50%and81%afterre-immunization[26,58,59].19

Inastudyallchildren(100%)reachedseroconversionafterone,twoorthreevaccinations[38].After20

the last vaccine dose 96.8% (31/32) of the children retained high-median antibody titers. In 2021

patients,VZV-specificCD4+Tcell responseswerecomparedpre-andpost- immunizationandthey22

showedasignificantincrease.23

24

BMT25

In four studies an immunogenicity assessment was performed by humoral tests, in one study by26

19

cellular tests and in one study by humoral and cellular tests. In two BMT studies the test was1

unspecified.2

Three studies with patients who received an MMR immunization within 24 months after BMT3

showedahigher seroconversion rate for rubella (86-100%) than formeasles (33-46%)andmumps4

(29-80%)[11,39,64].Itwasobservedthatchildrenseroconvertedmorefrequentlytomeaslesifthey5

were immunizedmore than15monthsafterBMT(35%prior toversus78%after15months) [64].6

Seroconversionrateswere86%forrubella,43%formeaslesand29%formumpsinpatientstreated7

withcalcineurininhibitorsandMMFafteraprimaryMMRvaccine[11].8

Inanotherstudy,afteraprimarymeaslesvaccinedose,allpatientsseroconvertedand78%remained9

seropositive for at least 12 months [65]. However, only 44% of these patients were on10

immunosuppressivedrugsatthetimeofvaccination.11

ForvaricellavaccinationafterBMT,seroconversionratesvariedbetween33and89%afteraprimary12

VV[11,27,66,67].Inthestudyinwhichonly33%seroconversionwasachieved,patientswereunder13

GvHD-prophylaxiswith calcineurin inhibitors andMMF. In theother studiespatientswerewithout14

immunosuppressivetreatment.15

16

Clinicalprotectionofvaccines17

In the IMID group, 12/202 patients (6%) who received a VV nevertheless developed a varicella18

infection or HZ. 8/19,630 patients (0.04%) receiving a HZV later had a HZ infection despite19

vaccination.YF-,MMR-,Polio,BCG-andtyphoidfever-vaccinatedpatientsappearedtobeprotected20

anddidnotdevelopaninfection.21

In the SOT group, 7/192 (3.6%) patients developed a varicella infection despite being vaccinated22

againstvaricella.2/38(5.3%)intheBMTgroupdevelopedvaricellainspiteofaVV.Patientsinthe23

SOT and BMT group who were vaccinated against YF, MMR and BCG were protected against24

infection.Follow-upperiodsforclinicalprotectionvariedbetween6weeksto12.5years.25

26

20

Discussion1

Whether live vaccines can be administered to immunocompromised patients is an often-2

encountered problem by physicians caring for this specific patient group. On the one hand these3

patientsareespeciallyvulnerablefrominfections(manyofthemvaccine-preventable)ontheother4

handthereisapotentialriskofharmingthepatientbytheadministrationofavaccinecontainingan5

attenuated vaccine strain,which has the theoretical potential to revert to the original pathogenic6

form and to induce infection in the immunocompromised individual. Apart from infecting the7

immunocompromised person, more vaccine-related side effects as well as re-activation of the8

underlying disease is feared. Therefore this review summarizes available information in order to9

inform the practitioner of currently available evidence by reviewing and giving an overview on10

currentlyavailableliteratureonthistopic.11

Generallylocalandsystemicreactionsweremild.WhiletheywererareinIMIDpatients(prevalence12

of 1%), they occurred more frequently in BMT (6%) and SOT patients (18%). The percentages of13

adverseevents(AEs)appearlowcomparedtoAEsreportedinthegeneralpopulation[68–71].Thisis14

mostlikelyduetounderreportingofAEsinourincludedstudies.15

Altogether, 11 SAEs due to local or systemic reactions including three deaths were reported;16

however, none of the deathswas vaccine-associated. All reported SAEs occurred in IMID patients17

afterHZV. Intheothervaccinationgroups,numbersofpatientswere low,thusSAEsmaynothave18

beenobservedduetothelimitedsamplesizes.AlsointheliteraturelocalorsystemicSAEsafterlive19

vaccinations are extremely rare. For examples, anaphylactic reactions after YFV occur in 0.8-20

1.8/100,000administereddosesandthrombocytopeniaafterMMRvaccinationisestimatedtooccur21

inoneoutof30,000-40,000administeredMMRdoses[72,73].22

Inthe2010publishedrecommendationsonYFVonimmunizationpracticesoftheCentersforDisease23

ControlandPreventionreportonseveralYEL-AVDcasesinindividualswithunderlyingautoimmune24

conditions:threepatientswithSLE,twowithAddison'sdisease,onewithCrohn'sdisease,onewith25

21

polymyalgia rheumatica and hypothyroidsm, one with ulcerative colitis, and one withmyasthenia1

gravis [74]. In direct correspondence with one of the authors, she confirmed that a number of2

viscerotropicdiseaseshaveoccurredinpersonswithautoimmunediseases.However,itcouldnotbe3

clarifiedwhetherthesepatientswereonimmunosuppressiveorimmunomodulatorytherapyatthe4

timeofYFV.Thus,itremainsunclearhowtointerpretthisinformation.Thesafetymonitoringboard5

in Switzerland has not detected a severe infectionwith a vaccine strain in an immunosuppressed6

patientbetween2001andMay2016[personalcommunication].7

Infections through vaccine strains were extremely rare. However, two of themwere deadly. One8

occurred in apatientwithRA/SLEoverlapwho receivedYFV fourdaysprior to commencementof9

MTX/dexamethasone treatment. However, the administered vaccine lot was associatedwith a 2010

times higher risk of YEL-AVD compared to other YFV lots. A fatal disseminated BCG infectionwas11

reporteduponvaccinationofathree-month-oldinfantborntoamotherunderIFXtreatment.Thus,12

infantsborn to immunosuppressedmothers shouldbevaccinatedwithcaution.Theothervaccine-13

associatedinfectionswereeitherself-limitingorresolvedupontreatment.14

Regarding reactivation of the underlying disease, apart from one article, no increase of flares of15

underlying autoimmune conditions was encountered. One study detected a more than 12 times16

elevatedriskofMSexacerbationafterYFV[29].However,thisself-controlledcaseseriesstudywas17

criticizedformethodologicalissues[75].18

InSOTpatients,one liver transplant rejectionwas reported threeweeksaftermeaslesvaccination19

[37].Acuteorganrejectionscanoccurinaround15-25%oflivertransplantrecipients[76–78].Thusit20

isnotsurprisingtoseeanacuteorganrejectionthreeweeksaftermeaslesvaccination(oneof27121

livertransplantpatientswhoreceivedalivevaccine),whichismostlikelyonlytimelybutnotcausally22

associated to vaccination. Details such as numbers on non-serious specific systemic and local23

reactionswereoftennotpresentedinthepublications.24

25

22

Immunogenicity data are difficult to interpret as a large variety of serological and cellular test1

methodswereused.YF(re)vaccinationsappearedtobe immunogenic inmostpatientgroups.TNFi2

andMTXtherapyseemedto reduce immuneresponsesafterVVandHZvaccination.This is in line3

withstudiesoninactivatedvaccines,suchaspneumococcalandhepatitisAvaccine[79,80].Rubella4

vaccinations appeared more immunogenic than measles and mumps vaccination, which is also5

knowninnon-immunosuppressedindividuals[73].ForVV,onevaccinedidoftennotsuffice,buttwo6

ormorevaccinedosesgenerallyconferredsatisfactoryimmunity.7

Moststudies includedinthissystematicreviewwereconductedinanon-randomized,uncontrolled8

andunblindedwayandthusarepronetobias.Onlyeightof64includedstudieswereRCTs.Onlyin9

one study blinding of patients and study personnel was performed. However, as literature is10

generally scarce on live vaccines in the immunosuppressedwe included observational studies and11

case reports as our aim was to compile all available evidence on live vaccinations in12

immunosuppressedIMID,SOTpatientsaswellasBMTpatientswhoreceivedalivevaccinelessthan13

two years after transplantation. Furthermore, this systematic review may have missed published14

studiesasthesearchwasconductedinEnglish.Eventhoughweincludedgreyliterature,publication15

biasmayhavelimitedtheidentifiablestudies/casereports.16

17

AYEL-AVDoccurs inanestimated0.4of100,000administeredvaccinedoses[81]. Inour identified18

studies and case reports we found one YEL-AVD in a RA/SLE patient who was vaccinated with a19

specificvaccinestrainassociatedwithahigherYEL-AVDrisk. It iswellpossiblethatmoreYEL-AVDs20

were simply missed/or have not occurred as patient numbers who received a live vaccine are21

extremely low.Severereactionsor infectionsmayonlybediscovered ifa largenumberofpatients22

withtheseconditionsreceivelivevaccines.23

24

25

26

23

Conclusion1

Overall, the identified data on live vaccinations in IMID and SOT patients on immunosuppressive2

treatmentaswellaspatientslessthantwoyearsafterBMTarenotsufficientlyrobusttochangethe3

currentlyavailableinternationalvaccinationrecommendationswhichgenerallyareveryrestrictiveon4

livevaccinesunderimmunosuppressionorshortlyafterBMT.Onlyeightrandomizedcontrolledtrials5

couldbeidentifiedandallwereconductedinIMIDpatients.However,patientgroups,medications,6

medicationdosagesandlivevaccinationswerediversewithintheseeighttrialsandgenerallypatient7

numberswerelow.8

From the available evidence we cannot conclude that live vaccines are safe altogether in9

immunosuppressedIMID,SOTandwhenadministeredwithintwoyearsafterBMT.However,despite10

the limitations discussed above it is re-assuring that in the examined patient groups serious side11

effects or infections by the attenuated vaccine strain were extremely scarce after primary12

vaccinationsandrevaccinationswiththeexaminedvaccines(MMR,YFV,VV,HZV,oraltyphoidfever,13

oralpolio,BCG,smallpox).14

We believe that our research of the existing literature is of help to the interested specialist15

confrontedwiththedecisionprocessonwhethertovaccinateanimmunosuppressedpatient.More16

evidence regarding the safety and immunogenicity of live vaccinations in IMID and SOT patients17

undervarious immunosuppressivetherapiesaswellas inpatients less thantwoyearsafterBMT is18

urgently needed. Vaccination recommendations need to be adapted on a regular basis, as more19

scientific data regarding vaccination safety and efficacy, new vaccines as well as new20

immunosuppressivetherapieswillbecomeavailable.21

Funding22

Thisresearchdidnotreceiveanyspecificgrantfromfundingagenciesinthepublic,commercial,or23

not-for-profitsectors.24

24

ConflicofInterest1

None2

Acknowledgements3

Wewould like to thank Erin Staples, Valeriu Toma (Swiss safetymonitoring board) aswell as the4

contactedauthorsforsharingtheirexperiencesandinformationwithusduringthedevelopmentof5

thissystematicreview.6

Authorship7

Allauthorshavemadesubstantialcontributionstotheconceptionofthesystematicreviewincluding8

serach termdefinition. SB andVKJperformedeligibility assessmentof articlesbasedon titles, key9

words,andabstractsindependently.ECconductedtheeligibilityassessmentbasedonthefullarticle;10

thiswascheckedbySBandVKJ.ECperformedthedataextraction,whichwascheckedbySBandVKJ.11

Allauthorshavemadesubstantialcontributionsintheinterpretationoftheextracteddata,drafting12

ofthesystematicreviewandrevisingitcriticallyforimportantintellectualcontent.Allauthorshave13

approvedthefinalversionbeforesubmission.14

15

16

25

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