vaccine delivery digest 201703 docx -...

VaccineDeliveryResearchDigest,STARTCenter–March2017

VACCINEDELIVERYRESEARCHDIGEST

UNIVERSITY OF WASHINGTONSTRATEGIC ANALYSIS , RESEARCH, & TRAINING (START) CENTER

REPORTTO THEBILL & MELINDAGATES FOUNDATION

MARCH15 , 2017

PRODUCEDBY: LEVINE , GA ; SLYKER , J .

VaccineDeliveryResearchDigest,STARTCenter–March2017 2

TABLEOFCONTENTS

1. Vialusage,devicedeadspace,vaccinewastage,anddoseaccuracyofintradermaldeliverydevicesforinactivatedpoliovirusvaccine(IPV). 3o Alaboratory-basedanalysisoftheparametersandperformanceofdifferentintradermaldelivery

devicesthatcouldbeusedforIPVadministration,andcomparisonofvaccinewastage,lossandvaccineproductcostsusingdifferentdevices.

2. Investigatingsocio-economicinequityinaccesstoandexpendituresonroutineimmunizationservicesinAnambrastate. 4o Across-sectionalhouseholdsurveyconductedintwocommunitiesinAnambraState,southeastNigeria.

Investigatorsexploretheassociationbetweenaccesstoroutineimmunizationandhouseholdsocio-economicstatus,andothercorrelatesofimmunization.

3. Thepolioendgame:rationalebehindthechangeinimmunisation. 6o Areviewofglobalpolioeradicationeffortsandstrategiestoreachandmaintainelimination.

4. ModelingthePotentialforVaccinationtoDiminishtheBurdenofInvasiveNon-typhoidalSalmonellaDiseaseinYoungChildreninMali,WestAfrica. 7o AmathematicalmodelingstudytoestimatethepotentialimpactofNTSvaccinationprogramsin

BamakoonpediatriciNTSdiseasecasesanddeaths.5. EstimatedEffectofInactivatedPoliovirusVaccineCampaigns,NigeriaandPakistan,January2014-April

2016. 8o AretrospectivecohortstudytoevaluatetheeffectofIPVandtOPVpoliovaccinecampaignsinNigeria

andPakistan.6. Knowledge,attitudes,practicesandwillingnesstovaccinateinpreparationfortheintroductionofHPV

vaccinesinBamako,Mali. 9o Across-sectionalhouseholdsurveyofadultsandadolescentsintwourbanareasofBamako,todescribe

knowledgeofHPVandSTIsandtoexploreattitudesandpracticesrelatedtoHPVvaccinationandHPVvaccinationdecision-making.

7. Leveragingcontactnetworkstructureinthedesignofclusterrandomizedtrials. 10o Amodelingstudyoftheimpactofusingdifferentnetworkstructuresor“clusterconnectively”-

informeddesignsforclusterrandomizedcontrolledstudiesofvaccinationforoutbreaks.8. TheroleofthevaccinesindustryinMissionGrandConvergence. 11

o Acommentaryabouttheimportantroleoftheprivatesectorindevelopment,productionandsupplyofvaccinesglobally,anddiscussionofthecontinuedimportanceofthatroleashealthoutcomesandequitycontinuetoimproveglobally.

9. Timelinessandriskfactorsassociatedwithdelayforpneumococcalconjugate10-valentroutineimmunizationinBrazilianchildren. 12o Apopulation-basedretrospectivecohortstudyofchildreninCentralBraziltoevaluatetimelinessof

receivingeachPCV10doseandriskfactorsfordelaysinfirstdoseandnon-completionofcompletionPCV103+1schedule.

10. PerspectiveonGlobalMeaslesEpidemiologyandControlandtheRoleofNovelVaccinationStrategies.13o Anarrativereviewofglobalmeaslesepidemiology,novelmeaslesvaccinationstrategies,andproposed

pathwaytowardglobalmeasleselimination. APPENDIX 14


1. Vialusage,devicedeadspace,vaccinewastage,anddoseaccuracyofintradermaldeliverydevices

forinactivatedpoliovirusvaccine(IPV).JarrahianC,Rein-WestonA,SaxonG,CreelmanB,KachmarikG,AnandA,ZehrungD.Vaccine.2017Feb8.[Epubaheadofprint]PMID:28189403

ABSTRACTINTRODUCTION:Intradermaldeliveryofafractionaldoseofinactivatedpoliovirusvaccine(IPV)offerspotentialbenefitscomparedtointramuscular(IM)delivery,includingpossiblecostreductionsandeasingofIPVsupplyshortages.Objectivesofthisstudyweretoassessintradermaldeliverydevicesfordeadspace,wastagegeneratedbythefillingprocess,doseaccuracy,andtotalnumberofdosesthatcanbedeliveredpervial.METHODS:Devicestestedincludedsyringeswithstaked(fixed)needles(autodisablesyringesandsyringesusedwithintradermaladapters),aluer-slipneedleandsyringe,amini-needlesyringe,ahollowmicroneedledevice,anddisposable-syringejetinjectorswiththeirassociatedfillingadapters.Eachdevicewasusedtowithdraw0.1-mLfractionaldosesfromsingle-doseIMglassvialswhichwerethenejectedintoabeaker.Bothvialanddevicewereweighedbeforeandafterfillingandagainafterexpulsionofliquidtorecordchangeinvolumeateachstageoftheprocess.Datawereusedtocalculatethenumberofdosesthatcouldpotentiallybeobtainedfrommultidosevials.RESULTS:Resultsshowwidevariabilityindeadspace,doseaccuracy,overallwastage,andtotalnumberofdosesthatcanbeobtainedpervialamongintradermaldeliverydevices.Syringeswithstakedneedleshadrelativelylowdeadspaceandlowoverallwastage,andcouldachieveagreaternumberofdosespervialcomparedtosyringeswithadetachableluer-slipneedle.Ofthedisposable-syringejetinjectorstested,onewascomparabletosyringeswithstakedneedles.DISCUSSION:IfintradermaldeliveryofIPVisintroduced,selectionofanintradermaldeliverydevicecanhaveasubstantialimpactonvaccinewastedduringadministration,andthusontherequiredquantityofvaccinethatneedstobepurchased.Anidealintradermaldeliverydeviceshouldbenotonlysafe,reliable,accurate,andacceptabletousersandvaccinerecipients,butshouldalsohavelowdeadspace,highdoseaccuracy,andlowoverallwastagetomaximizethepotentialnumberofdosesthatcanbewithdrawnanddelivered.WEB:http://dx.doi.10.1016/j.vaccine.2016.11.098IMPACTFACTOR:3.62CITEDHALF-LIFE:5.50STARTSCIENTIFICCOMMENT:Authorsestimatethat,accountingforvariabilityindeadspace,doseaccuracy,andoverallwastage,thenumberofIDdosesavailableina5-doseIMvialcouldrangefrom15.7to27.1,andfromanywherebetween29.8and50.8IDdosesina10-doseIMvial.Authorspointoutthatvariabilityintheamountofvaccinewastedindifferentdeliverydevicesresultsinexcessproductionandsubstantiallyinflatesthecostofpurchasingvaccines.Figure1showsphotographsofarangeofspecificintradermaldeliverydevisesevaluatedbyauthors,eachofwhichcanbefilledonsiteandusedforIPVdelivery.


2. Investigatingsocio-economicinequityinaccesstoandexpendituresonroutineimmunizationservicesinAnambrastate.

SibeuduFT,UzochukwuBS,OnwujekweOE.BMCResNotes.2017Feb1;10(1):78.PMID:28143605

ABSTRACTIntroduction:Addressingexistinginequitiesintheutilizationofpriorityhealthservicessuchasroutineimmunizationisacurrentpublichealthpriority.Increasingaccesstoroutineimmunizationfromthecurrentlowlevelsamongstallsocio-economicstatusgroupsinNigeriaischallenging.However,littleisknownonthelevelofSESinequityinutilizationofroutineimmunizationservicesandsuchinformationwhichwillinformthedevelopmentofstrategiesforensuringequitableprovisionofroutineimmunizationservicesinthecountry.Thestudywasacrosssectionalhouseholdsurvey,whichwasundertakenintworandomlyselectedcommunitiesinAnambraState,southeastNigeria.Apre-testedintervieweradministeredquestionnairewasusedtocollectdataonlevelsofaccesstoRIbychildrenunder-2yearsfromrandomlyselectedhouseholds.Ineachhousehold,datawascollectedfromtheprimarycaregiversortheirrepresentative(intheirabsence).Therelationshipbetweenaccesstoroutineimmunizationandsocio-economicstatusofhouseholdsandotherkeyvariableswasexploredindataanalysis.RESULT:Householdsfromhighsocio-economicstatus(well-off)groupsutilizedroutineimmunizationservicesmorethanthosethatbelongtolowsocio-economicstatus(poor)groups(X2=9.97,p<0.002).Itwasfoundthathigherpercentageoflowsocio-economicstatushouseholdscomparedtothehighsocio-economicstatushouseholdsreceivedroutineimmunizationservicesatpublichealthfacilities.Householdsthatbelongtolowsocio-economicstatusgroupshadtotravellongerdistancetogettohealthfacilitiesconsequentlyincurringsometransportationcost.Themeanexpendituresonservicechargeforroutineimmunizationservices(mostlyinformalpayments)andtransportationwereUS$1.84andUS$1.27respectively.Logisticregressionshowedthataccesstoroutineimmunizationwaspositivelyrelatedtosocio-economicstatusandnegativelyrelatedtodistantofahouseholdtoahealthfacility.CONCLUSION:Abilitytopayaffectsaccesstoservices,evenwhensuchservicesarefreeatpointofconsumptionwithlowersocio-economicstatusgroupshavinglessaccesstoservicesandalsohavingotherconstraintssuchastransportation.Hence,innovativeprovisionmethodsthatwillbringroutineimmunizationservicesclosertothepeopleandeliminateallformalandinformaluserfeesforroutineimmunizationwillhelptoincreaseandimproveequitablecoveragewithroutineimmunizationservices.WEB:http://dx.doi.10.1186/s13104-017-2407-1IMPACTFACTOR:1.60CITEDHALF-LIFE:0.00STARTSCIENTIFICCOMMENT:Althoughtheproportionaccessingprivateroutineimmunizationserviceswashigherinthehighestwealthquintile,andtheproportionaccessingpublicserviceswashigherinthelowestwealthquintile,allSESgroupsaccessedservicesinbothsectors.Approximately27%ofthelowestquintileSESgroupaccessedprivateservicesandapproximately57%ofthehighestwealthquintileaccessedpublicservices.Butagain,althoughtheproportionpayingdirectcostsforimmunizationserviceswashighestamongthehighestwealthquintile,evenamongthelowestquintilemorethanhalfofrespondentspaidatleastsomedirectcosts.AlthoughthedistancetraveledtoaccessserviceswasslightlylongeramongthelowerSESgroup,theexpenditureontransportationwassimilarbetweenthehighestandlowestquintiles.ThismightbepartiallyexplainedbyadifferenceinthedistributionoftransportationmodesusedacrossSESgroups.Table5reportslogisticregressionmodelcoefficientsforspecificfactorsassociatedwithaccesstoroutineimmunizationservices;althoughthesedemonstratewhichco-factorsarestatisticallysignificantinmultivariablemodels,coefficientsaredifficulttointerpret.Wethereforeprovideexponentiatedcoefficientsbelow,whichcanbeinterpretedasoddsratios(ORs).Notethatthe“geographiclocation”variablewasnotdefined,andthuswhatconstitutedeach“geographiclocation”categorycomparedisunclear.Alsonotethatonly“geographiclocation”andSEScoefficientswerestatisticallysignificant.

VaccineDeliveryResearchDigest,STARTCenter-March2017

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Geographiclocation:OR=0.94;Distance(km):OR=0.99;SES(one-unithigherquintilecomparedwithone-unitlowerquintile):OR=1.05;Formaleducation(years):OR=0.99.*(ORsestimatedifferenceinaccess(accessingversusnotaccessingservices)associatedwitheachexplanatoryfactor,comparingaone-highertoaone-unitlowervalueofthefactor,adjustingforallotherfactorslisted.)


3. Thepolioendgame:rationalebehindthechangeinimmunisation.GaronJ,PatelM.ArchDisChild.2017Jan17.[Epubaheadofprint]PMID:28096107

ABSTRACTThedecadeslongefforttoeradicatepolioisnearingthefinalstagesandoralpoliovaccine(OPV)ismuchtothankforthissuccess.Ascasesofwildpolioviruscontinuetodwindle,casesofparalysisassociatedwithOPVitselfhavebecomeaconcern.Astype-2poliovirus(oneofthree)hasbeencertifiederadicatedandalargeproportionofOPV-relatedparalysisiscausedbythetype-2componentofOPV,theWorldHealthAssemblyendorsedthephasedwithdrawalofOPVandtheintroductionofinactivatedpoliovaccine(IPV)intoroutineimmunisationschedulesasacrucialstepinthepolioendgameplan.TherapidpaceofIPVscale-upanduptakerequiredadequatesupply,planning,advocacy,trainingandoperationalreadiness.Similarly,thesynchronisedswitchfromtrivalentOPV(allthreetypes)tobivalentOPV(types1and3)involvedanunprecedentedlevelofglobalcoordinationandcountrycommitment.TheimportantshiftinvaccinationpolicyseenthroughglobalIPVintroductionandOPVwithdrawalrepresentsanhistoricalmilestonereachedinthepolioeradicationeffort.WEB:http://dx.doi.org/10.1136/archdischild-2016-311171IMPACTFACTOR:0.19CITEDHALF-LIFE:10.00STARTSCIENTIFICCOMMENT:AuthorsconcludethatimportantrelevantquestionscurrentlyforIPVstrategyarethelengthoftimethatwillberequiredforIPVadministrationfollowingeradicationcertification,andtheidealdosingstrategyinlow-resourcesettings.Authorsrecommendthatfollowingeradicationcertification,“personnel,infrastructure,resourcesandprocesses”beleveragedtoaddressotherglobalhealthpriorities.Figure4isamapdepictingendemiccountriesandcasecountsin1988and2016.


4. ModelingthePotentialforVaccinationtoDiminishtheBurdenofInvasiveNon-typhoidalSalmonellaDiseaseinYoungChildreninMali,WestAfrica.

BornsteinK,HungerfordL,HartleyD,SorkinJD,TapiaMD,etal.PLoSNeglTropDis.2017Feb9;11(2):e0005283.PMID:28182657

ABSTRACTBACKGROUND:Insub-SaharanAfrica,systematicsurveillanceofyoungchildrenwithsuspectedinvasivebacterialdisease(e.g.,septicemia,meningitis)hasrevealednon-typhoidalSalmonella(NTS)tobeamajorpathogenexhibitinghighcasefatality(~20%).WhereinfantvaccinationagainstHaemophilusinfluenzaetypeb(Hib)andStreptococcuspneumoniaehasbeenintroducedtopreventinvasivediseasecausedbythesepathogens,asinBamako,Mali,theirburdenhasdecreasedmarkedly.Inparallel,NTShasbecomethepredominantinvasivebacterialpathogeninchildrenaged<5years.WhileNTSisbelievedtobeacquiredorallyviacontaminatedfood/water,epidemiologicstudieshavefailedtoidentifythereservoirofinfectionorvehiclesoftransmission.ThishasprecludedtargetingfoodchaininterventionstodiminishdiseasetransmissionbutconverselyhasfosteredthedevelopmentofvaccinestopreventinvasiveNTS(iNTS)disease.WedevelopedamathematicalmodeltoestimatethepotentialimpactofNTSvaccinationprogramsinBamako.METHODOLOGY/PRINCIPALFINDINGS:AMarkovchaintransmissionmodelwasdevelopedutilizingage-specificBamakodemographicdataandhospitalsurveillancedataforiNTSdiseaseinchildrenaged<5yearsandassumingvaccinecoverageandefficacysimilartotheexisting,successfullyimplemented,Hibvaccine.AnnualiNTShospitalizationsanddeathsinchildren<5years,withandwithoutaSalmonellaEnteritidis/SalmonellaTyphimuriumvaccine,werethemodel'soutcomesofinterest.Perthemodel,highcoverage/highefficacyiNTSvaccinationprogramswoulddrasticallydiminishiNTSdiseaseexceptamonginfantsage<8weeks.CONCLUSIONS/SIGNIFICANCE:ThepublichealthimpactofNTSvaccinationshiftsasdiseaseburden,vaccinecoverage,andserovardistributionvary.OurmodelshowsthatimplementinganiNTSvaccinethroughananalogousstrategytotheHibvaccinationprograminBamakowouldmarkedlyreducecasesanddeathsduetoiNTSamongthepediatricpopulation.ThemodelcanbeadjustedforuseelsewhereinAfricawhereNTSepidemiologicpatterns,serovarprevalence,andimmunizationschedulesdifferfromBamako.WEB:http://dx.doi.org/10.1371/journal.pntd.0005283IMPACTFACTOR:4.45CITEDHALF-LIFE:3.20STARTSCIENTIFICCOMMENT:AuthorsestimatediNTScoverageforparameterinputsfromasmallsampleof61caretakersofinfants6-8monthsoldinBamako,basedonHibvaccinecoverage.Amongthissample98%hadreceived>1doseand90%hadreceivedall3.Rangeswerefurtherexpandedbasedondatafromalargerpopulation-basedsampleinKenya.iNTSvaccineefficacyparameterinputswerebasedonHibandpneumococcalconjugatevaccinefromAfricancountries.Figure5reportstheage-specificexpectednumbersofcasesandfatalcasesunderscenariosofiNTSvaccination:a)noiNTSvaccination;b)6-weekiNTSvaccinationat100%efficacyand100%coverage;3)6,10and14-weekvaccinationwithcoveragevaryingbydose(3doses90%and1dose98%)andefficacydependingonnumberofdosesreceived(3doses95%,1dose45%).Table5reportstheproportionalreductioniniNTScasesanddeathsinscenarioswithdifferentvaccineefficacy,serovardistributionanddosingregimenassumptions.Mostscenariosresultedinsimilarproportionalreductionsindeaths(approximately30-45%reduction),butassumingS.Typhimuriumwastheonlycausalpathogen,authorsestimatean80%reductionisiNTS-relatedmortality.Proportionalreductionsincasesrangedfromapproximately50%for3-dosewithlowefficacyduetoimmunesuppression,and80%,withhighvaccineefficacyestimates.Inabsoluteterms,authorsestimateaminimumofbetween4-23pediatriccasesperyearwouldbepreventedbyvaccination,assumingthelowestrangesofvaccineefficacy,andamaximumof29pediatriccasespreventedperyear,assumingthehighestvaccineefficacy.Three-dosevaccinationat6,10and14weekswasestimatedtopreventbetween21-23casesperyearand1-3deaths,assumingefficacyandeffectivenesssimilartoatrialintheGambia.


5. EstimatedEffectofInactivatedPoliovirusVaccineCampaigns,NigeriaandPakistan,January2014-April2016.

ShirreffG,WadoodMZ,VazRG,SutterRW,GrasslyNC.EmergInfectDis.2017Feb;23(2):258-263.PMID:27861118

ABSTRACTIn2014,inactivatedpoliovirusvaccine(IPV)campaignswereimplementedinNigeriaandPakistanafterclinicaltrialsshowedthatIPVboostsintestinalimmunityinchildrenpreviouslygivenoralpoliovirusvaccine(OPV).WeestimatedtheeffectofthesecampaignsbyusingsurveillancedatacollectedduringJanuary2014-April2016.InNigeria,campaignswithIPVandtrivalentOPV(tOPV)substantiallyreducedtheincidenceofpoliomyelitiscausedbycirculatingserotype-2vaccine-derivedpoliovirus(incidencerateratio[IRR]0.17for90daysaftervs.90daysbeforecampaigns,95%CI0.04-0.78)andtheprevalenceofvirusinenvironmentalsamples(prevalenceratio[PR]0.16,95%CI0.02-1.33).CampaignswithtOPValoneresultedinsimilarreductions(IRR0.59,95%CI0.18-1.97;PR0.45,95%CI0.21-0.95).InPakistan,theeffectofIPV+tOPVcampaignsonwild-typepolioviruswasnotsignificant.ResultssuggestthatadministrationofIPValongsideOPVcandecreasepoliovirustransmissionifhighvaccinecoverageisachieved.WEB:http://dx.doi.org/10.3201/eid2302.161210IMPACTFACTOR:4.89CITEDHALF-LIFE:6.30STARTSCIENTIFICCOMMENT:Figure1depictstheeffectofmassvaccinationcampaignswithinactivatedpoliovirusvaccineplustrivalentoralpoliovirusvaccine(IPV+tOPV)ortOPValoneonpoliovirusdetectioninpeopleandfromenvironmentalsamples,inNigeriaandPakistanfrom2014–2016.Resultsdemonstratethesubstantialdifferencesineffectacrossthesetwosettings.Authorsalsonotethatacrossstates/regionswithinacountry,therewassubstantialvariationintheeffectofthestrategies;withinacountry,theincidenceofcasesandprevalenceofpathogensisolatedfromenvironmentalsamplevariedsubstantially.Becauseofthiswithin-countryheterogeneity,authorspreferredamixed-effectsregressionmodel(asopposedtofixed-effect),whichallowstheeffectofthestrategiestodifferacrosslocation.AuthorsproposethatthelackofeffectofIPV+tOPVmasscampaignsonWPV1incidenceorenvironmentalprevalencecouldbeexplainedbylowstatisticalpower,lowcoverageduringthecampaignsandrestrictioninthetargetagegroupsforvaccination.


6. Knowledge,attitudes,practicesandwillingnesstovaccinateinpreparationfortheintroductionofHPVvaccinesinBamako,Mali.

DeGrootAS,TounkaraK,RochasM,BesemeS,YektaS,etal.PLoSOne.2017Feb13;12(2):e0171631.PMID:28192460

ABSTRACTAlthoughscreeningforpre-cancerouscervicallesionsandhumanpapillomavirus(HPV)vaccinationareacceptedandeffectivemeanstopreventcervicalcancer,womeninMalihavelimitedaccesstotheseinterventions.Inaddition,cervicalcancerpreventionbyHPVvaccinationhasbeencontroversialinsomesettings.ToreducecervicalcancerprevalenceandincreaseHPVvaccineuptake,itisimportanttounderstandthelevelofknowledgeaboutcervicalcancerscreeningandpracticesrelatedtovaccinationinat-riskpopulations.Inthisstudy,thelevelofknowledgeaboutHPVandcervicalcancerandattitudestowardsvaccinationwereassessedamong301participants(maleandfemale,adultsandadolescents)inahouse-to-housesurveyintwourbanneighborhoodsinBamako,Mali.ThesurveywascombinedwithabriefeducationalsessiononHPV.Priortotheeducationsession,overallknowledgeofHPVinfectionandcervicalcancerwasverylow:only8%knewthatHPVisasexuallytransmittedinfection(STI).Lessthan20%ofwomenhadeverconsultedagynecologistandlessthan3%hadeverhadcervicalcancerscreening.AfterhearingadescriptionofHPVvaccine,morethan80%wouldacceptHPVvaccination;fathersandhusbandswereidentifiedasprimarydecisionsmakersandlocalclinicsorthehomeaspreferredsitesforvaccination.ThisstudyprovidesinformationonSTIknowledgeandvaccineacceptanceinBamako,Maliin2012,priortotheintroductionofHPVvaccination.WEB:http://dx.doi.org/10.1371/journal.pone.0171631IMPACTFACTOR:3.23CITEDHALF-LIFE:2.70STARTSCIENTIFICCOMMENT:AfterreceivingthebriefHPVeducationalintervention,respondentsreportedcommunityclinicsandtheirhomesweretheirpreferredlocationsforreceivingHPVvaccination.WhenpromptedfortheirpreferredmethodofreceivinginformationaboutHPVvaccine-relatedappointments,respondentsreportedpreferringhomevisitstoSMSreminders.Figure4describestheindividualdecision-makinganddecision-makingautonomyforHPVvaccinationamongdifferentagesandgenders.Aboutathirdofadultwomenreportedthatthedecisiontovaccineherchildwouldbemadebyherspouse,aquarterreportedtheywouldmakethedecisionthemselves,and16%saidbothsheandherpartnerwoulddecidetogether.Incontrast,noadultmalesreportedtheirspousewouldmakethedecisionalone,about10%saidtheythemselveswouldmakethedecisionaloneandapproximately1%saidthedecisionwouldbemadetogetherwiththeirspouse.Adolescentfemalesandmalesalsohaddifferentperceptionsaboutdecision-makingautonomy.Whereasapproximately16%offemalesreportedtheywouldmakethedecisionwiththeirparents,44%ofmalessaidtheywouldmakethedecisionwiththeirparents.Amongfemales,27%saidtheythemselveswouldmakethedecision,butonlyabouthalfofthat,approximately15%ofmales,feltthedecisionwouldbetheirsindependently.


7. Leveragingcontactnetworkstructureinthedesignofclusterrandomizedtrials.HarlingG,WangR,OnnelaJP,DeGruttolaV.ClinTrials.2017Feb;14(1):37-47.PMID:27798376

ABSTRACTBACKGROUND:InsettingsliketheEbolaepidemic,whereproof-of-principletrialshaveprovidedevidenceofefficacybutquestionsremainabouttheeffectivenessofdifferentpossiblemodesofimplementation,itmaybeusefultoconducttrialsthatnotonlygenerateinformationaboutinterventioneffectsbutalsothemselvesprovidepublichealthbenefit.Clusterrandomizedtrialsareofparticularvalueforinfectiousdiseasepreventionresearchbyvirtueoftheirabilitytocapturebothdirectandindirecteffectsofintervention,thelatterofwhichdependsheavilyonthenatureofcontactnetworkswithinandacrossclusters.Byleveraginginformationaboutthesenetworks-inparticularthedegreeofconnectionacrossrandomizedunits,whichcanbeobtainedatstudybaseline-weproposeanovelclassofconnectivity-informedclustertrialdesignsthataimbothtoimprovepublichealthimpact(speedofepidemiccontrol)andtopreservetheabilitytodetectinterventioneffects.METHODS:Weseveraldesignsforclusterrandomizedtrialswithstaggeredenrollment,ineachofwhichtheorderofenrollmentisbasedonthetotalnumberofties(contacts)fromindividualswithinaclustertoindividualsinotherclusters.Ourdesignscanaccommodateconnectivitybasedeitheronthetotalnumberofexternalconnectionsatbaselineoronconnectionsonlytoareasyettoreceivetheintervention.Wefurtherconsidera"holdback"versionofthedesignsinwhichcontrolclustersareheldbackfromre-randomizationforsometimeinterval.Weinvestigatetheperformanceofthesedesignsintermsofepidemiccontroloutcomes(timetoendofepidemicandcumulativeincidence)andpowertodetectinterventioneffect,bysimulatingvaccinationtrialsduringanSEIR-typeepidemicoutbreakusinganetwork-structuredagent-basedmodel.WecompareresultstothoseofatraditionalSteppedWedgetrial.RESULTS:Inoursimulationstudies,connectivity-informeddesignsleadtoa20%reductionincumulativeincidencecomparedtocomparabletraditionalstudydesigns,buthavelittleimpactonepidemiclength.Powertodetectinterventioneffectisreducedinallconnectivity-informeddesigns,but"holdback"versionsprovidepowerthatisveryclosetothatofatraditionalSteppedWedgeapproach.CONCLUSION:Incorporatinginformationaboutclusterconnectivityinthedesignofclusterrandomizedtrialscanincreasetheirpublichealthimpact,especiallyinacuteoutbreaksettings.Usingthisinformationhelpscontroloutbreaks-byminimizingthenumberofcross-clusterinfections-withverymodestcostintermsofpowertodetecteffectiveness.WEB:http://dx.doi.org/10.1177/1740774516673355IMPACTFACTOR:1.84CITEDHALF-LIFE:5.60STARTSCIENTIFICCOMMENT:Figure1isaflowcharttoguideappropriateselectionandtypologyofthedifferentconnectivity-informeddesignsdescribedinthepaper,basedonattributesoftheresearchscenario.Figure2isadepictionofbetween-clusterconnectivity(or“ties”),andaschematicforhowitiscalculatedatdifferenttimesinaclusterrandomizedtrial,basedondifferentnumbersofindividualsconnectedwithinandbetweenclusters,inthedifferenttypesofconnectivity-informeddesigns.Authorsdescribethatthebasictrade-offbetweenatraditionalcluster-RCTandaconnectivity-informeddesignisthattheformerhasmorestatisticalpowertodetectinterventioneffects,whilethelattertypesprovidefasterepidemiccontrol.However,themagnitudeofthetrade-offdependsonanumberoffactors,includingthetypesandamountofconnectednessinthestudypopulation,designused,timingofplannedanalyses,andfeaturesofthecausativeagent.Knowledgeofthestructureoftheconnectednesswithinthestudypopulation(howconnectedarethosewithinandbetweenclusters)isessentialindeterminingthebalanceofsuchtrade-offs.Authorsemphasizethepotentialutilityofthisclassofdesignsforeffectivenesstrials,whenefficacyhasalreadybeenestablished.


8. TheroleofthevaccinesindustryinMissionGrandConvergence.AlmondJ,MedagliniD.Vaccine.2017Jan20;35Suppl1:A24-A28.PMID:28017440

ABSTRACTThevastmajorityofvaccinesusedthroughouttheworldaresuppliedbytheprivatesector.ItisessentialthereforethattheindustryiscloselyengagedinfuturepolicydevelopmentsatanationalandinternationallevelandisabletorespondtothechangingneedsandprioritiesthatmayberequiredtoensurethesuccessofMissionGrandConvergence.Uniquely,themajorvaccinecompanieshavetheexpertiseandtechnicalcapacitytodevelop,produceandsupplyvaccinesonaglobalscale.ThroughpartneringwithGovernments,charitiesandNGOs,theymustplayapivotalroleintheMissionand,atthesametimeasagreeingonobjectivesthatmaynotbeentirelymarketdriven,mustbeabletosustaintheircommercialobligationstoshareholders.Similarly,smallandmediumsizedcompanies,withtheglobalinvestormarketandgovernmentincentivesthatunderpinandsupportthem,alsohaveaveryimportantroletoplay;forexampleininnovationaroundagivendiseaseandontechnology,processandplatformdevelopmentacrossthewholevaluechain.Theindustryatlargeisthereforeanessentialplayer.IndeedMissionGrandConvergencecanonlysucceedwiththefullandwillingparticipationofthevaccinesindustry.WEB:http://dx.doi.org/doi.10.1016/j.vaccine.2016.10.084IMPACTFACTOR:3.62CITEDHALF-LIFE:5.50STARTSCIENTIFICCOMMENT:Authorsdiscusstheimportanceforprivatevaccinemanufacturerstoanalyzewell-informed“businesscases”todetermineprioritizationinresearchanddevelopment,production,anddistributionofvaccines.Abusinesscasewouldincludethefollowing:

• Determiningregion-specificestimatesofthecostofdiseasetreatment• Assuminga“price-neutral”approachtovaccinedevelopment/production/distributioncostsrelativeto

treatmentcostsamonghealthauthoritiesthatwouldprocureit• Determiningindirectdiseasecosts/assessing“populationbenefits”aboveandbeyondtreatmentbenefit• Assessingquality-adjustedlife-yearslostassociatedwiththedisease(encourageshigherpossiblepricing)• Assessingglobalvaccinedevelopmentcosts(includingclinicalresearchandlicensure;capitalcostsand

productionfacilitycosts)• Forecastingvaccinesalestoestimatepotentialrevenue• CalculationofNetPresentValue

AuthorsexplainthatiftheNetPresentValueispositive,thereisabusinesscasefordevelopment.Thenextstepwouldbeevaluationof“scientificfeasibility”,basedonexpertdeterminationofthefollowing:

• Whetherantigens/componentstousetoproduceaprotectiveimmuneresponseinrecipientareknown;• Whethertheproductissafe;• How“complex”thevaccineneedstobe;• Whetherthereisafeasibleclinicaldevelopmentpathwayandwhethertheprocessislikelytobe

“industrialisable”toproduceadequateproductatscale,atreasonableprice.Authorsemphasizetheimportancetothefieldofhavingpeopleinvaccinologywhoaretrainedinbothacademicdisciplinesandinindustryskillsandprocesses,andrecommendjointandcollaborativetrainingprogramswithdiversecomponentsacrossdisciplines.Theyencouragethedevelopmentoftrainingandengagementopportunitiesviapartnershipandcollaborationacrossthesectors.


9. Timelinessandriskfactorsassociatedwithdelayforpneumococcalconjugate10-valentroutineimmunizationinBrazilianchildren.

SartoriAL,MinamisavaR,AfonsoET,PolicenaGM,PessoniGC,etal.Vaccine.2017Feb15;35(7):1030-1036.PMID:28108230

ABSTRACTBACKGROUND:Vaccinationcoverageistheusualmetricstoevaluatetheimmunizationprogramsperformance.Forthe10-valentpneumococcalconjugate(PCV10)vaccine,measuringthedelayofvaccinationisalsoimportant,particularlyasyoungerchildrenareatincreasedriskofdisease.RoutinelycollectedadministrativedatawasusedtoassessthetimelinessofPCV10vaccination,andthefactorsassociatedwithdelaytoreceivethefirstandseconddoses,andthecompletionofthePCV103+1schedule.METHODS:Apopulation-basedretrospectivecohortstudywasconductedwithchildrenbornin2012inCentralBrazil.ChildrenwhoreceivedthePCV10firstdoseinpublichealthserviceswerefollowed-upuntil23monthsofage.TimelinessofreceivingeachPCV10doseatanygivenagewasdefinedasreceivingthedosewithin28daysgraceperiodfromtherecommendedagebytheNationalImmunizationProgram.Log-binomialregressionmodelswereusedtoexamineriskfactorsfordelaysofthefirstdoseandthecompletionPCV103+1schedule.RESULTS:Intotal,14,282childrenwereincludedinthecohortofstudy.Delayedvaccinationoccurredin9.4%,23.8%,36.8%and39.9%childrenforthefirst,second,thirdandtheboosterdoses,respectively.Atotalof1912children(12.8%ofthecohort)werenotadequatelyvaccinatedatthe6monthsoflife;1,071(7%)receivedtheseconddoseafter6monthsofage,784(5.4%)didnotreceivetheseconddose,and57(0.4%)receivedthefirstdoseaftersixmonthsoflife.CONCLUSION:AconsiderabledelaywasfoundinPCV10thirdandboosterdoses.Almost2thousandchildrenhadnotreceivedtherecommendedPCV10dosesat6monthsofage.TimelinessofvaccinationisanissueinBrazilalthoughhighvaccinationcoverages.WEB:http://dx.doi.org/10.1016/j.vaccine.2017.01.012IMPACTFACTOR:3.62CITEDHALF-LIFE:5.50STARTSCIENTIFICCOMMENT:AuthorsfoundthathigherlevelofmaternaleducationalattainmentandreceiptofmoreprenatalvisitswerebothassociatedwithlargerlikelihoodofreceiptwithoutdelayinfirstdoseofPCV10inthechild,andincompletion.Inmultipleregressionanalysis,authorsfoundthattheinfluenceofreceiptofadequateprenatalcareoncompletionofPCV103+1amongthosewhoreceivedfirstdose,dependedonmaternaleducation.Amongthosewithloweducationalattainment,havinglessthan7prenatalvisitswasaparticularlystrongriskfactorfornotcompletingPCV103+1.


10. PerspectiveonGlobalMeaslesEpidemiologyandControlandtheRoleofNovelVaccinationStrategies.

CoughlinMM,BeckAS,BankampB,RotaPA.Viruses.2017Jan19;9(1).PMID:28106841

ABSTRACTMeaslesisahighlycontagious,vaccinepreventabledisease.Measlesresultsinasystemicillnesswhichcausesprofoundimmunosuppressionoftenleadingtoseverecomplications.In2010,theWorldHealthAssemblydeclaredthatmeaslescanandshouldbeeradicated.MeasleshasbeeneliminatedintheRegionoftheAmericas,andtheremainingfiveregionsoftheWorldHealthOrganization(WHO)haveadoptedmeasleseliminationgoals.Significantprogresshasbeenmadethroughincreasedglobalcoverageoffirstandseconddosesofmeasles-containingvaccine,leadingtoadecreaseinglobalincidenceofmeasles,andthroughimprovedcasebasedsurveillancesupportedbytheWHOGlobalMeaslesandRubellaLaboratoryNetwork.Improvedvaccinedeliverymethodswilllikelyplayanimportantroleinachievingmeasleseliminationgoalsasthesedeliverymethodscircumventmanyofthelogisticissuesassociatedwithsubcutaneousinjection.Thisreviewhighlightsthestatusofglobalmeaslesepidemiology,novelmeaslesvaccinationstrategies,anddescribesthepathwaytowardmeasleselimination.WEB:http://dx.doi.org/10.3390/v9010011IMPACTFACTOR:1.98CITEDHALF-LIFE:6.30STARTSCIENTIFICCOMMENT:Authorsdescribekeychallengesinvaccinedeliverysystemsformeaslesvaccineasrelatingto1)coldchainrequirements;2)injectionsafetyanddisposalofcontaminatedwaste;and3)requirementsforavailabletrainedpersonneltoadministerthevaccine,anddiscussnovelstrategiestoaddresstheseneeds.Onestrategyunderinvestigationwasdeterminingmethodstoblockplacentally-transferredmaternalantibodiesininfants,sothatthevaccinecouldbedeliveredearlierandstillproducealastinginfantresponse.Alternatedeliverysystems,whichmayhelpalleviatechallengesinwastemanagementandrequirementsforskilledpersonnel,includeintradermalmicroneedlesandrespiratoryadministrationviaaerosolizedvaccine(nebulizedliquidanddrypowderformulations).Unfortunately,thoughtrialsinaerosolizedroutesappearedtoresultinsufficientimmuneresponseinolderchildren,resultsininfantsindicatedlessimmuneresponse,althoughincreasedexposuretimetonebulizedvaccinedidinducesufficientimmuneresponseamonginfants.Unfortunately,amajorchallengeindevelopingaerosolizedformulationsislowerconsistencyinthedosedeliveredthancomparedtosubcutaneousdeliverymethods.Drypowerformulations,whichimprovethermostability,haverelativelymorelimitedhumandata;phase1datasuggestsacceptableimmunogenicityandsafety,butthisformulationhasnotbeenevaluatedinchildrentodate.Althoughmicroneedlepatchesareapromisingnewapproachwhichwouldreducetheneedfortrainedstaff,lackofhumanclinicaldataoraplanforlarge-scalecommercialproductionlimitutilityintheshort-term.Table1summarizesclinicalresearchonalternative(non-subcutaneousinjection)vaccinedeliveryapproaches.


APPENDIX:PUBMEDSEARCHTERMS

(((((vaccine[tiab]ORvaccines[tiab]ORvaccination[tiab]ORimmunization[tiab]ORimmunisation[tiab]ORvaccine[mesh]ORimmunization[mesh])AND(logistics[tiab]ORsupply[tiab]OR"supplychain"[tiab]ORimplementation[tiab]ORexpenditures[tiab]ORfinancing[tiab]OReconomics[tiab]OR"Costeffectiveness"[tiab]ORcoverage[tiab]ORattitudes[tiab]ORbelief[tiab]ORbeliefs[tiab]ORrefusal[tiab]OR"Procurement"[tiab]ORtimeliness[tiab]ORsystems[tiab]))OR("vaccinedelivery"[tiab]))NOT("invitro"[tiab]OR"immuneresponse"[tiab]ORgene[tiab]ORchemistry[tiab]ORgenotox*[tiab]ORsequencing[tiab]ORnanoparticle*[tiab]ORbacteriophage[tiab]ORexome[tiab]ORexogenous[tiab]ORelectropor*[tiab]OR"systemsbiology"[tiab]OR"animalmodel"[tiab]ORcattle[tiab]ORsheep[tiab]ORgoat[tiab]ORrat[tiab]ORpig[tiab]ORmice[tiab]ORmouse[tiab]ORmurine[tiab]ORporcine[tiab]ORovine[tiab]ORrodent[tiab]ORfish[tiab]))AND(English[LA])("2017/1/15"[PDAT]:"2017/2/14"[PDAT]))*OnMarch2,2017,thissearchofEnglishlanguagearticlespublishedbetweenJanuary15,2017andFebruary14,2017andindexedbytheUSNationalLibraryofMedicineresultedin191uniquemanuscripts.

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