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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
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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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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
References1
[1] KengsakulK,SathirapongsasutiK,PunyaguptaS.Fatalmyeloencephalitisfollowingyellow2fevervaccinationinacasewithHIVinfection.JMedAssocThai2002;85:131–4.3
[2] NinaneJ,GrymonprezA,BurtonboyG,FrancoisA,CornuG.DisseminatedBCGinHIV4infection.ArchDisChild1988;63:1268–9.5
[3] DavisLE,BodianD,PriceD,ButlerIJ,VickersJH.Chronicprogressivepoliomyelitissecondary6tovaccinationofanimmunodeficientchild.NEnglJMed1977;297:241–5.7
[4] MitusA,HollowayA,EvansAE,EndersJF.Attenuatedmeaslesvaccineinchildrenwithacute8leukemia.AmJDisChild1962;103.9
[5] BiétryF,PitzurraR,SchwenkglenksM,MeierCR.Helsana-Arzneimittelreport2014.10
[6] VonkemanH,tenNapelC,RaskerH,vandeLaarM.Disseminatedprimaryvaricellainfection11duringinfliximabtreatment.JRheumatol2004;31:2517–8.12
[7] TakahashiE,KurosakaD,YoshidaK,YanagimachiM,KingetsuI,YamadaA.[Onsetofmodified13measlesafteretanercepttreatmentinrheumatoidarthritis].NihonRinshoMenekiGakkai14Kaishi2010;33:37–41.15
[8] ScheinbergM,Guedes-BarbosaLS,MangueiraC,RossetoEA,MotaL,OliveiraAC,etal.16Yellowfeverrevaccinationduringinfliximabtherapy.ArthritisCareRes(Hoboken)172010;62:896–8.18
[9] CarpenterPA,EnglundJA.HowIvaccinatebloodandmarrowtransplantrecipients.Blood192016;127.20
[10] ZhangJ,XieF,DelzellE,ChenL,WinthropKL,LewisJD,etal.Associationbetweenvaccination21forherpeszosterandriskofherpeszosterinfectionamongolderpatientswithselected22immune-mediateddiseases.JAMA2012;308:43–9.23
[11] SmallTN,IovinoCS,AbboudM,LubinM,PapadopoulosE,ScaradavouA,etal.Vaccine24responseinrecipientsofHLAmismatchedunrelateddoubleunitcordbloodtranplatation25(CBT).ASHAnnuMeetAbstr2010;116.26
[12] RussellAF,ParrinoJ,FisherCL,SpielerW,StekJE,CollKE,etal.Safety,tolerability,and27immunogenicityofzostervaccineinsubjectsonchronic/maintenancecorticosteroids.Vaccine282015;33:3129–34.29
[13] MeetingofGlobalAdvisoryCommitteeonVaccineSafety,18-19June2008.Relev30ÉpidémiologiqueHebd/SectD’hygièneDuSecrétariatLaSociétéDesNations=Wkly31EpidemiolRec/HealSectSecrLeagNations2008;83:287–92.32
[14] WhittemburyA,RamirezG,HernándezH,RoperoAM,WatermanS,TiconaM,etal.33ViscerotropicdiseasefollowingyellowfevervaccinationinPeru.Vaccine2009;27:5974–81.34
[15] PileggiGS,TerreriMTRA,BarbosaCMPL,FerrianiVPL.Measles,mumpsandrubella35vaccinationsafetyinpatientswithjuvenilerheumaticdiseasestakingimmunosuppressive36drugs.AnnRheumDis2012;71:260–260.37
[16] UedaK,YamadaI,GotoM,NanriT,FukudaH,KatsutaM,etal.Useofalivevaricellavaccine38topreventthespreadofvaricellainhandicappedorimmunosuppressedchildrenincluding39MCLS(muco-cutaneouslymphnodesyndrome)patientsinhospitals.BikenJ1977;20:117–23.40
26
[17] BarbosaCMPL,TerreriMTRA,RosárioPO,deMoraes-PintoMI,SilvaCAA,HilárioMOE.1Immuneresponseandtolerabilityofvaricellavaccineinchildrenandadolescentswith2systemiclupuserythematosuspreviouslyexposedtovaricella-zostervirus.ClinExpRheumatol3n.d.;30:791–8.4
[18] ZhangJ,DelzellE,XieF,BaddleyJW,SpettellC,McMahanRM,etal.Theuse,safety,and5effectivenessofherpeszostervaccinationinindividualswithinflammatoryandautoimmune6diseases:alongitudinalobservationalstudy.ArthritisResTher2011;13:R174.7
[19] BadshaH,DaherM,EdwardsCJ.Livepoliovaccineexposurewhilereceivinganti-TNFtherapy8forreactivearthritis.IntJRheumDis2010;13:184–6.9
[20] CheentK,NolanJ,ShariqS,KihoL,PalA,ArnoldJ.CaseReport:Fatalcaseofdisseminated10BCGinfectioninaninfantborntoamothertakinginfliximabforCrohn’sdisease.JCrohns11Colitis2010;4:603–5.12
[21] GundersenSG,BjorvatnB.Vacciniaandtopicalsteroids:acasereport.ActaDermVenereol131980;60:445–7.14
[22] WeinbergA,HorslenSP,KaufmanSS,JesserR,Devoll-ZabrockiA,FlecktenBL,etal.Safety15andimmunogenicityofvaricella-zostervirusvaccineinpediatricliverandintestinetransplant16recipients.AmJTransplant2006;6:565–8.17
[23] LevitskyJ,TeHS,FaustTW,CohenSM.Varicellainfectionfollowingvaricellavaccinationina18livertransplantrecipient.AmJTransplant2002;2:880–2.19
[24] KraftJN,ShawJC.VaricellainfectioncausedbyOkastrainvaccineinahearttransplant20recipient.ArchDermatol2006;142:943–5.21
[25] ShinjohM,MiyairiI,HoshinoK,TakahashiT,NakayamaT.Effectiveandsafeimmunizations22withlive-attenuatedvaccinesforchildrenafterlivingdonorlivertransplantation.Vaccine232008;26:6859–63.24
[26] ShinjohM,HoshinoK,TakahashiT,NakayamaT.Updateddataoneffectiveandsafe25immunizationswithlive-attenuatedvaccinesforchildrenafterlivingdonorliver26transplantation.Vaccine2015;33:701–7.27
[27] KussmaulSC,HornBN,DvorakCC,AbramovitzL,CowanMJ,WeintrubPS.Safetyofthelive,28attenuatedvaricellavaccineinpediatricrecipientsofhematopoieticSCTs.BoneMarrow29Transplant2010;45:1602–6.30
[28] ChouJF,KernanNA,ProckopS,HellerG,ScaradavouA,KobosR,KnowlesMA,Papadopoulos31EB,CassonA,CopelandC,Torok-CastanzaJ,ZakakN,RuggieroJST.Safetyand32immunogenicityoftheliveattenuatedvaricellavaccinefollowingTrepleteorTcelldepleted33relatedandunrelatedallogeneichematopoieticcelltranplantation(allHCT).BiolBlood34MarrowTransplant2011;17:1708–13.35
[29] FarezMF,CorrealeJ.Yellowfevervaccinationandincreasedrelapserateintravelerswith36multiplesclerosis.ArchNeurol2011;68:1267–71.37
[30] HeijstekMW,PileggiGCS,Zonneveld-HuijssoonE,ArmbrustW,HoppenreijsEPAH,Uiterwaal38CSPM,etal.Safetyofmeasles,mumpsandrubellavaccinationinjuvenileidiopathicarthritis.39AnnRheumDis2007;66:1384–7.40
[31] HeijstekMW,KamphuisS,ArmbrustW,SwartJ,GorterS,deVriesLD,etal.Effectsofthelive41attenuatedmeasles-mumps-rubellaboostervaccinationondiseaseactivityinpatientswith42
27
juvenileidiopathicarthritis:arandomizedtrial.JAMA2013;309:2449–56.1
[32] DaltonSJ,HaeneyMR,PatelL,DavidTJ.Exacerbationofatopicdermatitisafterbacillus2Calmette-Guérinvaccination.JRSocMed1998;91:133–4.3
[33] NysaeterG,BerstadA.LivetyphoidvaccineforIBD-patients-welltoleratedandwithpossible4therapeuticeffect.DrugTargetInsights2008;3:119–23.5
[34] El-DaroutiMA,HegazyRA,AbdelHayRM,AbdelHalimDM.Liveattenuatedvaricellavaccine:6aneweffectiveadjuvantweaponinthebattlefieldagainstsevereresistantpsoriasis,apilot7randomizedcontrolledtrial.JAmAcadDermatol2012;66:511–3.8
[35] El-DaroutiMA,HegazyRA,AbdelHayRM,RashedLA.StudyofThelper(17)andTregulatory9cellsinpsoriaticpatientsreceivingliveattenuatedvaricellavaccinetherapyinarandomized10controlledtrial.EurJDermatol24:464–9.11
[36] GuzmanRR,VillasorRP,CaneteRR,EslavaAG,CornejoSA,PicazoEA,etal.Beneficialroleof12bacillecalmette-guerin(BCG)vaccinationinthemanagementofsystemiclupus13erythematosus:areportofthreecases.PhilippJInternMed1983;21:3329–34.14
[37] RandEB,McCarthyCA,WhitingtonPF.Measlesvaccinationafterorthotopicliver15transplantation.JPediatr1993;123:87–9.16
[38] Posfay-BarbeKM,PittetLF,SottasC,GrilletS,WildhaberBE,RodriguezM,etal.Varicella-17zosterimmunizationinpediatriclivertransplantrecipients:safeandimmunogenic.AmJ18Transplant2012;12:2974–85.19
[39] PauksenK,DurajV,LjungmanP,SjölinJ,ObergG,LönnerholmG,etal.Immunitytoand20immunizationagainstmeasles,rubellaandmumpsinpatientsafterautologousbonemarrow21transplantation.BoneMarrowTransplant1992;9:427–32.22
[40] SlifkaMK,LeungDYM,HammarlundE,RauéH-P,SimpsonEL,TofteS,etal.Transcutaneous23yellowfevervaccinationofsubjectswithorwithoutatopicdermatitis.JAllergyClinImmunol242014;133:439–47.25
[41] KernéisS,LaunayO,AncelleT,IordacheL,Naneix-LarocheV,MéchaïF,etal.Safetyand26immunogenicityofyellowfever17Dvaccineinadultsreceivingsystemiccorticosteroid27therapy:anobservationalcohortstudy.ArthritisCareRes(Hoboken)2013;65:1522–8.28
[42] StuhecM.Yellowfevervaccineusedinapsoriaticarthritispatienttreatedwith29methotrexate:acasereport.ActaDermatovenerologicaAlpina,Pannonica,Adriat302014;23:63–4.31
[43] OliveiraACV,MotaLMH,Santos-NetoLL,SimõesM,Martins-FilhoOA,TauilPL.32Seroconversioninpatientswithrheumaticdiseasestreatedwithimmunomodulatorsor33immunosuppressants,whowereinadvertentlyrevaccinatedagainstyellowfever.Arthritis34Rheumatol(Hoboken,NJ)2015;67:582–3.35
[44] BorteS,LiebertUG,BorteM,SackU.Efficacyofmeasles,mumpsandrubellarevaccinationin36childrenwithjuvenileidiopathicarthritistreatedwithmethotrexateandetanercept.37Rheumatology(Oxford)2009;48:144–8.38
[45] TackeCE,SmitsGP,vanderKlisFRM,KuipersIM,ZaaijerHL,KuijpersTW.Reducedserologic39responsetomumps,measles,andrubellavaccinationinpatientstreatedwithintravenous40immunoglobulinforKawasakidisease.JAllergyClinImmunol2013;131:1701–3.41
28
[46] KatsushimaN,YazakiN,SakamotoM,FujiyamaJ,NakagawaM,OkuyamaY,etal.Application1ofalivevaricellavaccinetohospitalizedchildrenanditsfollow-upstudy.BikenJ1982;25:29–242.3
[47] SpethFabian,HaasJohannesPeter,LoeberSusanne,HinzeClaas.Varicellavaccinationin4patientswithpediatricrheumaticdiseasesreceivingimmunosuppression:Proposalofapre-5vaccinationchecklisttoensuresafety.ArthritisRheumatol2015;74:94.6
[48] BarbosaCMPL,TerreriMTRA,LenClaudioA,deMoraes-PintoMI,RosárioP,HilárioMOE.7Varicellavaccineinchildrenandadolescentswithsystemiclupuserythematosus(SLE)8ImmunogenicityandSafety.ArthritisRheum2009;60:1521.9
[49] PileggiGS,deSouzaCBS,FerrianiVPL.Safetyandimmunogenicityofvaricellavaccinein10patientswithjuvenilerheumaticdiseasesreceivingmethotrexateandcorticosteroids.11ArthritisCareRes(Hoboken)2010;62:1034–9.12
[50] PileggiGCS,deSouzaCBS,FerrianiVPL.SafetyandEfficacyofvaricellavaccineinpatients13withjuvenilerheumaticdiseases:afiveyearsexperience.AnnRheumDis2012;71:430.14
[51] ToplakN,AvčinT.Long-termsafetyandefficacyofvaricellavaccinationinchildrenwith15juvenileidiopathicarthritistreatedwithbiologictherapy.Vaccine2015;33:4056–9.16
[52] LuY,BousvarosA.Varicellavaccinationinchildrenwithinflammatoryboweldiseasereceiving17immunosuppressivetherapy.JPediatrGastroenterolNutr2010;50:562–5.18
[53] FarrayeF,WasanS,BergA,Ganley-LealL,LiangYM.Immuneresponseandsafetyofherpes19zostervaccineinIBDpatientsonmethotrexateorthiopurines.77thAnnu.Sci.Meet.otAm.20Coll.Gastroenterol.LasVegas,USA,2012.21
[54] BergerJR.Varicellavaccinationafterfingolimod:Acasereport.MultSclerRelatDisord222013;2:391–4.23
[55] GuthridgeJM,CogmanA,MerrillJT,MacwanaS,BeanKM,PoweT,etal.Herpeszoster24vaccinationinSLE:apilotstudyofimmunogenicity.JRheumatol2013;40:1875–80.25
[56] McGrawC,IngleseM,PetraccaM,HanniganC,MillerA.Anopen-labelobservationalpilto26studytoevaluatethesafetyandimmunogenicityoftheherpeszostervaccinainpatientswith27multiplesclerosis.Neurology2013;80:p01.181.28
[57] SlifkaMK,HammarlundE,LewisMW,PooreEA,HanifinJM,MarrKA,etal.Antiviralimmune29responseafterliveyellowfevervaccinationofakidneytransplantrecipienttreatedwithIVIG.30Transplantation2013;95:e59–61.31
[58] KanoH,MizutaK,SakakiharaY,KatoH,MikiY,ShibuyaN,etal.Efficacyandsafetyof32immunizationforpre-andpost-livertransplantchildren.Transplantation2002;74:543–50.33
[59] KawanoY,SuzukiM,KawadaJ,KimuraH,KameiH,OhnishiY,etal.Effectivenessandsafety34ofimmunizationwithlive-attenuatedandinactivatedvaccinesforpediatricliver35transplantationrecipients.Vaccine2015;33:1440–5.36
[60] KhanS,ErlichmanJ,RandEB.Livevirusimmunizationafterorthotopiclivertransplantation.37PediatrTransplant2006;10:78–82.38
[61] GernerP,BallauffA,AbramowU,LainkaE,GierenzN,HoyerPF.Immunizationwiththe39measles-mumps-rubellavaccineinchildrenbeforeandafterlivertransplantation.GerJ40Gastroenterol2009;47:P098.41
29
[62] ZamoraI,SimonJM,DaSilvaME,PiquerasAI.Attenuatedvaricellavirusvaccineinchildren1withrenaltransplants.PediatrNephrol1994;8:190–2.2
[63] ChavesTdoSS,LopesMH,deSouzaVAUF,DosSantosSDS,PereiraLM,ReisAD,etal.3Seroprevalenceofantibodiesagainstvaricella-zostervirusandresponsetothevaricella4vaccineinpediatricrenaltransplantpatients.PediatrTransplant2005;9:192–6.5
[64] ShawPJ,BleakleyM,BurgessM.Safetyofearlyimmunizationagainst6measles/mumps/rubellaafterbonemarrowtransplantation.Blood2002;99:3486.7
[65] MachadoCM,deSouzaVaUF,SumitaLM,daRochaIF,DulleyFL,PannutiCS.Earlymeasles8vaccinationinbonemarrowtransplantrecipients.BoneMarrowTransplant2005;35:787–91.9
[66] SauerbreiA,PragerJ,HengstU,ZintlF,WutzlerP.Varicellavaccinationinchildrenafterbone10marrowtransplantation.BoneMarrowTransplant1997;20:381–3.11
[67] ChouJF,KernanNA,ProckopS,HellerG,ScaradavouA,KobosR,etal.Safetyand12immunogenicityoftheliveattenuatedvaricellavaccinefollowingTrepleteorTcell-depleted13relatedandunrelatedallogeneichematopoieticcelltransplantation(alloHCT).BiolBlood14MarrowTransplant2011;17:1708–13.15
[68] Swissmedic.ProductinformationStamaril®.January20132013.16
[69] Swissmedic.ProductinformationPriorix®.Oct20152015.17
[70] Swissmedic.ProductinformationVarilrix®.July20152015.18
[71] Swissmedic.ProductinformationZOSTAVAX®.Febr20162016.19
[72] WorldHealthOrganization.InformationSheetObservedRateofVaccineReactionsMeasles,20MumpsandRubellaVaccinesn.d.21
[73] PlotkinSA,OrensteinWA,OffitPA.Vaccines.6thed.Philadelphia,Pennsylvania:Elsevier22Saunders;2012.23
[74] StaplesJE,GershmanMD,FischerM.YellowFeverVaccine:Recommendationsofthe24AdvisoryCommitteeonImmunizationPractices(ACIP).MorbMortalWklyRep2010.25
[75] PoolV,GordonDM,DeckerM.Methodologicalissueswiththeriskofrelapsestudyin26patientswithmultiplesclerosisafteryellowfevervaccination.ArchNeurol2012;69:144;27authorreply144–5.28
[76] MalufDG,StravitzRT,CotterellAH,PosnerMP,NakatsukaM,SterlingRK,etal.Adultliving29donorversusdeceaseddonorlivertransplantation:a6-yearsinglecenterexperience.AmJ30Transplant2005;5:149–56.31
[77] GruttadauriaS,VastaF,MandalàL,CintorinoD,PiazzaT,SpadaM,etal.Basiliximabina32triple-drugregimenwithtacrolimusandsteroidsinlivertransplantation.TransplantProc3337:2611–3.34
[78] MaY,WangG-D,HeX-S,LiJ-L,ZhuX-F,HuR.Clinicalandpathologicalanalysisofacute35rejectionfollowingorthotopiclivertransplantation.ChinMedJ(Engl)2009;122:1400–3.36
[79] KapetanovicMC,SaxneT,SjoholmA,TruedssonL,JonssonG,GeborekP.Influenceof37methotrexate,TNFblockersandprednisoloneonantibodyresponsestopneumococcal38polysaccharidevaccineinpatientswithrheumatoidarthritis.Rheumatol2006;45:106–11.39
30
[80] AsklingHH,RomboL,vanVollenhovenR,HallénI,ThörnerÅ,NordinM,etal.HepatitisA1vaccineforimmunosuppressedpatientswithrheumatoidarthritis:Aprospective,open-label,2multi-centrestudy.TravelMedInfectDis32014:http://dx.doi.org/10.1016/j.tmaid.2014.01.005.4
[81] CentersforDiseaseControlandPrevention.NotesfromtheField:FatalYellowFever5Vaccine–AssociatedViscerotropicDisease—Oregon,September2014.MorbMortalWkly6Rep2015:March20,2015/64(10);279–81.7
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