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A comparative study to evaluate the safety and immunogenicity of two lots of Haemophilus influenzae type-B conjugate vaccine manufactured at different scales

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A comparative study to evaluate the safety and immunogenicity of two lots of Haemophilus influenzae type-B conjugate vaccine manufactured at different scales
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  This article appeared in a journal published by Elsevier. The attachedcopy is furnished to the author for internal non-commercial researchand education use, including for instruction at the authors institutionand sharing with colleagues.Other uses, including reproduction and distribution, or selling orlicensing copies, or posting to personal, institutional or third partywebsites are prohibited.In most cases authors are permitted to post their version of thearticle (e.g. in Word or Tex form) to their personal website orinstitutional repository. Authors requiring further informationregarding Elsevier’s archiving and manuscript policies areencouraged to visit:http://www.elsevier.com/copyright  Author's personal copy Vaccine 29 (2011) 5363–5367 ContentslistsavailableatScienceDirect Vaccine  journalh   omepage:www.elsevier.com/locate/vaccine A   comparative   study   to   evaluate   the   safety   and   immunogenicity   of    two   lots   of Haemophilus   influenzae   type-B   conjugate   vaccine   manufactured   atdifferent   scales Siddhivinayak   Hirve a ,   Ashish   Bavdekar b ,Sanjay    Juvekar a ,Dhiraj   Agarwal a ,   Prajakt   Barde c ,Somnath   Mangrule c , Moreshwar   Patwardhan c ,Anand   Pandit b ,Prasad   S.Kulkarni c , ∗ a ShirdiSaiBabaRuralHospital,KEMVadu,Pune,   India b KingEdwardMemorialHospitalResearchCentre,Pune,India c SerumInstituteofIndia,Pune,India a   rtic   l   e   in   fo  Articlehistory: Received9April2011Receivedinrevisedform20   May2011Accepted23May   2011 Available online 7 June 2011 Keywords: Haemophilusinfluenzaetype-BVaccineSII   HibP RO SmallscaleIndustrialscaleAnti-PRPantibodies a   b   s   t   r   a   c   t Objective:   Tocompare   theimmunogenicityandsafetyoftwodifferent   lotsofSII   Haemophilus   influenzaetype-B–tetanus   toxoidconjugate   (SIIHibP RO )   vaccine   manufactured   atdifferentscales   when   given   in3-dose   schedule. Design: Phase   IV,   open   label,comparative,randomized   parallel   group   study. Setting: Shirdi   Sai   Baba   Hospital,   VaduBudruk,   PuneandPediatrics   Department   ofKingEdward   MemorialHospital   ResearchCentre,Pune. Subjects: 204normal   healthy   infants   of    age   6–8weeks   atthetimeof    firstvaccination. Methods:   The   eligible   subjects   received3   dosesof0.5ml   of    SIIHibP RO  vaccine   ofeitherlot   dependingupon   randomizationnumber,   intramuscularly   in   rightthighin   the   EPIschedule   of    6,   10and14weeks.They   alsoreceived   concomitantlyDTP-HB   vaccine   intramuscularlyon   left   thigh   and   OralPoliovaccine(OPV).   Solicited   reactions   were   captured   for   7   days   following   each   vaccination;   theevents   beyond   7   daystill   day28werecaptured   as   unsolicited   adverse   events.SeriousAdverseEvents   (SAEs)   werelooked   forthroughout   thesubject   participation.   Bloodsamples   werecollected   atbaseline   (before   thefirstdose)andone   month   after   the   thirddosefor   anti-PRP(polyribosylribitol   phosphate)antibodies. Results:   In   both   groups,   more   than   98%   subjects   achievedshort-term   seroprotection(anti-PRP   ≥ 0.15    g/ml)after   3   doses.Thelong-term   seroprotection(anti-PRP ≥ 1    g/ml)was   87%   and80%in   infants   receivinglot   manufactured   atindustrial   scale   andsmall   scale   respectively.   Short   andlongtermseroprotection   andGMTsincreased   significantlyas   compared   tobaseline   inboth   the   groups.Overall   localpain   (52%and   58%),redness(30%and41%),swelling(34%   and44%),fever(6%   and   6%)   and   irritability   (52%and50%)   werereportedin   infants   receiving   lotmanufacturedatindustrialscale   and   small   scalerespec-tively.Majority   of    the   reactionsweremildand   resoled   without   anysequelae.   Four   SAEs,   noneofthemcausally   related   to   the   study   vaccine,   occurred   during   study. Conclusion:   SIIHibP RO  vaccines   manufactured   in   small   andindustrial   scaleare   equally   immunogenic,   safeandconfer   adequate   seroprotection   toinfants   of6–14weeks   of    age.Scalingup   production   process   hasnotaffectedthesafetyand   immune   response   in   thetarget   population. © 2011 Elsevier Ltd. All rights reserved. 1.Introduction Haemophilusinfluenzaetype-B(Hib)infectionisa   significantpublichealthconcernespeciallyinmiddleandlowincomecoun-tries.Atleast3millioncasesofseriousdiseaseandapproximately386000deathsoccureveryyear.Themajorityof    Hibmorbidityandmortalityoccursindevelopingcountries[1]. ∗ Correspondingauthor.Tel.:+912026602384;fax:+912026993945. E-mailaddress: drpsk@seruminstitute.com(P.S.Kulkarni). InIndia,thoughtheexactincidenceofthediseaseisnot   known,Hibisthemostcommonendemiccauseofbacterialmeningitisinchildren.PneumoniacausedbyHibisaleadingkillerofchildreninareaswhereinfantmortalityremainshigh.Itisfurthercomplicatedbywidespreadmulti-drugresistance[2–4]. Hib   conjugatevaccineswereintroducedinthelate80sandareverysafeandeffective.TheWorldHealthOrganization(WHO)andtheIndianAcademyofPediatrics(IAP)recommendinclusionoftheHibvaccineaspartofinfantimmunizationprograms.TheGovern-mentofIndiahasrecentlyapprovedintroductionofHibvaccineinExpandedProgrammeonImmunization(EPI)inaphasedmanner[5]. 0264-410X/$–seefrontmatter © 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.vaccine.2011.05.081  Author's personal copy 5364  S.Hirveetal./Vaccine  29 (2011) 5363–5367  In2007,SerumInstituteofIndiaLtd.,Pune(SIIL)developedanindigenous,lowcostHibvaccine(SIIHibP RO ).Thevaccinehasundergoneclinicaltrialsinadultsandinfantsandwasfoundhighlysafeandimmunogenic[6].TheDrugControllerGeneralofIndia(DCGI)hasgivenalicensetomarketSIILHibvaccine.ThiswasoneofthefirstfewHibvaccineslicensedindevelopingcountries.Till    July2007,SIIHibP RO  vaccinewasmanufacturedina   specificfacilityusingsmall-scalefermentationandconjugationmethod.FromAugust2007,themanufacturingprocesswas   scaleduptoindustriallevel.ThenewlotsofSIIHibP RO  vaccineare   nowbeingproducedusinglarge-scalefermentationandconjugationmethod.ThescaleupforHibproductionwasdoneatthestagesof fermentation,polysaccharidepurificationandconjugation.Forfer-mentation,thescaleupwas40-fold(from20L    to800L).Variousphysicalparametersandprocessparameterswerestrictlycon-trolled,includinggrowthkineticsbasedon   opticaldensityat590nmatboththescales.Duringpolysaccharidepurification,thechangeinscalewas ∼ 13-fold(from60L    [3pooled20L    scalefer-mentorlots]to800L[onesinglefermentorlot]).Monitoringof molecularsizeofpurifiedpolysaccharideandimpuritiesandfur-thercharacterizationofpolysaccharideby   usingprotonNMR    wasdonetoensurethatpolysaccharideisidenticalatboththescales.Duringconjugation,thechangeinscalewas ∼ 5-fold,i.e.from15gto74g.Astrictcontroloverdegreeofactivationofpolysaccharide,molecularsizeandtiters,wasexercisedtoensuretheconsistencyof processatboththescales.Conjugationkineticswerecarefullymon-itoredatboththescales.Freeunconjugatedpolysaccharidewasremovedbyprecipitationusingammoniumsulphateat   boththescales.FinalqualityofconjugateswasassessedbyvariousqualitycontroltestsasperWHO   recommendations.Thesetests,ultimatelydemonstratedthatpurifiedHibconjugatesatboththescaleshadsimilarqualityattributes.ThepresentstudywasundertakentocompareclinicallytheimmunogenicityandsafetyofSIIHibP RO  lotsproducedinindustrialandsmallscalemanufacturingprocesses. 2.Materialsandmethods  2.1.Studydesign Thiswasa   prospective,double-blind,randomized,PhaseIVstudytocomparetheimmunogenicityandsafetyoftwodifferentlotsofSIIHibP RO  vaccinemanufacturedat   smallandlargescales.The   studywasconductedatShirdiSaiBabaRuralHospital,Vadu,PuneandthePediatricsDepartmentofKingEdwardMemorialHos-pitalResearchCentre,Pune.Thesubjectswererandomizedtooneofthetwogroupsandreceived3dosesofthevaccinesmanufac-turedfromindustrial-scalefacility(Lot1)orsmall-scalefacility(Lot2).  2.2.Studyprocedure Potentialeligiblechildrenwereidentifiedat   thecommunitylevelinVaduareaandatimmunizationandwellbabyclinicsinKEMHospital,Puneandtheirparentswereprovidedinformationtosolicittheirchild’sparticipationinthestudy.Childrenofwillingparentswerescreenedandenrolledaftertakingwritteninformedconsentfromtheirparents.Childrenwereassignedinto2groupsusingacomputergeneratedran-domizationblockingscheme(1:1).Eachchildreceived0.5ml   of SIIHibP RO  vaccineofeitherlot,intramuscularlyinthe   antero-lateralaspectofrightthighintheEPIscheduleof6,10and14weeks.ThechildalsoconcomitantlyreceivedDTP-HBvaccineintramuscularlyonleftthighandOralPoliovaccine(OPV).Allthesubjectswereobservedfor30min   foranyimmediatehyper-sensitivityreactions.Theparentsweregivenathermometer,ameasuringscaleanddiarycards.Siteinvestigatorstrainedpar-entsforrecordinganddocumentingadverseeventsinadiary.Onallstudyvisits(6,10,14and18weeks),physicalexaminationwereperformedandinformationon   adverseeventsandconcomi-tant   medicationweresolicited.Theinvestigatorsreviewedthediarycardsandtranscribedadverseeventsintocasereportforms(CRF).Threemillilitresofvenousbloodsampleswere   collectedatbaselineandonemonthafterthethirddoseforanti-PRP(polyribo-sylribitolphosphate)antibodies.Serumwasseparatedwithin4handserastoredat   − 20 ◦ Consite.AllthesampleswereshippedtoSuperReligareLaboratoriesLimited,Mumbaiat − 20 ◦ C,wheretheyweretestedinduplicates.ThelabisaccreditedbytheCollegeof AmericanPathologists(CAP).Attheendofeachvisit,parentswereinvitedtobringtheirchildtothestudycentreon   visitsscheduledat4weeksinterval.Those,whomissedscheduledvisits,wereremindedtelephonicallytovisitthestudycentrewithinthepermissible7daystimewindow.Thelastvisitwasscheduled4weeksafterthethirddoseofthevaccineat18weeksofage.  2.3.Studysubjects Normalhealthyinfantsofage6–8weekswhoseparentswerewillingtocomplywiththestudyproceduresandgavewritteninformedconsentandwho   wereresidentofstudyareawereenrolled.Parallelparticipationinotherstudies,immunodeficiency,malignancy,receiptimmunosuppressivetherapyfora   periodof >1week,clinicalhistoryofHibinfectionorvaccination,bleed-ingdisordercontraindicatingintramuscularvaccination,allergyorhypersensitivityto   any   ofthe   vaccinecomponent,anychronicill-nessincludinghepatic,renalrespiratory,cardiovascular,endocrineandneurologicalillness,receiptofbloodor   blood-productsinthepastwereexclusioncriteria.Febrileillnessatthetimeofscreeningwasatemporaryexclusioncriterion.  2.4.Studyvaccines TwolotsofHibvaccine,manufacturedandprovidedbySIIL,wereusedinthestudy.Boththelotsofthe   vaccineswerereleasedbyCentralDrugsLaboratory(CDL),Kasauli,beforeuseinthe   study.SII   HibP RO  isa   lyophilisedvaccineofcapsularpolysaccharideof Hib,covalentlyboundtotetanustoxoid(carrierprotein).Eachsin-gle0.5ml   humandosecontains10  gPRP,coupledwith19–33  gtetanustoxoid.ThesubjectsinGroupAreceivedeitherthestudyvaccine(SIIHibP RO  vaccinepreparedinindustrialscalefacility,BatchNo.H-044,Expirydate:March2011)whilesubjectsinGroupBreceivedthereferencevaccine(SIIHibP RO  vaccinepreparedinsmallscalefacility,BatchNo.H-027,Expirydate:October2010).Thecompositionofboththevaccinesissimilar.Thevaccineislyophilisedwithasterilediluentinaseparatecontainer.Thevac-cinewasreconstitutedby   addingthediluenttothevialcontainingpellet.  2.5.Serologicalassay Quantitativeestimationofanti-PRPantibody(IgG)wascarriedoutbyELISAtechniquesusingcommerciallyavailableVaccZyme TM kit,   manufacturedbyBindingsite,Birmingham,UK.   Allthestepsdescribedinthemanufacturer’skitliteraturewerestrictlyfollowedwhileperformingassays.Validityofeachrunofthetestwaseval-uatedas   perthe   manufacturer’sinstructions.Anti-PRPantibodies ≥ 0.15  g/mlwas   consideredseroprotective,while ≥ 1  g/mlwas  Author's personal copy S.Hirveetal.    /    Vaccine  29 (2011) 5363–5367  5365 Subject screened N = 205 Screening failuren = 01 Subject Enrolled & Randomized N = 204 Group B (N =99) Group A (N = 101) Lost to Follow-up (N = 06) Lost to follow-up (N = 09) Randomization error (N= 04) Withdrawal due to SAE (N=01)Blood Samples not available (N = 2)Blood Samples not available (N = 6) PPA Population (N =85) PPA Population (N =91) ITT Population (N =200) Fig.1. ConsolidatedStandardsofReportingTrials(CONSORT)statementofsubjectdisposition. consideredindicativeoflong-termsero-protection.Actualvaluesof antibodieswereconsideredforgeometricmeantitrecalculations.  2.6.Safetyassessment  Allsubjectswereobservedfor30min   forany   immediatehyper-sensitivityreactions.During7daysfollowingeachdoseofthevaccine,injectionsitereactionslikepain,redness,swelling;andsystemicreactionssuchas   feverandirritabilitywereactivelysolicited.Parentsweretrainedtocaptureallsolicitedreactionsinasubjectdiary.Theeventsbeyond7daystillday28were   capturedasunsolicitedadverseevents.SAEswerelookedforthroughoutthesubjectparticipation.Parentswere   alsoinformedtonotifyinvesti-gatororstudystaffimmediatelyifanyeventoccurredduringthestudyperiod.Investigatorsassessedtheseverityandcausalityrela-tionshipofallsolicitedandunsolicitedadverseeventswithstudyvaccinesusingpre-definedcategories. 3.   Statisticalanalyses Theprimarystudyhypothesiswas   thatthepost-vaccinationlong-termsero-protectionrate   withthevaccineproducedatindus-trialscaleisnon-inferiortoonewiththevaccineproducedatsmallscale.Samplesizewascalculatedbasedontheformulagivenby Jonesetal.[7].At5%   significancelevel(i.e. ˛ =0.05),80%power(1 − ˇ =   0.80)and10%delta,samplesizeof184subjectswerecon-sideredadequatetoget160evaluablesubjects(80subjectsineachgroup),considering15%   dropouts.AgewassummarizedinmeanandSDandsexaspercentage(%).Percentageofsubjectswithshort-termandlong-termseroprotectionwascalculatedatpre-andpost-vaccinationalongwith95%confidenceintervals(CI).Sta-tisticaltestfornon-inferiorityforseroprotection(shortandlongterm)betweentwogroupswas   doneby   ‘Chi-square’test.McNe-mar   testwas   usedtocomparepairedproportionsforshort-termandlong-termseroprotection.GMTsofantiPRPantibodywerecal-  Author's personal copy 5366  S.Hirveetal./Vaccine  29 (2011) 5363–5367   Table1 Immunogenicityoftwo   lots   ofSIIHibPro(95%CIinparenthesis).BaselineOnemonthpost-vaccinationGroupA   (H-044)GroupB(H-027)GroupA(H-044)GroupB(H-027)Anti-PRP ≥ 0.15  g/ml83.5%[76.6,90.7]73.6%[63.3,82.3]100%[96.2,   100.0]98.9%[93.9,100.0]Anti-PRP ≥ 1  g/ml29.4%[20.0,40.3]23.1%[14.9,33.1]87.1%[78.0,93.4]80.2%[70.5,87.9]GMT   0.50[0.38,0.66]0.40[0.29,0.54]6.18[5,8]   6.03[4,8] culatedinboththegroups,alongwith95%CI.Unpaired t  -testwasusedforpre-andpost-vaccinationGMT   comparison,whilepairsofpre-andpost-vaccinationGMTswerecomparedusingpaired t  -test.Thesafetyevaluationincludedpercentage(%)ofsubjectwithsolicitedreactionsandunsolicitedadverseeventsalongwith95%CI.Intention-To-Treat(ITT)analysiswasusedforsafetyevalua-tion.ITTincludedalltheenrolledsubjectswhoreceivedat   leastonedoseofthevaccine.Perprotocolanalysis(PPA)was   usedforimmunogenicityevaluation.ThePPAincludedonlythosesubjectswhoreceivedthreedosesofthevaccine,completedthestudypro-tocolandhadgivenboththebloodsamplesforanalysis. 4.Ethicalconsideration Allthestudydocumentswereapprovedbythe   EthicsCommit-tee,KEMHospitalResearchCentre,Pune.Thestudywas   conductedasperethicalprinciplesoftheDeclarationofHelsinki,GoodClinicalPracticesguidelines,andIndianregulatoryandethicalguidelines.Subjectinformationsheetandinformedconsentforminlocallan-guageswereusedtoobtainconsentfromparents.Nochangeintheconductofthestudyorplannedanalyseswasinstitutedafterthestartofthestudy. 5.Results 5.1.Subjectdisposition Afterexcludingfourchildrenduetorandomizationerrorsandonechildduetoscreeningfailure,a   totalof200children(101chil-dreninGroupA,i.e.studyvaccineand99childreninGroupB,i.e.referencevaccine)wereincludedintheITTanalysis.Afurtherlosstofollowupof15childrenandinabilitytocollectabloodspecimenin   another8childrenresultedin176subjects(85and91chil-drenfromGroupA   andGroupBrespectively)asthePPpopulation(Fig.1). 5.2.Demographics Themeanagewas47.80days(SD ±   4.48).About54%subjectsweremale.Themeanweightwas3.9kg(SD ±   0.63),whilemeansupinelengthwas   54.5cm(SD ± 2.72).Thesecharacteristicsweresimilarbetweenthe   groups. 5.3.Immunogenicityresults Therewas   nosignificantdifferenceinshorttermprotection(83.5%and73.6%)andlongtermprotection(29.4%and23.1%)betweenthetwo   groupsbeforevaccination(  p ≥ 0.05).Follow-ingthreedosesofthevaccines;almostallchildrenachievedshort-termprotection.Theincreasefrombaselinewassignificant(  p -value ≤ 0.05).Similarly,long-termseroprotectionincreasedsig-nificantlytomorethan80%inbothgroupsascomparedtobaseline(  p ≤   0.05)(Table1).Similarly,therewas   nosignificantdifferenceinthepre-vaccinationGMTsinbothgroups(0.5and0.4inGroupsAandBrespectively;  p -value ≤   0.05)PostvaccinationGMTsweresignif-icantlyhigherascomparedtopre-vaccinationtitreinboththegroups(increasedto6.18and6.03inGroupsAandBrespectively;  p -value ≤ 0.05)Post-vaccinationGMTsinboththegroupswerehowevercomparable(  p -value ≥ 0.05)(Table1). 5.4.Safetyresults Pain,rednessandswellingwerereportedinbothgroups.Inmajorityofindividuals,severityofadversereactionswasmild(Table2)andresolvedwithoutanysequelaewithin7days.Reportedsolicitedsystemicreactionswerefeverandirritabil-ity.Reportedtemperaturewasintherangeof38–41.1 ◦ C.Durationoffeverwas1–4days.Inmajorityofsubjects,irritabilitywasmild(Table3).Exceptfortwocases,allcasesoffeverandirritabilitywereassessedas“possibly”relatedtotheHibvaccineortheconcomi-tantlyadministeredDTP-HBvaccine.Boththereactionsresolvedwithoutanysequelae.Fewunsolicitedadverseevents(fever,irritability,anorexia,diarrhea,vomiting,cold,cough,coldandcough,eyeinfection,rashonfaceandthroatpain)werereportedinthe   secondtothefourthweekperiodfollowingavaccinedose.Mostofthemweremildinseverityandwereequallydistributedinboththestudygroups.Noneofthemwerecausallyrelatedtothe   studyvaccine.Allofthemresolvedwithoutanysequelae.  Table2 ReportedsolicitedlocalreactionsinITTpopulation( n =   200).Adversereaction  n ,%andCIDose1Dose2Dose3OverallGroup-A( n   =101)Group-B( n =   99)Group-A( n =   101)Group-B( n =   99)Group-A( n =101)Group-B( n =   99)Group-A( n   =   303)Group-B( n =   297)Pain Severe6.97.14.0   4.02.07.14.36.1Any56.462.654.552.544.657.651.857.695%   CI46.2–66.352.3–72.244.2–64.242.2–62.734.6–54.847.2–67.546.0–57.651.7–63.3Redness Severe0.0   0.00.0   0.00.0   0.0   0.00.0Any   31.740.430.740.427.741.430.040.795%   CI22.8–41.730.6–50.821.9–40.730.6–50.819.3–37.631.6–51.824.9–35.535.1–46.6Swelling Severe0.0   0.00.0   0.00.0   0.0   0.00.0Any 39.6   49.532.740.429.741.434.043.895%   CI30.0–49.939.3–59.823.6–42.830.6–50.821.0–39.631.6–51.828.7–39.638.0–49.6
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