controlled human hookworm infection accelerating human hookworm vaccine development david diemert-匠人.pdf

该【controlled human hookworm infection accelerating human hookworm vaccine development david diemert-匠人 】是由【刘备文库】上传分享，文档一共【8】页，该文档可以免费在线阅读，需要了解更多关于【controlled human hookworm infection accelerating human hookworm vaccine development david diemert-匠人 】的内容，可以使用淘豆网的站内搜索功能，选择自己适合的文档，以下文字是截取该文章内的部分文字，如需要获得完整电子版，请下载此文档到您的设备，方便您编辑和打印。OpenForumInfectiousDiseasesMAJORARTICLEControlledHumanHookwormInfection:AcceleratingineDevelopmentDavid?Diemert,1,2Doreen?Campbell,1Jill?Brelsford,1Caitlyn?Leasure,1Guangzhao?Li,1Jin?Peng,1Maria?Zumer,2Naji?Younes,3MariaElena?Bottazzi,4Rojelio?Mejia,4David?I.?Pritchard,5JohnM.?Hawdon,1,*andJeffreyM.?Bethony1,*1DepartmentofMicrobiology,ImmunologyandTropicalMedicine,2DepartmentofMedicine,and3MilkenInstituteSchoolofPublicHealth,eWashingtonUniversity,WashingtonDC;4DepartmentofPediatrics,SectionofPediatricTropicalMedicine,TexasChildren’ineDevelopment,NationalSchoolofTropicalMedicine,BaylorCollegeofMedicine,Houston,Texas;5DepartmentofPharmacy,UniversityofNottingham,Nottingham,UnitedKingdomBackground.?Controlledhumanhookworminfection(CHHI)ina-tion-challengemodel(HVCM)(NaL3)accordingtocurrentGoodManufacturingPractice(cGMP).?cGMP-gradeNaL3wereproducedforaphase1trialin20healthy,hookworm-na?veadultsintheUnitedStates,–18weekspostinfectionforsafety,tolerability,andpatencyofN.?.?,pain,.?americanusinfectionin90%.?Theinoculumof50NaL3waswelltoleratedandconsistentlyinducedpatentN.?.?challengemodel;controlledhumanhookworminfection;currentgoodmanufacturingpractice;ine;,ThenextstageofclinicaldevelopmentfortheHHVistoineefficacy,whichconventionallyrequirescostlytract[1].ChronichookworminfectioncaninduceirondeficiencyfieldtrialsinNecator-endemicareas,withlargesamplesizesanemia,withchildrenandwomenofchildbearingagebeingmost(~1200volunteers)andlengthyduration(1–2?years)[8].Toatrisk[2].Currentcontroleffortsrelyonmassdrugadminis-mitigatetheexpenseandriskofsuchtrials,weproposeahook-tration(MDA)withabenzimidazole(BZ)ination-challengemodel(HVCM)toprovideearlyinfectionsbutdoesnotpreventre-infection[3].Furthermore,ineefficacythatwouldentailimmuniz-developmentofresistancetoBZs,asseeninlivestock[4,5],isainghookworm-na?veadultsfromnonendemicareaswithcandi-,inesandthenchallengingthemwithinfectiveNecatorine(HHV)-americanuslarvae(NaL3).EfficacywouldbedeterminedbytherentHHVcandidateantigens,Na-GST-1andNa-APR-1,haveabsenceofpatentinfection(nodetectableeggsinfeces)orabeenevaluatedinclinicaltrialsintheUnitedStates,Brazil,andreductionininfectionintensity(expressedbyeggspergramGabonandhavebeenfoundtobesafeandimmunogenic[6,7].[EPG]inatedcontrols[7,9,10].Althoughhookworm-na?vevolunteershavebeeninfectedwithN.?americanusinpriorstudies[11–20],wereporttheReceived10January2018;editorialdecision9April2018;*EqualcontributionCorrespondence:D.?Diemert,MD,DepartmentsofMedicineand?Microbiology,ImmunologyManufacturingPractice(cGMP)wereadministeredtohealthyandTropicalDiseases,eWashingtonUniversitySchoolofMedicineandHealthSciences,hetolerabilityofdifferentdosesandto2300EyeStreetNW,Ross524,Washington,DC20037(******@).??TheAuthor(s)-mercial-NoDerivslicence(/licenses/by-nc-nd//),mercialreproductionanddistributionofthework,inanycGMPManufactureofNaL3medium,providedtheoriginalworkisnotalteredortransformedinanyway,-use,pleasecontactjournals.******@DOI:(IMRG)attheination-Challenge?Model???OFID???1Downloadedfromhttps://academic./ofid/article-abstract/5/5/ofy083/4976553bygueston20May2018UniversityofNottingham,UnitedKingdom,underan(SupplementaryMethods).ThestudywasapprovedbytheInvestigationalMedicinalProductDossierfromtheUKGWUInstitutionalReviewBoard(IRB),-(UKMIA[IMP]3057).Briefly,feceswerecollectedfromasioncriteriaarelistedintheSupplementaryMethods.-.,fecalsampleswereexaminedweeklyinvestigationalmedicinalproducts,per21CFR§(r)bybothsalineflotationandquantitativepolymerasechain(1)(SupplementaryMethods).Fecalmaterialwasmixedreaction(qPCR)methodstodetectN.?americanuseggs[10].withamphotericinBandgentamicinfor6hours,towhichSampleswerefurtheranalyzedbytheMcMaster(MM)tech-activatedcharcoal(FisherScientific,Loughborough,UK)niqueandqPCRtoassessintensityofinfection,expressedaswasadded,andincubatedfor10?ordingtoEPGoffeces[9].amodifiedHaradaMorimethodtorecoverNaL3[21,22].RecoveredNaL3wereisolatedandwashedrepeatedlyinster-(motility),iden-TimetopatentinfectionwasdisplayedusingKaplan-Meiertity(lectin-bindingassay),andmicrobialcontamination(USPestimates,withlog-parethedistribu-<61>and<62>,andthenreleasedbyIMRG(SupplementarytionoftimetopatencybetweendosegroupsandcensoringofMethods)eWashingtonUniversityearlywithdrawalsorthosefailingtodeveloppatentinfection.(GWU)at19oC–25oCinatemperature-<61><62>)binedyeastandusedtodisplaytrendsineosinophilcountsandfecalEPGsbymoldcounts,-WhitneyUtestswereusedtoevaluatediffer-andPseudomonasaeruginosa,afterarrivalatGWU?-Administration(FDA)InvestigationalNewDrug?(IND)appli-(#015752).A?Coxproportionalhazardsmodelwasusedtoevaluatetheeffectsofcovariates(eg,NaL3doseoreosinophilcount)onStudy??generalizedlinearmixed-effectsmodelwasThephase1trial(NCT01940757)wasanopen-labeldoseconstructedusingthePROCGLIMMIXproceduretodeter-escalationstudyof20healthy,hookworm-heeffectsofeosinophilcountandNaL3doseonEPG18–45?eWashingtonUniversity(Washington,).InCohort1,10volunteersreceivedaninoculumof25ofinfectionintensity,asmeasuredbyMMandqPCR,signedNaL3;inCohort2,-ontoasterilegauzepad,.(ROC)uracyofMMandAfterremoval,thegauzewasplacedintosterilewatertocountqPCRindiscriminatingbetweenpatencyandnopatency,,withatleast8wereconductedusingSAS,(Cary,NC),andfiguresmitteewereconstructedusingRsoftware().,7,14,and28?dayspostinfection(.)andthenweeklyuntiltreat-PowerCalculationsfor?HVCMmentwith3dailydosesof400?mgalbendazoleonday84fortheDatafromthecurrentstudywereusedtocalculatethesamplefirst14participants,andonday126forthelast6.?Ateachvisit,,swelling,,abdominalpaininfectioninthe3interventiongroups(ie,ineorbloating,nausea,vomiting,diarrhea,cough,)withtheproportionwithpatentinfectioninapleteddailysymptomdiariesforthedurationcontrol(placebo)groupusinga1-sidedFisherexacttest,-BonferroniprocedurewasAdverseeventsweregradedasmild(easilytolerated),mod-(interferedwithactivitiesofdailyliving),orsevere(pre-RESULTSventedactivitiesofdailyliving)andassignedcausalityrelativepletebloodcountswereperformedpriortoOf31adultsscreened,6declinedorwerelosttofollow-upNaL3applicationandatregulartimepointsstartingatweek5beforeenrollment,5wereineligible,and20(5malesand52???OFID???Diemertet?alDownloadedfromhttps://academic./ofid/article-abstract/5/5/ofy083/4976553bygueston20May2018Table?1.?IncidenceandSeverityofApplicationSite,RespiratoryandGastrointestinalSolicitedAdverseReactionsFollowingApplicationof25or50NaL3byCHHI25NaL3(n?=?10)50NaL3(n?=?10)–10––Pruritus10––82–Pain1––4––Tenderness4––8––Swelling2–141–Bruising3––1––RespiratoryreactionsSorethroat22–7––Cough22–7––GastrointestinalreactionsAbdominalbloating43–42–Abdominalpain53–32–Nausea32–32–Vomiting12––––Diarrhea32–5––Flatulence6––11–,:CHHI,)meteligibilitycriteriaandof26(4–69)(SupplementaryFigure?1).Reasonsforexclusionin3participantsinthe50NaL3cohortandlastedamedianofitantmedicaldiagnosessuchasirritablebowel107?daysafterresolutionoftherash;in2cases,thehyperpig-syndrome,Hashimoto’sthyroiditis,,albeitfading,atthefinal?(range)was25(19–45)mon(Table?1)-occurredprimarilyaferweek4?.(Figure?2).TeincidenceipateinanIRB-approvedsubstudyandwerenottreatedwithandtimingofthesesymptomswerenotsignifcantlydiferentalbendazolebuthaveremainedinfectedtoserveasdonorsofbetweenthe2dosecohorts(SupplementaryTable?1).Increasedfecalsamples,fromwhichN.?americanuseggswillbeproducedfatulence(7/10inthe25NaL3cohortand3/),abdominalbloating(7/10inbothcohorts),andabdom-%%forthe25and50NaL3cohorts,respec-inalpain(8/10inthe25NaL3cohortand5/10inthe50NaL3tively(P?=?.56,Wilcoxonrank-sum?test).cohort)plaints,allofSafetyof?-urredin3participantsinthe25NaL3cohort,althoughApplicationofNaL3tohealthy,hookworm-na?(1participantinABCohort1withdrewearlyandwastreatedwithalbendazoleonday63duetomovingunexpectedlyfromthearea).(Table?1).urredin9/10and10/10participantsinthe25and50NaL3cohorts,respectively,andrangedfrommaculopap-ulartovesicular(Figure?1).Rashesweremildinseverity,exceptfor1moderatecaseinthe25NaL3cohort;topicalcorticoster-oidswereusedin6/?1.?RepresentativeimagesofrashinducedbyapplicationofNaL3tothepadfollowingNaL3applicationandlastedamedian(range),,-Challenge?Model???OFID???3Downloadedfromhttps://academic./ofid/article-abstract/5/5/ofy083/4976553bygueston20May2018AB2020SevereModerateModerateMildMild15151010NumberofeventsperdayNumberofeventsperday55000371428354249566370778403714283542495663707784WeekpostinfectionWeekpostinfectionFigure?2.?,abdom-inalbloating,nausea,vomiting,ordiarrheathatwasassessedasbeingrelatedtocontrolledhumanhookworminfection.