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A dose escalation safety and immunogenicity study of a new live attenuated human rotavirus vaccine (rotavin m1) in vietnamese children

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c o m / l o c a t e / v a c c i n e Dang Duc Anha,∗, Nguyen Van Tranga, Vu Dinh Thiema, Nguyen Thi Hien Anha, Nguyen Duc Maob, Yuhuan Wangc, Baoming Jiangc,∗∗, Nguyen Dang Hiend,1, Le Th

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Vaccine

jo u r n al h om ep a ge : w w w e l s e v i e r c o m / l o c a t e / v a c c i n e

Dang Duc Anha,∗, Nguyen Van Tranga, Vu Dinh Thiema, Nguyen Thi Hien Anha, Nguyen Duc Maob, Yuhuan Wangc, Baoming Jiangc,∗∗, Nguyen Dang Hiend,1, Le Thi Luand,1, the Rotavin-M1 Vaccine

Trial Group2

a The National Institute of Hygiene and Epidemiology, Hanoi, Viet Nam

b Preventive Medicine Center, Phu Tho Province, Viet Nam

c Centers for Disease Control and Prevention, CDC, Atlanta, GA, USA

d Center for Research and Production of Vaccines and Biologicals, Hanoi, Viet Nam

Article history:

Received 13 May 2011

Received in revised form 14 July 2011

Accepted 25 July 2011

Keywords:

Rotavirus vaccine

Rotavin-M1

Vietnam

Safety

Immunogenicity

Vaccine dose

Rotarix TM

© 2011 Elsevier Ltd All rights reserved

夽 Presented in part: 9th International Rotavirus Symposium, June 2010,

Johannes-burg, South Africa.

夽夽 Disclaimer: The findings and conclusions in this report are those of the authors

and do not necessarily represent the views of the Centers for Disease Control and

Prevention.

∗ Corresponding author Tel.: +84 439712989; fax: +84 438212660.

∗∗ Corresponding author Tel.: +1 404 639 2861; fax: +1 404 639 3645.

E-mail addresses: ducanh@nihe.org.vn , ducanhnihe@hn.vnn.vn (D.D Anh),

bxj4@cdc.gov (B Jiang).

1 Drs Hien and Luan are members of the Board of Directors, POLYVAC, Vietnam.

2 See Appendix A

1 Introduction Rotavirus (RV) is the most important cause of acute gas-troenteritisin children worldwide In Vietnamrotavirus causes

an estimated 122,000–140,000 hospitalizations and 2900–5400 deathsperyearamongchildrenunder5yearsofage[1].Overthe past13years,sentinelhospitalsurveillanceidentifiedrotavirusin 44–62%ofchildrenadmittedforthetreatmentofacutediarrheain Vietnam[2–4].Suchahighburdenofdiseasejustifiedaccelerated developmentofanewandlocallymanufacturedvaccineagainst rotavirusinVietnam.Itisestimatedthatifavaccinewas intro-ducedinthecurrentchildhoodimmunizationschedule,itcould 0264-410X/$ – see front matter © 2011 Elsevier Ltd All rights reserved.

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vaccineefficaciesandcoverage[5]

TheGovernmentofVietnamhaspursuedapolicyto

encour-agelocalvaccineproductionsothecountrycouldbeself-reliant

with affordable vaccines for its population [6] Over the past

decades, several locally produced vaccines for poliomyelitis,

cholera,Japaneseencephalitis,andDiphtheria–Pertussis–Tetanus

have contributed to the reduction in the prevalence of these

diseasesandtothestatusofpoliomyelitis-free.Whiletwo

com-mercialrotavirusvaccines,RotarixTM(GSK,Belgium)andRotaTeq®

(Merck),havebothbeentestedinVietnam,onlyRotarixTMis

cur-rentlyavailableinprivatemarket.TheliquidformulaofRotarix

when tested in two schedules, 1-month and 2-month interval

betweendosescomparedwithplacebocontrolin375childrenhad

aseroconversionrateof63.3%and81.5%,respectively[7].RotaTeq

showedaseroconversionrateof87.8%andanoverallefficacyof

63.9%(72.3%inthefirstyearand64.6%inthe2ndyear

following-up)inaphase3efficacytrialinVietnam[8].However,neitherof

thetwovaccinesiscurrentlyavailableatanaffordablepricefor

thenationalprogram(e.g.RotarixintheprivatemarketcostsUS

$35perdose).Therefore,thecandidatevaccine,Rotavin-M1,was

developedinordertofillthisneedforamoreaffordablevaccinefor

Vietnamesechildren[6].ThisvaccineissimilartoRotarixTM,and

wasdevelopedbyselectingacommonG1P[8]strainand

attenu-atingitthroughserialpassagesandplaquepurificationinqualified

VerocellsunderGLPconditions

Inthisstudy,wesoughttoevaluatethesafetyand

immuno-genicityofRotavin-M1producedbytheCenterforResearchand

ProductionofVaccinesandBiologicals(POLYVAC)inadult

volun-teersandininfantsinVietnam.Inaddition,weevaluateddifferent

dosagesandschedulestodeterminethebestregimentotestina

clinicaltrial

2 Materialsandmethods

2.1 Vaccine

Thevaccine,Rotavin-M1,manufacturedbyPOLYVAC-Vietnam,

wasdevelopedfromaG1P[8]strainrecoveredin2003fromachild

hospitalizedforthetreatmentofacutegastroenteritisinNhaTrang

city(KH0118-2003)[6].Themasterandworkingseedsofthis

vac-cinewereproducedunderGLPconditionsusingqualifiedVerocells

andreagentsattheUSCentersforDiseaseControlandPrevention

(CDC).Pilotvaccinelot,passage48,wasproducedbyonepassage

inVerocellsfromtheworkingseed,whichwasprovidedbythe

JapanesePolioResearch Instituteandapprovedforvaccine

pro-ductionbyWHO.Thesecellshavebeenusedfororalpoliomyelitis

vaccineproductionatPOLYVAC.Themastervirusseedfor

Rotavin-M1wastestedforporcinecircovirususingreal-timeRT-PCRatthe

USCDCandappearedtobefreeofporcinecircovirusDNA.Thetest

forporcinecircovirusinpilotvaccinelotwasnotdone

2.2 Participantsandstudydesign

Thetrials wereplannedin two stages, thefirst –a Phase 1

trial for safety in adult volunteers of a high titer preparation

of thevaccine (106.3FFU/dose) Whenresults of this trialwere

evaluatedbytheDataSafetyandMonitoringCommitteeandthe

vaccine was deemed to be safe for further study in infants, a

Phase1and2adaptivetrialwasconducted.Thistrialassessedthe

safetyandimmunogenicityoftwodifferentpreparationsof

vac-cine,oneoflowtiter(106.0FFU/dose)and thesecondwithhigh

titer(106.3FFU/dose) that wasadministered in either a 2 vs 3

doseschedulestoinfants6–12weeksofage.Acomparisongroup

wasincludedof infantswhoreceivedthelyophilizedRotarixTM

vaccine,anestablishedrotavirusvaccineofGSKthatwaslicensed

tobeusedinVietnam.ThestudywasconductedaccordingtoGood ClinicalPracticeandinaccordancewiththeDeclarationofHelsinki,

asamendedinSomersetWest,RepublicofSouthAfrica,inOctober

1996.Theprotocolandconsentformwasreviewedandapproved

bytheEthicalandScientificCommitteesoftheNationalInstitute

ofHygieneandEpidemiology(NIHE)andoftheMinistryofHealth, GovernmentofVietnam,priortoinitiatingthestudy

2.2.1 Phase1study ThePhase1studywasconductedinaCareerTrainingSchool, ThanhSondistrict,PhuThoprovincewithatotalof29healthyadult volunteers18–49yearsofage.Followingreceiptofinformed con-sent,eachofthevolunteerswasscreenedbyaphysiciantoensure theywerehealthywithnoactivemedicalproblemsandaskedto provideabloodspecimentotestforbloodcountsandlevelsofblood ureanitrogen(BUN)andtransaminase.Thevolunteerstheneach received2dosesofthehightitervaccine,106.3focus-formingunits [FFU],at1-monthinterval.Afteradministrationofeachdoseofthe vaccine,thevolunteerswerefolloweddailyfor10daysforadverse eventsandforfecalsamplecollection.Duringthenext20days,the volunteerswerefollowedbyphonetoensuretheyhadnosequelae (e.g.diarrhea,vomitingandintussusception).Serumsamplestaken beforeand30daysafterthe1stand2nddosesweretestedfor3 bloodcounts,BUNconcentrationandserumtransaminaselevels DataonthevolunteerswerereviewedbytheDataSafety Monitor-ingBoard(DSMB).Noadverseeventsorchangesinbloodcounts, BUNortransaminasewerereported.TheDSMBjudgedthevaccine

tobesafepermittingthestudiestocontinueininfants

2.2.2 Phase2study Phase2wasadoseandschedulerangingstudy,conductedat

12medicalcentersinThanhSondistrict,PhuThoprovincesfrom November2009throughApril 2010.Infants6–12weeksofage wereeligibleforinclusioninthestudyiftheywerebornatfull term(38weeks)andwerefreeofobvioushealthproblem.Infants wereexcludediftheywereimmunocompromised,hadahistoryof allergicreactiontoanyvaccinecomponentsorhadreceived vac-cinesagainstrotavirusorwereinvolvedinanyothervaccinetrials

atthesametime.Infants(n=200)wererandomlyassigned to5 groups(40infants/group)(Fig.1).Twogroupsreceived2oraldoses

ofRotavin-M1in1of2titers–106.0or106.3FFUat6–12weeks

ofage(forthefirstdose)and2monthslaterfortheseconddose (groups2Land2H),respectively.These2vaccinetiterswerealso giventoinfantsona3-doseschedule,beginning at6–12weeks

ofageforthefirstdoseand1monthand2monthslaterforthe 2ndand3rddoses(groups3Land3H,respectively).RotarixTMwas usedasthevaccinecontrolandwasgivento40infantsat6–12 weeksofageand 1monthlater(GroupRotarixTM).GSK recom-mendsthatthefirstdoseofRotarixTMbestartedbetween6and14 weeksofageandthattheseconddosebeseparatedbyatleast1 month.Thevaccinerecipients,theparents/guardians,the labora-torystaff,thefieldteamsandworkingdoctorsdidnotknowthe codingassignmentofthesegroups.Othervaccines(BCG,oralpolio vaccine,Diphtheria–Tetanus–PertussisandhepatitisB)usedinthe country’sExpandedProgramofImmunization(EPI)were adminis-terednormallytotheseinfantsondifferentdays(10–20daysbefore

orafterrotavirusvaccinewasadministered)

2.3 Assessmentofimmunogenicity Serumsampleswereobtainedfortestinglevelsofanti-rotavirus IgAand IgGantibodyonthedaythatthefirstdosewas admin-isteredand1month afterthesecondorthirddose.Inaddition, serum samples were also obtained from groups that received

3 dosesof vaccine (groups3L and 3H) immediatelybeforethe

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Fig 1 Study design including vaccination and sampling schedules for different

vac-cination groups Arrows in figure indicate times for each vaccination dose (wide

arrows) and for collection of samples of blood (thin solid arrows) and stool (dotted

arrows) In 3-dose regimen (a), groups 3L and 3H received 3 doses of Rotavin-M1

10 6.0 FFU/dose and 10 6.3 FFU/dose, respectively In 2-dose regimen (b), groups 2L and

2H received 2 doses of Rotavin-M1, 10 6.0 FFU/dose and 10 6.3 FFU/dose, respectively

(n = 40/group) Group Rotarix TM received 2 doses of Rotarix TM and only had serum

samples 1 and 2 according to schedule (c).

3rddose(Fig.1).Eachbloodsample froma childwascollected

in2tubes,onewithanti-coagulant(EDTA)(wholeblood)andone

withoutanti-coagulant(serum).Serumandwholebloodsamples

wereimmediatelytransferredtotheprovincialhospitalfor

anal-ysisofblood cellcounts(redblood cells,white bloodcells and

platelet),transaminaselevels(aspartateaminotransferase,ASTand

alanineaminotransferase,ALT)andBUNwithin4haftercollection

Aliquotsofserumsamplesforantibodydetectionwerestoredat

−20◦CattheDistrictPreventiveMedicineCenter,ThanhSon

dis-trict,PhuThoProvinceuntiltheywereshippedtothelaboratoryat

NIHE

Theimmunogenicityofthevaccinewasevaluatedatthe

Vac-cineImmunologyLaboratory,NIHE,bymeasuringseroconversion

ofrotavirus IgAantibody,usingan end-pointELISA[9].Briefly,

96-wellmicrotiterplates(NUNC,Langenselbold,Germany)were

coatedwithrabbit-antiRRVhyperimmuneserum(obtainedfrom

Dr BaomingJiang, CDC) Virus (RRV)and mock-infected

super-natantwereaddedtotheplatesinalternatewells.Serumsamples

in 2-fold serial dilutions starting at 1:10 were added tothese

virus/mockwells.Biotinylatedanti-humanIgA(␣)(Kirkegaardand

PerryLaboratory,Gaithersburg,Maryland)andperoxidaselabelled

extravidin(Sigma–Aldrich,Inc,St.Louis,MO)wereaddedforthe

detectionofRVspecificIgAantibody.Positiveandnegativecontrol

seraweretestedinthesamemanner.Antibodytitersinserumwere

calculatedasthereciprocalofthehighestdilutionthatgaveamean

opticaldensitygreaterthanthecut-offvalue(mean+3standard

deviationsofthenegativecontrolandblottowells).AnIgAtiterof

20orhigherwasconsideredpositive.Seroconversionwasdefined

asariseinanti-rotavirusIgAtiterfromundetectable(≤10)in

pre-vaccinationserumto≥20inpost-vaccinationserumora≥4-fold

risefrompre-vaccinationtopost-vaccinationserum.Forquality

assurance,ananonymizedsubsetofserumspecimens(52samples) werealsoshippedandtestedatCDC.Agreementbetweentwo lab-oratories(antibodytiterswithin2-folddilutionofthesamples)was

>90%

2.4 Assessmentofreactogenicityandsafety For30daysfollowingeachvaccineadministration,parentsor guardianswereaskedtonotegeneralsymptoms(cough,running nose,diarrhea,irritability,lossofappetite,feverandvomiting)ona dailydiarycard.Dailytemperaturewasrecordedandatemperature

>38◦Cwasconsideredasfever.Anysevereunsolicitedsymptoms andseriousadverseeventswerereportedthroughoutthestudy period(90daysforeachchild).Aliquotsofbloodfromeachchild

ateachtimepointwerealsoassayedforserumtransaminaseand BUN

2.5 Viralsheddingandstraincharacterization

Weattemptedtocollectdailystoolsamplesduringthe7days followingeachdosetoassessvirusshedding.Inaddition,stool sam-pleswerealsocollectedateveryepisodeofdiarrheaduringthe studyperiodandtestedforrotavirusantigenbyELISA(ProSpecT, Oxoid,UK).AllrotaviruspositivespecimenswereGandP-typed

by RT-PCR[3,10].To distinguishvaccinefrom wildviruses,we sequencedthe VP7 gene of theG1P [8]samples fromdiarrhea casesandselectedG1P[8]samplescollectedwithin7daysof vac-cineadministration(non-diarrhealsamples),usinganABIPrism BigDyeTerminatorCycleSequencing(AppliedBiosystems,Foster City,CA)andcomparedthesequenceswiththecorrespondinggene sequencesofRotavin-M1andRotarixTM

2.6 Statisticalanalysis DatawasmanagedusingMicrosoftVisualFoxpro7.0software (Microsoft)andanalysedusingtheStata11.1program.Themean bloodcellcountsandconcentrationsofBUNandtransaminasewere comparedbetweengroupswithaPairedStudent’st-Test.Between groups,thepercentagesofchildrenwithadverseeventswere com-paredusingFisher’sExactTest

Theanalysisforreactogenicitywasperformedonthe intention-to-treatpopulation(includingallchildrenwhoreceivedatleast1 doseofvaccine).Thenumberofchildrenwithgeneralsymptoms wasdeterminedforeachgroupafteradministrationofeachvaccine doseandcomparedbetweengroups

Theanalysisofimmunogenicitywasalsoperformedforboththe perprotocolandintention-to-treatpopulations(atleast2dosesof vaccinewererequired).TheIgAseroconversionrate(with95%CI) wascalculatedforeachgrouptoevaluatetheimmuneresponses inducedbythevaccinesandgeometricmeanantibodytiters(GMT) were calculated for those individuals who seroconverted.Viral sheddingwascalculatedasthepercentage ofchildrenshedding viruseachdaypost-vaccinationwhenstoolsampleswereavailable

Inaddition,thepercentofchildrenwhoshedatleastonceduring the7-dayobservationperiodaftereachdosewasalsocalculated

3 Results 3.1 Safetyinadultvolunteers

We firsttestedthesafety of2doses ofthehighertiter vac-cine (106.3FFU/dose) in 29 adult volunteers aged 18–40 years Duringthe30dayspost-vaccinationofeachdose,nodiarrheaor severeadverse reactionwasreported byanyof thevolunteers One month aftereach dose, neitherblood cell counts norBUN concentrationincreased.Serumtransaminaselevelsstayedbelow

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10%ofvolunteersafter2dosesofvaccination.Oneindividualhad

elevatedlevelsofbothSGOTandSGPT(71and48IU/ml,

respec-tively)beforevaccinationandthelevelsremainedinthis range

after2dosesofvaccine.Nosheddingofthevaccinevirusoccurred

in these adults following vaccination Thus the Ethical Review

Committeesallowedthevaccinetobetestedfurtherin healthy

infants

3.2 Infantstudy

Atotalof200subjects(119boysand81girls)wereenrolledin

theinfantstudy.Theirmeanage(±SD)was8.7±1.6weeksatthe

timetheyreceivedthefirstdoseand17.2(±1.6)weeksatthetime

of2nddoseforgroups2Land2H.Forgroups3Land3H(the3-dose

group),themeanagewas13(±1.6)weeksatthetimeof2nddose

and17.9(±1.6)atthe3rddose.Aftereachvaccinedose,the

chil-drengainedweightandheightnormallyandwefoundnodifference

betweenvaccinationgroups.Thebloodcellcounts,serum

transam-inaselevelsandBUNwerenormalandnosignificantincreasewas

observedovertherangeofnormalhealthyinfantsafter

adminis-trationofeachvaccinedose

3.3 Reactogenicityandsafetyofinfantstudy

Duringthe entireobservationperiod (90days afterthefirst

dose), no serious adverse events that required hospitalization

and no cases of intussusception were recorded We observed

all infants for acute reactions for 30min following

vaccina-tion and parents observed their infants for 30 days aftereach

dosetonoteadverseeventsincludingdiarrhea,fever,vomiting,

loss of appetite, cough, allergy, abdominal pain and

irritabil-ity These symptoms following vaccination were grouped into

3 time periods: immediate reactions(i.e within 30min), short

term reactions (within 7 days post-vaccination) and longer

term reactions (from 8 through 30 days post-vaccination)

(Table1)

Aftereachdose,noimmediatereactionswereobserved.After

anydosefewerchildren reportedanysymptomswithin7 days

comparedtothe3-weekperiodfrom8to30dayspast

vaccina-tion.Fewerchildrenreportedanysymptomsafterdose2anddose

3,comparedwithdose1.Irritabilityand feverwerethe2most

frequentlyreportedsymptomsfollowingadministrationanydose

ofRotarixTMorRotavin-M1butnoneofthedifferencesbetween groupsreachedsignificance

Ofspecialnotes, within7daysafterreceivingthefirstdose,

3 children from group 3L (7.5%), 3 from group 2H (7.5%), 1 fromgroup3H(2.5%)and1fromgroupRotarixTM(2.5%) exhib-itedmilddiarrhea.Giventhesmallnumbers,thisdifferencewas notstatisticallysignificantandsuggestedthat thevaccinevirus hadbeenadequatelyattenuated(Table1).Rotavirusantigenwas isolated in fecal specimens from 1 case in each of the groups RotarixTM,3Hand2H duringthisperiod.Fromdays8–30, diar-rheaepisodes were reported only in groups RotarixTM and 3H (1 and 4 cases, respectively),of which only one case in group 3H was positive for rotavirus While a few infants had mild diarrhea after administration of dose 2 or 3, only 1 case in group3H (within 7 days afterdose2) and 1 case in group 3L (within7daysafterdose3)wereidentifiedasrotavirusG1P[8] SequencesofVP7geneofthesesamplesrevealedthattheywere 100%homologouswiththesequenceofRotavin-M1orRotarixTM

(inrespectivegroups).Ofnote,RotarixTM andRotavin-M1share 93.6%homologyinthe793nucleotidesequenceofVP7geneand 94.7%homologyinthe263aminoacidsequenceoftheencoded protein

3.4 Immunogenicity SerumsampleswereanalysedatNIHEandanonymizedresults were confirmed at CDC Most infants (94.5%) did not have detectableRV-IgAbeforevaccinationandallchildrenwithone pre-vaccinationserumandatleastonepost-vaccinationserumsamples wereincludedin theanalysisof immunogenicity Oneof the2 childrenwhowasseropositivebeforevaccinationseroconverted (group3H,datanotshown).Onemonthafterthe2nddoseof vac-cine,therateofseroconversiontoRotavin-M1vaccinewas61% (95%CI(45%,76%))forgroup2L(106.0FFU)and73%(95%CI(58%, 88%))forgroup2H(106.3FFU)(Table2).TheIgA-GMT,rangingfrom

76(group2H)to89(group2L),didnotdifferbetweenthesetwo groups.Forgroupsreceiving3dosesofvaccines(groups3Land3H), anti-RV-IgAseroconversionratesat1monthafter2dosesof vac-cinewere51%(95%CI(36%,67%))forgroup3L(106.0FFU)and61% (95%CI(45%,77%))forgroup3H(106.3FFU).TheIgAseroconversion rates1monthafterdose3increasedto56%(95%CI(39%,71%))in group3Land63%(95%CI(46%,79%))ingroup3H.TheIgA-GMTdid notincreasesignificantlyingroup3H(from61postdose2to83

Table 1

Number of infants with adverse events after vaccination with Rotavin-M1 or Rotarix TM during 30 days after each dose Diarrhea is defined as having more than 3 loose stools per day Diarrhea in these children is not accompanied with vomiting or fever (>37.5 ◦ C) In the majority of cases, diarrhea lasted 1–4 days Difference between groups was not significant *Figure in bracket indicates the number of samples positive for Rotavin-M1 or Rotarix vaccine.

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Table 2

Anti-RV-IgA antibody responses after administration of Rotavin-M1 vaccine (groups 2L, 2H, 3L and 3H, compared to Rotarix TM ).

Note: a Number of subjects for immunogenicity analysis (intention-to-treat) b Number of subject for immunogenicity analysis (per protocol) c Percentage of subjects sero-converted for RV-IgA d 95%CI, exact 95% confidence interval e GMT: geometric mean titers (and 95%CI) calculated for seropositive samples only.

Forchildrenreceiving3dosesofvaccine(groups3Land3H),

serumsampleswerecollected1monthafterdose2and1month

afterdose3todeterminewhetherathirddosemightimproved

theseroresponse.The3rddoseinducedseroconversionin5and3

morechildreningroup3Land3H,respectively,whohadfailedto

seroconvertafterthefirst2doses.Themajorityofchildren(14in

group3Land16ingroup3H)convertedafterseconddoseanddid

notfurtherconvertafterthethirddose.Threechildren(7.5%)from

eachgroup(3Land3H)seroconvertedafterbothdose2anddose

3

3.5 Viralsheddingaftereachdose

Weexaminedthekineticsofrotavirussheddinginvaccinated

children(Figs.2and3).Theprevalenceofchildrensheddingvirus

wasgreaterinthegroupofchildrenwhoreceivedRotarixTM(65%

afterthe1stdose)vs.anygroupthatreceivedRotavin-M1(44–48%

afterthe1stdose)(Fig.2).Furthermore,afterthefirstdose,

shed-ding of RotarixTM peaked 1 or 2 days earlier than shedding of

Rotavin-M1(Fig.3).Nonetheless,weobservedlittledifferencein

Fig 2 Dynamics of viral shedding within 7 days post-vaccination after each dose.

Percent of children shed virus in stool per day after each vaccination dose was

illus-trated The ratio was calculated per number of stool available each day because not

all children could produce stool every day for 7 days Stool samples were

consid-ered positive for RV if it is positive in ELISA (ProSpecT) and confirmed by G and P

genotyping All the samples collected during 7 days after each dose are typed as

G1P [8] Asterisk: group Rotarix TM ; opened triangle: Group 2L, 2 doses, 10 6.0 FFU;

opened circle: Group 2H: 2 doses, 10 6.3 FFU/dose; closed triangle: Group 3L, 3 doses,

0%

10%

20%

30%

40%

50%

60%

1 2 3 4 5 6 7 1 2 3 4 5 6 7 1 2 3 4 5 6 7

2L 3L Rotarix 3H 2H

Days after dose 1 Days after dose 2 Days after dose 3 Fig 3 Shedding of vaccine virus after each dose Percent of infant shed virus at any time during 7 days after each dose was illustrated Asterisk: group Rotarix TM ; opened triangle: Group 2L, 2 doses, 10 6.0 FFU; opened circle: Group 2H: 2 doses,

10 6.3 FFU/dose; closed triangle: Group 3L, 3 doses, 10 6.0 FFU/dose; and closed circle: Group 3H, 3 doses, 10 6.3 FFU/dose.

thepatternofsheddingbetweenthe4groupsreceived Rotavin-M1.Viralsheddingreducedsignificantlyinanygroupafterdose2 (6–20%)(Fig.2).Interestinglyafterdose3,30–37%ofchildrenshed thevirusatday3post-vaccinationinboth3Land3Hgroups

4 Discussion ThisreportdocumentsthefirstPhase1and Phase2 clinical studiesofanewcandidaterotavirusvaccinedevelopedin Viet-nam,Rotavin-M1.Theliveoralvaccine,whichhasbeendescribed previously,isderivedfromthemostcommonstrainofRotavirus, genotypeG1P[8],obtainedfromaVietnamesechildwithdiarrhea, attenuatedbycellpassage(>30×),plaquepurification,and pre-paredinVerocellsforhumanstudies[6].APhase1trialin29adult volunteersdemonstratedthatthevaccineadministeredorallyina titerof106.3FFU/dosewasnotassociatedwithsymptoms,adverse eventsorlaboratorychangesinblood countsorselected chem-istryandlittlevirusshedding,similartothatreportedforRotarixTM [11].TheDSMBreviewedthedataandapprovedthecontinuation

ofstudiesininfants

InthePhase1–2adaptivestudy,thecandidatevaccine admin-istered in eithera low (106.0FFU/dose)or high(106.3FFU/dose) titerona2-or3-dosescheduletoinfants6–12weeksofagedid notcausesignificantormorediarrheathanthatassociatedwith thelicensedvaccine,RotarixTM,demonstratingthatthecandidate strainhadbeensuccessfullyattenuated.Inthisstudy,thenumberof childrenwithdiarrheaepisodeswaslow,mainlyafterthe1stdose andtherewasnodifferencebetweenRotavin-M1andRotarixTM Thesediarrheaepisodesweremildsincetheywerenot accompa-niedbyvomitingandfever.Howeverhighernumbersofdiarrhea casesoccurredinthegroupreceiving106.3FFU/doseeventhough yetvaccineviruswasonlyfoundin3diarrheacasescumulatively

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suggestingthatdietorbacterialandprotozoalinfectionsmightbe

thecauseofdiarrheainthesechildren.InanotherRotarixTMtrialin

Vietnam,thepercentageofchildrenwithdiarrheaaftereach

vac-cinationdosewas3.1–6.1%,equivalenttowhatwasfoundinthis

study[7].RotarixTMat105.6–106.8CCIDalsocaused8.5–11%

diar-rheacaseamongchildrenintheUSandCanada[12].Thedetection

ofvaccinevirusindiarrheacasesisnotanuncommonphenomenon

intrialsusingattenuatedvaccine.Inadose-escalationstudyof116E

rotavirusvaccineinIndia,virusvaccinewasalsoisolatedin2outof

19diarrheacasesand2outof17diarrheacasesafterthe1stdose

of104FFUand105FFU,respectively[13].Thus,therateofdiarrhea

observedinourstudyiscomparabletosimilarstudiesofRotarixTM

andotherliveattenuatedrotavirusvaccinesanditisunlikelythat

thevaccinecausessignificantnumbersofdiarrheacasesinour

chil-dren.Nonetheless,furtherinvestigationisinprogressinalarger

groupofinfantstodetermineifthe106.3FFUdosecancausean

increaseindiarrheacasesamongvaccinees

ThesafetyprofileofRotavin-M1isalsofeaturedinthatthe160

infantswhoreceivedthevaccineineitherofthe2or3dosesdid

nothaveanysevereadverseevents,anysignificantexcessof

symp-tomsofdiarrhea,vomiting,feverorirritability,oralterations in

bloodcountorselectedbloodchemistriescomparedtothegroup

thatreceivedthelicensedvaccine.Adverseeffectsmainlyoccurred

afterthe1stdoseanddecreasedconsiderablyafterthe2ndand3rd

doses,similartoadverseeventsobservedduringinRotarixTMtrials

inVietnamorinothercountries[7].Asacomparison,whenthe

liquidformRotarixTMwastested,approximately50–65%children

developedfeverduringtheobservationperiod[7].InSingapore,

feverrateaftervaccinationreached25–30%aftereachdoseofthis

licensedvaccine[14]

Oncesafetywasestablished,thePhase2studyexaminedthe

immuneresponseandsheddingfrombothalowandahightiter

formulationofthevaccineandbotha2-dose(8and16weeks)and

a3-dose(8,12and16weeks)schedule.Theseresultswere

com-paredwithagroupthatreceivedthelicensedvaccine,RotarixTM,in

itsstandard2-doseschedule.Overall,theimmuneresponse

mea-suredasa 4-foldriseinIgAtiterstorotavirusrangedfrom51%

to73%,arangesurroundingtheresponseobservedforRotarixTM

(58%).Whilethehighertiterformulationperformedslightlybetter

thanthelowtiterpreparation,theadditionofathirddosetothe

schedule(i.e.8,12and16weeks)didnotdramaticallyimprovethe

immuneresponsetothevaccine.Thismightbeexplainedbythe

observationthathightitersoftheremainingtransplacental

anti-bodyagainstrotaviruscaninhibittheimmuneresponsetothe2nd

doseofvaccineinthe8-12-16-weekschedule.Steelefoundthat

2dosesofRotarixTMgivenat10and14weeksperformedaswell

as3dosesgivenat6,10,and14weeksbutbetterthan2doses

givenat6and10weeks[15].Inotherwords,theoldertheinfant

waswhenhereceivedthevaccine,thelowerwastheinitialtiterof

transplacentalantibodyandthebettertheimmuneresponsetothe

vaccine[16].Inboththe2andthe3doseschedulesinourstudy,

lastdosewasadministeredwhentheinfantwasthesameage,i.e

18weeks(95%CI(16.6–19.2)),unlikestudieswiththeRotarixTM

vaccinewhereathirddosewasaddedtothescheduleat14weeks

Therefore,theimmuneresponseto2dosesofthehightiter

Rotavin-M1vaccineat2-monthintervalyieldedthemostrobustimmune

response

Ofthesamenotes,anintervalof2monthsbetweendoseswas

more efficientin inducing immune response compared toa

1-monthintervalinbothlowandhighertiterformulation.Similar

observationsweredocumentedwhentheliquidformRotarixTM

wastestedin Vietnamesechildren[7].In thatstudy,2dosesof

RotarixTM, delivered1 month apart gave a seroconversion rate

of 63.3% at 1 month after the 2nd vaccine dose The same 2

dosevaccine however, when delivered 2 months apart gave a

seroconversionrateof81.5%.Applicationofthis2-monthinterval between2dosesofRotarixTMinEuropeancountriessuchasSpain, ItalyandFinlandledtohighseroconversionratesof92.3–94.6% [17].Thusagain,thehigherimmuneresponsewiththis2-month schedulemightbeassociatedwiththeslightlyolderchildrenwho areimmunologicallymorematurecomparedtothosewiththe 1-monthschedule[7]

TheimmuneresponsesinducedbyRotavin-M1are compara-bletothose seenin theRotarixTM groupinthis studyandin a previousstudythatemployedtheliquidformofthevaccinewith

asimilarschedule(58–63.3%)[7].It isnotedthatthepatternof IgAresponsetorotavirusvaccineinVietnamseemstofollowthe trendofdevelopingcountries.Inparticular,theIgAresponsesto RotarixTMinBrazil,Mexico,VenezuelaandVietnamwerereported

at61–65%,whicharelowerthanthoseinUSA,Canada,Europeand Singapore(78.2–88.3%)[18–21]andhigherthanthoseinMalawi andSouthAfrica[22].Inparticular,whenRotarixTMisintroducedin theexpandedimmunizationprogramofEuropeancountriessuch

asFrance,Germany,SpainandCzechrepublic,theIgAresponse rateswereveryhigh,82–94.6%[17].InSingaporetheresponsewas 76–91%dependingonthevaccinetiters[23,24].ThusinVietnam,

asinotherdevelopingcountries,thevaccineisfacingthepossible influenceofhighrotavirusdiseaseburden,malnutrition, concur-rentinfections,damagedgutmucosallayers,maternalantibodies andageoffirstadministrationaspreviouslydescribed[9,25,26] Theageatwhichthechildrenwasadministeredthefirstdose mightplayanimportantroleindeterminingseroconversionrates

InthisstudyandthestudywithRotarixTMinVietnamtheaverage ageoffirstdoseadministrationwas8weeks.Incomparison,the averageageforthefirstdoseintheUSis9–11weeksand11–17 weeksinSingapore[23,24].InFinlandandItaly,vaccinehasbeen usedatevenolderage(3months)[17].Itisgenerallybelievedthat vaccinationatolderageinducesbetterimmuneresponsespossibly duetoamorematureimmunesystemofthechildanddeclining maternalantibodytitersinbreastmilkorfromplacental transmis-sion.ThisnotionisalsosupportedbyastudyofRotarixTMinthe Philippinesinwhichchildrenwere5.5weeksofageatthefirst doseandtheseroconversionratewaslowercomparedtothatin Vietnamesechildren

Asvaccines, Rotavin-M1is very similartoRotarixTM in that botharederivedfromcommonG1P[8]strainsattenuatedbyserial passageandpreparedinVerocells.LikeRotarixTM,themajority

ofchildren shedafterthe1st doseof Rotavin-M1,whereas this proportiondeclinedconsiderablyafter2nddose,similartoother studies [24] Shedding of RotarixTM in different studies world-wideis35–80%,correspondingtothesheddingrateofthisvaccine foundinourstudy[27].Oneinteresting differencebetweenthe behaviorofthetwovaccinesistheincreasedsheddingobserved forRotarixTM (65%)comparedtoRotavin-M1(44–48%)afterthe 1st dose although this was not accompanied by an increased immuneresponse.Anotherdifferencebetweenthetwovaccines

isthatRotavin-M1vaccine,atthedosageof106.0FFUor106.3FFU causeddelayedinvirussheddingcomparedtoRotarixTMatdoses

of106CCID50(correspondingto105.5FFU/dose).Thesedifferences betweenthetwovaccinessuggestthatfurtherresearchonvaccine formulation,improvingtheyieldofvirussothathighertiter candi-datescouldbeavailablewhichhelpsadvancethedevelopmentof thislocallymanufacturedvaccinethroughefficacytrials

Inthisstudy,theRotavin-M1wasadministeredseparatelyfrom theoralpoliovirusvaccine(OPV)(10–20daysfromtheEPI sched-ule),thusthestudywasnotdesignedtoinvestigatetheeffectof othervaccines,inparticularOPVonRotavin-M1.Whilethe coad-ministration ofRotarixor RotaTeqwithOPVseemed toreduce seroconversionrates,antibodytitersandvaccinetakecompared

torotavirusvaccineswithoutOPV,thereductionswerenot statis-ticallysignificant[28,29].Thusfurtherstudyshouldbedesignedto

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immuno-genicityduetoconcomitantusageofOPVandRotavin-M1

This study has several limitations which will need to be

addressed asdevelopment of this vaccine progresses First, we

electedtouseRotarixTMinsteadofaplaceboforthecomparison

groupsowecouldwellmissimportantdifferencesinbackground

ratesofnaturalinfectionoverthecourseofthestudythatmight

havealteredourresults.TheaiminincludingRotarixisto

inves-tigateif Rotavinin anyscheduleor doseshows non-inferiority

toRotarix.Inaddition,sinceRotarix(lyophilizedform)hasbeen

licensedforuseinVietnamin2007,itisofethicalconsideration

forchildren participatingin thestudytobenefitfromthis

vac-cine.While theplacebo groupis important,this backgroundof

naturalinfectioncouldbederivedfromthepreviousstudywith

theliquidformofRotarixinVietnam[7].Inaddition,theinfants

wererandomizedsothiswouldlikelyhaveaffectedtheimmune

responsesintheRotarixTMgroupaswell.Moreimportantisthat

whileweattemptedtoexaminetwodifferenttiteredformulations,

106.0FFU/doseand106.3FFU/dose,thedifferenceinthese

prepa-rationsisnotgreat,perhapsnotevenwithinthevariabilityofour

titrationmethods.Consequently,whilewebelievethatthehigher

titermightbesuperior,wereallyhavenotexaminedthefullrange

oftiterstoseeifbysignificantlyraisingthetiter,wemightimprove

theimmuneresponse.Thisdecisionismorebasedupontheability

toraisethetiterofthevaccineduringproductionwhichwellcould

bethelimitingstep.Finally,whilewetesteda2-vs.3-dose

sched-ule,wemightwellimprovetheimmuneresponsetothevaccine

substantiallyifweweretoadministerthethirddoseatanolder

age,say20or28weeks,whentransplacentalantibodyhaswaned

Atthesametime,RotarixTMprovidedsubstantialefficacyin

Viet-nameseinfantsonasimilarscheduleandiftheimmuneresponse

isatallapredictorofefficacy,Rotavin-M1mightbeexpectedto

performcomparablyinaclinicaltrial

In conclusion,theVietnamese rotavirusvaccine,Rotavin-M1

hassafetyandimmunogenicityprofileinchildren,comparableto

RotarixTM.Amulti-centerstudyisinprogresstofurtherevaluate

thisvaccinationregimeninalargernumberofchildren

Acknowledgements

Wethankallthemedicalstaffs,thevolunteersandthechildren

inThanhSon,PhuThofortheirparticipationinthisstudy

WedeeplythankDrRogerI.Glass(FogartyInternational

Cen-ter,NationalInstitutesofHealth),DrTetsuYamashiro(Nagazaki

University),DrDuncanA.Steele(PATH)andDr.JonR.Gentsch(US

CDC)forcriticalreadingofthismanuscript

Conflictofinterest:DrsAnh,Trang,Thiem,Hien-Anh,Mao,Wang

andJianghavenoconflictofinterest.Financialsupport:The

Min-istryofScienceandTechnology,KC.10.33/06-10,Governmentof

Vietnam.Ethicalapproval:Thestudyandprotocol(No

962/CN-BYT-September29,2009)wereapprovedbytheEthicsCommitteesof

theNationalInstituteofHygieneandEpidemiologyandthe

Min-istryofHealth,GovernmentofVietnam

AppendixA

MembersoftheRotavin-M1VaccineTrialGroupinclude:NIHE

– VuThiBichHau,LeThiKimAnh,LeThiHongNhung,andLeHuy

Hoang;POLYVAC– NguyenThuyHuong,NgoThuHuong,Nguyen

Thi MaiHuong, TranBich Hanh,and DangNgan Ha; Centerof

PreventiveMedicine– PhuTho:NguyenThienAn;andCenterof

PreventiveMedicine,ThanhSon– PhuTho:NguyenThiLyandLe

ThiNgan

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