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FEEDBACKFROMTHEREGIONSANDCOUNTRIESONTHE

IMPLEMENTATIONOFSAGERECOMMENDATIONSONTYPHOID

VACCINES

NOVEMBER2010WHO/IVR

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FEEDBACKFROMTHEREGIONSANDCOUNTRIESONTHEIMPLEMENTATIONOFSAGERECOMMENDATIONSONTYPHOIDVACCINES

1.0.0 INTRODUCTIONIn the November 2007meeting of theWHO's Strategic Advisory Group of Experts (SAGE) onImmunization reviewed the available global evidence on global typhoid disease burden,assessedtheexperiencesandtheusefulnessoftyphoidvaccinesascomplementarytoolsinthecontrolandpreventionoftyphoid,andmadeseveralrecommendations[WERNo.1,4January2008, 83; 1‐6]. TheWHOwas requested to report back to SAGEwith the feedback from theWHO regional offices and countries on the implementation of these recommendations [seeAnnexI].WHOispleasedtoreport,inthefollowingsections,theprogressintheintroductionoftyphoidvaccinesincountries,andsomeofthechallengescountriesfaceintheimplementationofSAGErecommendationsontyphoidvaccineuse.2.0.0 ENGAGEMENTWITHWHOREGIONALOFFICESAlthoughtyphoidisseenglobally,thehighestincidenceisinSouth‐CentralAsiaandSouth‐EastAsia.StudiesinselectedsitesinfiveAsiancountriesshowedthattheannualtyphoidincidencevariedfrom24.2and29.0per100,000personyearsinVietNamandChina,to180.3per100,000personyears in Indonesia,and412.9to493.5per100,000personyears inPakistanand India,respectively [Ochiai et al,A studyof typhoid fever in fiveAsian countries: diseaseburdenandimplicationsforcontrols.BullofWHO,April2008,86(4)].Thoughtheincidenceratesmaybeanunderestimate of the true burden, as blood culturemethod is only about 50% sensitive, thisstudy was the first to be conducted in the region in standardized comparable manner.Therefore, the South‐East Asia (SEA) Regionwas the priority focus, followed by theWesternPacificRegions,andthentheEasternMediterraneanandtheEuropeanRegionsofWHO.OnlylimitedeffortsweremadetoengagetheRegionsoftheAmericasandtheAfricaweremade.EngagementwiththeRegionalOffices includedregularemailandtelephonecontactswiththeRegional Advisers and New Vaccines Medical Officer (where available) with the aim to puttyphoid discussions on the agenda of important regional meetings. Wherever possible,participationinclosecollaborationwithpartnerswassoughttobringfocusontyphoidissuesinRegional activities. In 2008 at the SEA Region Technical Advisory Group on ImmunizationMeeting in July, typhoid was discussed. It was recommended that countries review theirsurveillance for typhoid to get better data on the epidemiology of typhoid in the countries.Further,attheSEAEPIProgrammeManagersmeetinginAugust2009,thetopicwasrevisited.

AsthefirstandmostcriticalstepintheimplementationofSAGErecommendations,basedon theSAGE recommendations, theWHOrevised itsPositionPaperonTyphoidvaccinesandpublisheditintheWeeklyEpidemiologicalRecordinFebruary2008[WERNo.6,8Feb2008,83,49‐60].

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TwovisitsweremadetotheSouth‐EastAsiaRegionalOffice.Attheregionalmeetingofthefocalpoints forpandemicpreparedness inSeptember2009,typhoidwasdiscussed individuallywithcountry representatives where Nepal, Sri Lanka and Bhutan expressed interest to look attyphoid issues in their countries. Thiswas followedbyparticipationat the SEAGAVIRegionalWorking Group (RWG)Meeting in Katmandu in February 2010. Following the RWGmeeting,anothervisitwasmadetotheSEARegionalOfficeandIndia,Delhiinparticular.3.0.0 ENGAGEMENTWITHCOUNTRIESBasedonthecurrentlyavailable information(seesection2.0.0)priorityregionsaretheSouth‐EastRegionfollowedbytheWesternPacificandtheEasternMediterraneanRegionsand,onalimitedscale,theEuropeanRegionofWHO.Inaddition,basedontheinitialinterestintyphoidissuesexpressedbysomecountries,discussionsandsolicitation for informationwere initiatedwith key technical personnel and policy makers in these countries. Colleagues in the WHOregional and country offices played crucial role in facilitating the follow upwith countries ontheirstatus,vis‐à‐vis,typhoidcontrolanduseorintentiontousetyphoidvaccines.In close collaboration withWHO Country offices direct contacts were made with key policymakers and EPI programme managers in typhoid endemic countries. The countries wereprovidedbriefsummariesofwhatinformation/dataexistfortheirrespectivecountries,andtheinformation on typhoid vaccines, global policies on the use of vaccine. Information was alsosolicited from countries with regards to plans or intentions to use typhoid vaccine, typhoidsurveillanceandreportingincountries,etc.Inadditiontotheabove,Bhutan,FijiandNepal,SriLankawerevisitedonce; Indiawasvisitedtwice.Attempts were also made to encourage countries to include discussion on typhoid in theirNationalImmunizationTechnicalAdvisoryMeetings;itisknownthattheIndiaNTAGIdiddiscussitinatleastinonesession;NepalNITAGdiscusseditonce,andPakistanNITAGplannedtodosobutgotpostponed.AndfinallyatkeyglobalmeetingssuchastheGAVIPartnersForuminHanoiinNovember2009,the Global Vaccine Research Forum inMali in December 2010, the GIM in February 2009 inGeneva,andtheSEAROEPIProgrammeManagersandPartnersMeetingsinJuly2010,typhoidwasputontheagendaeitherassatellitesessionsorasoneofthemainagendaitems.Suchforaalsoprovidedtheopportunityforengagementwithindividualcountryofficialsonthesidelinesofthemeetingstodiscusscountryspecificissuesandplans.[forcountry‐by‐countrydetails,seeAnnexII]4.0.0 ENGAGEMENTWITHPARTNERSANDTHEGLOBALCOMMUNITYEvenatthegloballeveltyphoidhasbeenfeaturedregularlyatimportantmeeting.Sucheventsinclude the meeting of the Diarrheal and Enteric Vaccines Advisory Committee (DEVAC), inMalaga in September 2009, the GAVI Partners' Forum, Hanoi, in November 2009, the GlobalVaccineResearchForum,inMaliinDecember2009,theGlobalImmunizationMeeting(GIM)inGeneva in February 2010. Apart from these formal meeting, informal contacts through

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teleconferencesandemail changesweremaintainedona regularbasiswith the InternationalVaccineInstitute(IVI),theCoalitionagainstTyphoid(CaT),andDeliveryTeamfocalpointattheBill&MelindaGatesFoundation.5.0.0 FEEDBACK FROM THE REGIONS AND COUNTRIES ON THE IMPLEMENTATION OF SAGE RECOMMENDATIONSONTYPHOIDVACCINES5.1.0 GLOBALUSEOFTYPHOIDVACCINEANDEFFORTSTOACCELERATEUPDATE

In the WHO/UNICEF Joint Reporting Form (JRF), several countries indicate use oftyphoid vaccine,mostly targeting specific risk groups, e.g. food handlers, or high riskareas.Detailsabouthighriskareasarenotavailable.

Table1.CountriesreportingtyphoidvaccineuseintheWHO/UNICEFJoint ReportingForm(JRF),excludingvaccinationoftravelers

WHORegion Country Targetvaccinerecipient

AfricaRegion None None

RegionoftheAmericas

ArgentinaBrazilCuba

ArmySpecialgroups10,13,16years

EasternMediterraneanRegion

IraqKuwaitOmanQatarSaudiArabiaUnitedArabEmirate

HighriskgroupsFoodhandlersFoodhandlersFoodhandlersGroupsnotspecifiedFoodhandlers

EuropeanRegion

CyprusKazakhstanSloveniaUzbekistan

OnlyifspecificindicationsHighriskgroupsOnlyifspecificindicationsHighriskgroups

WesternPacificRegion

BruneiDarussalamMalaysiaRepublicofKoreaVietNam

NotspecifiedFoodhandlersHighriskgroupsPartofthecountry

[http://www.who.int/immunization_monitoring/en/globalsummary/Reschedule.Result.cfm,accessed15.09.2010]

Countrieswhousetyphoidvaccine,inatleastinpartsofthecountry,butdonotreport

thisintheJRFareChina,IndiaandPakistan. It is known thatmost developed countries offer the vaccines for travelers to typhoid

endemiccountries.ItisalsoknownthatmanyarmiesaroundtheworldusethevaccinealthoughonlyArgentinareportsitintheJRF.

Most recently Sri Lanka started typhoid vaccination, targeting high risk groups (e.g.healthworkers,foodhandlers,etc.)andpopulationsresidinginhighriskareas.In2009,

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SriLankaprocured20,000doesofViPSandusedtocontrolandoutbreakthatoccurredin the camps of the people displaced by war. Early this year they procured 200,000dosesanddistributedthevaccineto20districtswithguidelinesontheriskgroupstobetargeted.AlthoughtheyarecurrentlyusingtheViPS,SriLankaexpressedsomeinterestintheoralvaccinebutthecurrentpriceisclearlybeyondtheirreach.

SimilarlyFijistartedacampaignwithViPStoimmunize70,000people(above2yearsofage) residing in high endemic areas. They plan to introduce the vaccine as a school‐based routine programmeaswell as those considered 'high risk' groups such as foodhandlers.

NepaliskeentointroducetyphoidvaccineintheKatmanduValleytostartwith,butduetolackofresources,theplanninghasbeenkeptonholdatpresent.

SimilarlyBhutanwantstostrengthensurveillanceinthecapitalcity,Thimphu,butalsowants to introduce typhoid vaccine in one of the districtswhere outbreak of typhoidoccursregularly.AndpreferablytheywouldliketousetheTy21aoralvaccine

TheKyrgyzstanRepublic has interest to carry out a pilot project but before resourcescouldbefoundforthisactivity,thecountrywasengulfedinpoliticalviolence.Planstofollowupareonholdrightnow.Kyrgyzstan,too,wouldprefertheoralTy21avaccine.

The VIVA Initiative, funded by the Bill and Melinda Gates Foundation andadministered by the IVI, is working with both governmental and non‐governmentalsectorsinKarachi,Pakistan,andLalitpur,NepaltopilotintroducetheViPSvaccineforschoolchildren.Theprogramtargets240,000and120,000students,respectively.

5.2.0 FEEDBACK ON SPECIFIC ASPECTS OF THE TYPHOID VACCINATION RECOMMENDATION AND THE

CHALLENGESTOTHEIRSUCCESSFULIMPLEMENTATIONBYCOUNTRIES5.2.1 Financing

TheSAGErecommendationsdidstimulateinterest incountriestolookattheirtyphoiddisease burden and to explore the possibility of using vaccines as an adjunct toimprovedwaterandsanitationtocontrolandpreventtyphoid.However,countrieshavecompetingprioritieswithmultiplepublichealthinitiativesvyingforfunding,oftenfromthesamesource.Further,evenwithinthecurrentvaccinesportfolios,e.g.Hib,rotavirusand pneumococcal vaccines, countries struggle to balance their priorities, despitecommittedGAVIAlliancesupportforallofthesevaccines.Typhoid,atthistime,hasnodonorcommitmentand,despitebeing included inGAVI’sVaccine InvestmentStrategyPortfolio,isnotcurrentlysupportedbyGAVI.

Financingisaconstraint,notonlyforrolloutofvaccines,buteventoestablishcrediblesurveillance for typhoid. And in most countries the disease burden data is not wellestablishedand,whereinexistence,certainlynotgoodenoughtoprovidethebasisforidentifying"riskareas"toimplementthe"risk‐basedapproach"recommendation.

As a potential alternative financing approach, the above‐mentioned VIVA Initiative isexperimenting cross‐subsidization scheme to support the cost of the program. Thescheme charges one sector (private schools in Karachi and tourism industry inKathmandu) to subsidize the program cost of the main target population. The costrecoveryratewillbeavailableaftertheconductoftheprograminoneyeartime.

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5.2.2 Programstrategy Typhoid vaccines are one of the few new vaccines that do not fit the routine EPI

schedules,butmaywellprovidetheopportunitytorealisetheGIVSgoalofvaccinationbeyondtheinfantagegroup.DespitethechallengesthetyphoidvaccinesposeastheywouldrequirestrategiesoutsidetheroutineEPI,someofthecountries(Italkedto)arekeentopilotvaccineintroductionprogramme(Fiji,SriLanka,VietNam,Delhietc.).

Countries see school‐based vaccination as a viable option and the majority of thosecountriesconsideringadoptionoftyphoidvaccinewouldliketodeliverthroughatime‐bound, short campaign at some period of the school year, preferably at the start ofscholastic year. However, the Delhi experience [see Annex II] has demonstrated thefeasibility of delivering a vaccine outside the EPI Schedule by using the sameinfrastructureanddeliverysystemoftheexistingroutineimmunizationprogramme.

Implementingarisk‐basedvaccinationstrategyisachallengeformostcountriesduetothedifficultyofdefininghigh‐riskgroupsandpopulations.Allcountriesemphasize theneed to strengthen surveillance to generate better epidemiological information ontyphoid, but they all need support at least in the initial few years to kick‐start suchactivities.

Withtwovaccinesthatdiffervastlyincharacteristicsandwitharecommendationofrisk‐basedintroductionascomparedtouniversal,decisionontheintroductionofatyphoidvaccine isa complexprocess. Inorder toaiddecisionmakers,adraftdecisionmakingtoolfortheintroductionoftyphoidvaccines,isintheprocessofbeingfinalized.

5.2.3 Vaccinesoptions‐injectablevs.oral

AlthoughViPS, as a single dose vaccine, has its advantages particularly in a campaignsetting,somecountriesIvisitedarealsointerestedtoexplorepossibilitiesoftheuseoforalvaccinetoreducethenumberofinjections,iforalvaccineisaffordable.

Rightnowthewidespreaduseoftheoraltyphoidvaccineis limitedbyitsrelativehighcost compared to theViPS vaccine and, also, becauseof theneed to provide at leastthree doses given on alternate days. There is no experience in the use of the oralvaccineinarealprogrammesetting.

Given the limiteddurationofprotectionby the currently available vaccines, countriesmayneedtoconsidertheneedforrevaccinationdependingonthelocalepidemiology.Andthishaslogisticandcostimplicationsforanimmunizationprogramme.

5.2.4 Surveillance

All countries have a morbidity/mortality reporting system and most of them includetyphoid. However, the terms typhoid and enteric fevers are not well defined in suchreports

Further, the diagnosis of typhoid is often only based on clinical observation and notbacked by laboratory confirmation. Blood culture facilities are not available in mosthealthfacilities,particularlyintheperipheryofthehealthinfrastructurenetworks,andsimplediagnostickitsarenotwidelyavailable.

There is no example of sentinel surveillance targeting pre‐school and school‐agedchildren

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5.2.5 Diagnostics Typhoiddiagnosisisarealchallengeforcountries.Inmosthospitalsbloodcultureisnot

widely available. And where available, quality is uncertain. Even in the best ofcircumstancesbloodculturecanpickupbarely50%ofthetruecasesoftyphoid

Most hospitals use serological test, Widal being the most common. However, Widaltakes up to 18 hours to process and it is relatively expensive (at $5‐20 per test). Theresultisoftenbasedonasingletest,whichmaynothaveanysignificance.

Severalother serological tests todetectacuteS. Typhi infectionhavebeendevelopedwith sensitivity around70%and specificity around80%.Butnoneof the tests exceed60%ofdiagnosticaccuracyandcan’tbeconsideredasa“pointofcare”(POC)test.

POCtesting,definedasdiagnostictestingatornearthesiteofpatientcare,canincreasethe likelihood of disease confirmation, and improve disease‐specific treatment andpublichealthsurveillance.

Allcountriesexpressthedesiretohaveanaffordableandanaccuratediagnostictestfortyphoid

5.2.6 Outbreakcontrol

OneoftheimportantpartsoftheSAGErecommendationsreferstotheuseoftyphoidvaccine to interrupt outbreaks. Experience from China on the use of ViPS vaccine tocontrol typhoid outbreak is document. In recent times, there are a few otherexperiencesfromcountries.

Pondicherry, India, following the 2004 Tsunami, 17,000 doses of ViPS was used as apreventivevaccinationcampaign targetingprimarilychildrenbelow5yearsofage.NotyphoidcaseswerereportedinTsunamiaffectedareas.

Following the Pakistan earthquake in 2005, a pediatric Vi vaccination campaign wasundertaken in affected camps with over 50,000 doses administered. No cases wererecordedinthecampsinquestionoverthefollowing4‐6monthsinroutinesurveillance

Cyclone Tomas struck North and North‐Eastern part of Fiji inMarch 2010. By June amasscampaigntoreach70,000peopleintyphoidendemicareaswiththeViPSvaccinewas initiated and by end of August, more 60,000 were immunized. Although noepidemiological evaluation to assess the impacthasbeendone todate, it is reportedthatthenumberofcasesoftyphoidreportedhavedeclined

5.2.7 ThechallengeofS.Paratyhi

Styphiis,accordingtotheavailableepidemiologicalinformation,stillthemajorcauseoftyphoid fever. However, eexperience from Thailand as well as China show that as S.Typhiincidencedeclines,thereisaconcomitantriseintheincidenceofS.Paratyphi.Insome cases it may an un‐masking effect; in some cases, possibly replacementphenomenon.

Guilin, China, has discontinued active promotion of ViPS vaccine due to the rise ofparatyphoidcaseswhichresulted inpeoplequestioningtheefficacyandutilityofViPSagainstS.Typhoid

In Nepal, the Public Health Laboratory in Kathmandu found that the proportion of S.Paratyphiwas32.9%and62.5%in2007and2008,respectively

IntheabsenceofavaccineagainstS.Paratyphi,manycountriesareuncertainwhetherintroductionofavaccineagainstS.Typhiwouldhaveanyimpactatallonentericfevers.

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5.3.0 FEEDBACKONWHOPREQUALIFICATIONOFTYPHOIDVACCINES

WHOprequalificationofavaccineisanimportantsteptoassurecountriesofthequality

oftheproduct,particularly inthosecountrieswherenationalregulatoryauthoritiesdonothavethecapacitytoassessvaccinequality.SAGErecognizedthatandurgedthepre‐qualificationofthecurrentlylicensedimprovedtyphoidvaccines.WHOprequalificationisalsoarequirementforUNICEFprocurementandGAVIFinancing.

The system in place to assess the acceptability, in principle, of vaccines has beeneffective in promoting confidence in the quality of the vaccines shipped to countriesthroughUNpurchasingagencies.

Prequalificationprocessforthreetyphoidvaccinesproducedbydifferentmanufacturershave been initiated. Two out of three are purified Vi capsular polysaccharide ofSalmonella typhi (Ty2 strain) based vaccines. The thirdone is the liveoral attenuatedTy21avaccine.

Currently theprequalificationofoneof thepolysaccharidebasedvaccines isexpectedbyOctober‐November2010.Theliveoralattenuatedvaccineisadvancedintheprocessandprequalificationmaybeexpectedearly2011.Thethirdvaccineisstillontheinitialstagesoftheprocessbutprequalificationmaybeexpectedby3Q2011

5.4.0 UPDATEONNEWINITIATIVES

5.4.1 Sub‐SaharanTyphoidSurveillanceProject

The InternationalVaccine Institute (IVI) isconducting theMulti‐CountryTyphoidFeverSurveillanceProgram(TSAP)insub‐SaharanAfricawithsupportfromtheBill&MelindaGatesFoundation. Theprogram’saimtogeneratestandardizeddataonentericfever‐related illnessanddeath incountriesofsub‐SaharanAfrica inordertodriveevidence‐baseddecision‐makingonentericfevercontrolandpreventioninterventions, includingvaccination.Theprogramrequirestheachievementofseveralobjectives:1)todevelopa network of sentinel enteric fever surveillance sites in sub‐Saharan Africa; 2) toestimatetheburdenoftyphoidandparatyphoidthroughstandardsurveillancemethods;3)toidentifyadditionalendemicareasthroughmulti‐sitediseaseburdenstudies;and4)to advocate for the establishment of evidence‐based enteric fever control andpreventionpolicythatincludesvaccination.

A consortium of scientific and public health institutions working in the region wascreated and comprises of TF experts in the fields of epidemiology, laboratory testing,andpublichealth(PH).Basedonanevaluationofepidemiologicalsettingandlaboratoryinfrastructure,siteswereeitherconsideredGroup1Sites(G1S)orGroup2Sites(G2S).G1ShaveanexistingsurveillanceinfrastructurefortyphoidfeverwhileG2Sarelackingadequatesurveillance infrastructureat themoment.G1S includeGhana,Kenya,SouthAfrica,Tanzania,Nigeria,andUganda.G2SincludeBurkinaFaso,Ethiopia,GuineaBissau,Madagascar,Senegal,andSudan.Ageneralprotocolhasbeencompletedalongwithastandardized study design, which includes assessment of catchment population,inclusion and exclusion criteria, Case Report Form, datamanagement, and laboratoryrequirements for the culturing of Salmonella Typhi, as well as automated bloodculturingsystems,andthedevelopmentofQC/QAandproficiencytestingapproaches.

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Forthemajorityof thesites,surveillanceactivitieswillbehospital‐based.Subjectsarethosewhopresentatthehospital’s in‐andout‐patientwards,resideinthecatchmentareawith scientifically define population, and fulfill the inclusion criteria. Population‐based surveillance will be conducted in the Kibera slums of Nairobi, Kenya, incollaboration with the U.S. CDC and Kenya Medical Research Institute (KEMRI).Laboratory‐based surveillance will be conducted with the South African NationalInstitute of Communicable Diseases where subjects will be identified by specimenstestingpositiveforTFinthelaboratory.Thus,TSAPwillprovideauniqueopportunitytocomparethreetypesofPHsurveillanceintheAfricansetting.

5.4.2 Coalitionagainsttyphoid(CaT)

The Coalition against Typhoid, CaT, is an initiative lead by the Sabin Vaccine Institutewith support from the Bill & Melinda Gates Foundation. The main objective of theinitiativeistocoordinatetyphoidstakeholderstowardscommonobjectivesfortyphoidcontrolandprevention,andactasthecatalysttodevelopcomprehensiveandconcreteworkplansandfacilitateimplementationofsuchplansincountries.

The purpose of this group is to serve as a well‐respected, independent voice that iscomprised of typhoid experts and global health immunization stakeholders who candirectlyaddresstheissuesfacingthevaccinecommunityanddevelopaglobalworkplanforuseofvaccinestocontroltyphoid.

To lead this coalition and provide specific oversight to various activities, the SabinVaccine Institute has begun to chair the sessions of the coalition, which includesmembers from: the Agha Kahn University, Bharat Biotec, the Bill andMelinda GatesFoundation,theCentersforDiseaseControlandPrevention,Crucell,theGAVIAlliance,the InternationalVaccine Institute,NovartisVaccines InstituteofGlobalHealth,PATH,Sanofi‐Pasteur, theUnitedNations Children's Fund,University ofMarylandCenter forVaccineDevelopment,andtheWHO

6.0.0 NEXTSTEPSANDTHEFUTURE

Typhoidisadiseasethataffectstheweakestsectionsofsocietywhooftendonothavethe opportunity to voice their needs. Therefore, a concerted global effort to supportcountries through the initial steps are needed, even if not on the same scale ofinvestment for preparatory processes prior to introduction of other new vaccines inrecentpast,amodestinvestmenttosupportcountriesisessentialandanecessarypre‐requisite. The international donor community, including alliances committed to theachievementoftheMillenniumDevelopmentGoalsthroughreductionofmortalityandmorbidityfromcommondiseases,needtocometogethertocreatefundingmechanismsto help countries understand their disease burden better, help them prepare forpossibleuseofvaccinesandprovidefinancialassistancetothecountriesmost inneedbutunabletohelpthemselvestohaveaccesstotyphoidvaccines

Thecommitmentofseveralcountriestoaddresstyphoidissueisevidentinthattheyarealreadymovingaheadwithplansto introducetyphoidvaccinesdespitetheabsenceofsignificantsupportfromanywhere.Weneedtocontinuetobuildthemomentum

While the coming of conjugate vaccine against typhoid is much anticipated, there isroomtoexplore theoption foranoralvaccinethat isavailableandaffordable.As the

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infant immunization schedule gets more crowded with injectable vaccines, an oralvaccineisseenassomethinglesscomplicatedtohandle.Theglobalcommunityneedstorisetothischallengebyofferingoptionstoexpandtherangeofimmunizationschedules

The scientificand theglobal communitiesneed to rise to thechallenge todevelopaneasytouse,accurateandaffordablediagnostictoolfortyphoid

Inthecomingyears,morefocuswillbeplacedonAfrica,andresourcestosupportworkinAfricaiscriticalifwearetomakeanyprogressinthecontinentwithtyphoidcontrolandprevention

TherecentannouncementofthesupportfromtheBill&MelindaGatesFoundationforthe Coalition against Typhoid (CaT) is indeed welcomed, and this consortium willcertainlygoalongwayinbriningmorefocusontheneglectedissueoftyphoid.

AsacontinuationofthefeedbacktoSAGE,WHOIVRiscommittedtofacilitateendemiccountries to seek for a sustainable public health response to control and preventtyphoidintheircountries.

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1. In view of the continued high burden of typhoid fever and increasing antibiotic resistance, and given the safety, efficacy, feasibility and affordability of 2 licensed vaccines (Vi polysaccharide and Ty21a), countries should consider the programmatic use of typhoid vaccines for controlling endemic disease. 2. In most countries, control of the disease will require vaccination targeted only at high-risk groups and populations. 3. Countries should decide on the selection of populations and age groups to target, and on the delivery strategy (e.g. school-based or community based vaccination), which will depend on the local context (age pattern of the disease, school enrolment rates, etc.). 4. Countries should select typhoid vaccines depending on the capacity of the local Expanded Programme on Immunization and other logistic and cultural factors, and should utilize opportunities coupled with other public health interventions in the age groups referred to in paragraph 3. 5. The availability of the above-mentioned licensed typhoid vaccines will be enhanced by pre-qualification by WHO of these products and by enhanced global awareness and commitment to reduce the burden of typhoid disease. 6. Due to the epidemic potential of typhoid, and observations on the effectiveness of vaccination in interrupting outbreaks, typhoid vaccination is recommended for outbreak control. 7. Typhoid vaccination programmes should be implemented in the context of other efforts to control the disease, including health education programmes, improvements in water quality and sanitation, and programmes to train health professionals in diagnosis and treatment. 8. Given the importance of information on disease incidence for targeting vaccination and assessing its impact, priority should be given to strengthening surveillance systems for typhoid fever, including sentinel site surveillance in pre-school (2–4 years old) children and school-aged children (5–15 years old). The development of reliable and appropriate diagnostics assays for use in developing countries is required. 9. Development and research on new typhoid vaccines (such as the Vi conjugate vaccine) are encouraged, particularly for use in infants and young children, but this should not limit the use of currently available vaccines for control of endemic disease.

ANNEXISalientfeaturesoftheSAGErecommendationsontyphoidvaccines,Nov.

2007

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ANNEXIIDETAILEDUPDATEOFTHEFOLLOWUPACTIVITIESWITHREGIONSANDCOUNTRIESANDTHEIR

CURRENTSTATUSORFUTUREPLANS.1.0 SOUTH‐EASTASIAREGIONAt the South‐East Asia Regional Immunization Technical AdvisoryGroupmeeting in July 2008that the topicof typhoidcontrolandpreventionwas firstdiscussed.TheSEA‐ITAGrecognizedthat typhoidwas amajor public health concern inmanyMember States. However, the ITAGhighlightedtheneedtofirstfocusonstrengtheningsurveillancefortyphoidsothatbetterdatawould be available to aid future decisions. The recommendation from the ITAGmeetingwasthen fed to the Immunization Programme Managers meeting the same year (August 2008)wherecountrieswereencouragedtoreviewtheirsurveillancesystemandtoseehowtheycanbestrengthenedto includetyphoid.However,mostcountriesdidnottakeanyspecificactionsonthematter.Inearly2009,theSouth‐EastRegionalOfficeassistedtheInternationalVaccineInstitute,Seoul,to conduct ameetingon typhoid inBangkok inMarch2009,whichbrought togetherexperts,programmemanagersandgovernmentofficialsfromsomeofthetyphoidendemiccountriestodiscusshowbesttotakeforwardthetyphoidagendaintheRegion.Subsequent to these,after July2009, IVRactivelyengagedwith theRegionalOfficeaswellaswithcountriesusingbothformalandinformalchannels.InAugust2009,takingadvantageoftheSEARegionalPandemicInfluenzaVaccineDeploymentworkshopbeingheldinDelhi,discussionontyphoidvaccinewasalsoincluded,inadditiontodiscussionwithindividualcountrydelegatesonthesidelinesofthemeeting.SubsequenttothatindividualcountryhighleveldelegatesweremetattheGAVIPartnersForuminHanoiinNovember2009.InFebruary2010,typhoidwasalsoincludedon the agenda for themeeting of the South‐East Asia RegionalWorkingGroup (SEARWG)inKatmanduand,attheImmunizationandPartnersMeetinginDelhiinJuly2010.Apartfromtheseregionalfocusedactivities,individualcountrydiscussionswereheldandgivenbelowareinformationspecifictoeachcountryontyphoidrelatedissues.

Bangladesh

DiscussionswithhighleveldelegatesfromBangladeshattheGAVIForum,Hanoi,inNovember2009

Severalroundsofdiscussions,emailexchangeswiththeEPIProgrammeManageraswellasWHOmedicalofficerinDhakatooplace

Also, commissioned a brief review of available information on typhoid in thecountry.Dataontyphoidisincludedforroutinecollectiononlyfrom2008.Typhoidisrankedasthe8thmostimportantcauseofhospitaladmissionwithover400,000casesadmittedinhospitalswithtyphoidin2008.Otherprospectivestudies[Brookset al. Bacteremic typhoid fever in children in urban slum, Bangladesh. EmergingInfectDis,Vol.11,No.2,Feb2005]puts the incidenceof typhoid feverashighas390per 100,000person‐years, clearly highlighting themajor public healthburdenduetotyphoid.

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WithGAVIAlliance'ssupport,inrecentyears,BangladeshhasintroducedhepatitisBand Haemophilus influenzae type b (as the pentavalent). And currently they areactivelyplanning forpossible introductionof rotavirusandpneumococcalvaccinesand, even cholera vaccine. Therefore, Bangladesh feels that theydonot have thecapacity or the resources to take up typhoid in any significant way at present.Nevertheless they are interested to seek for support to strengthen typhoidsurveillanceinthecountry.

Bhutan Despiteitssmallpopulation(around750,000)morethan2000casesoftyphoidare

reported annually with occasional outbreaks, even forcing schools to close.Following the discussionswith the high delegation at theGAVI Partners Forum inHanoiinNovember,acountryvisitwasmadeinJune2010.

Bhutan is keen to explore the possibility of using typhoid vaccines tocontrol/prevent typhoid. They have specifically asked for assistance to strengthensurveillanceinthecapitalcity,andtoexplorethefeasibilityortheappropriatenessof introducing a typhoid vaccine (Ty21a preferred) in one small district wheretyphoidoutbreaksoccurannually.Furtherdiscussionsisongoing

Myanmar

Likeothercountries,theMyanmarhighleveldelegationattheGAVIPartnersForumin Hanoi were briefed about the possibilities of typhoid vaccination. It is known(althoughgettingdata is challenging) that typhoid isendemic inmostpartsof thecountry.

Thiswasfollowedupwithseveral informalcontactswiththeEPIPMManager,butnothing concrete has happened and there is no clear signal from the country onhowwemoveforward.

LikeotherhealthinterventionsforMyanmar,donorassistancewillbeneededonalongtermifwearetostartanyprogramme.

Nepal

FollowingthediscussionswiththehighleveldelegationattheGAVIPartnersForum,acountryvisitwasmade inFeb2010precededbydiscussionswithboththeWHOcountryofficeandtheEPIProgrammeintheMinistryofHealth,Nepal.

Typhoid and cholera are major issues in Nepal, particularly so in the Katmanduvalley.IntheAnnualReportpublishedbytheDepartmentofHealthshows203,172,271,437and463,104casesof typhoid reported for theyears2005/06,2006/07&2007/08,respectively.

Anetworkof11laboratoriesacrossthecountryparticipatesinabacterialdiseasessurveillance,primarilytotrackmultidrugresistance.ThePublicHealthLaboratoryinKatmandu servesas the reference laboratory for this surveillance. Salmonellawasincludedonthelistofpathogenssince2004.Fortheyears2006,2007,2008&2009,they identified 1611, 1512, 1697 and 1307 salmonella isolates at the NationalReference Laboratory, with an increasing trend in the proportion of S. Paratyphiidentified.

Drugresistanceispresentbutatverylowlevel,andalsoseemstoindicateaslightriseintrend

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NepalhashadexperiencewiththeuseofViPSvaccineasoneoftheimportanttrialswith ViPSwas carried out inNepal [Acharya et al. Prevention of typhoid fever inNepalwith the Vi capsular polysaccharide of Salmonella Typhi. TheNew EnglandJournalofMedicine,Vol.317,No.18,October1987.]

IVIisinitiatingapilotstudytoassessacceptabilityandusefulnessofchargingforthevaccinestogroupsthatcanpaytosubsidizegroupsthatcannotpayforthevaccinebutneedit.

Nepal isverykeentostarttyphoidvaccination, initiallytargetingKatmanduValley,although typhoid is reported fromalmostallpartsof thecountry. However, theywillneedassistance(technical&financial)toinitiatetheprogramme.

The VIVA Initiative is pilot introducing Vi polysaccharide vaccine utilizing a cross‐subsidizationscheme.Theprogramtargets120,000studentsinLalitpurDistrict(oneof the threedistrictsofKathmanduValley)usingpublichealth infrastructure. Theprogram will also examine the viability and sustainability of cross‐subsidizationschemewhereadultsinthetourismsectorwillbevaccinatedforaminimaluserfee,which is to be deposited in the vaccine revolving fund to support financing thepublichealthschool‐basedtyphoidvaccinationprogram.

Indonesia

Noindicationontheirinterestorintentions.ButIndonesiahasexperiencewiththeuseofViPStyphoidvaccine,[Ochiaietal.IntroducingVipolysaccharidetyphoidfevervaccinetoprimaryschoolchildreninNorthJakarta,Indonesia,viaanexistentschool‐basedvaccinationplatform.PublicHealth,2006,120],aswellastheoralTy21avaccine[Simanjuntaketal.OralImmunizationagainsttyphoidfeverinIndonesiawithTy21avaccine.Lancet,Vol.338,Oct1991]. Further,withBioFarma in Indonesia,prospect for sustainability ishigh if vaccines

weretobeused. IVIiscurrentlyindiscussionwithBioFarmafortechnologytransferforproductionof

VipolysaccharideandconjugatevaccinedevelopmentthroughVIVAInitiative.India

Typhoid is undoubtedly a major public health issue in India. In their routinereporting formorbidity andmortality, typhoid is included. It is reported from theCentralBureauofHealthIntelligence,GovernmentofIndia,thatin2007and2008,at least 820,360 and 934,469 cases of typhoid were reported nationwide, andtyphoid is listed among diseases that cause significant death.[http://www.cbhidghs.nic.in/writereaddata/linkimages/8%20Health%20Status%20Indicators4950277739.pdf, accessed 7September2010]

However,otherthanDelhiState,nootherplacesusetyphoidvaccineonaregularbasis

TheNational Technical Advisory Group on Immunization (NTAGI) did have a briefdiscussionontyphoidintheirmeetingin2009.Thegrouprecognizedthattyphoidisimportant and recommended the strengthening of surveillance for typhoid,particularlytolookatdifferentialsbetweenurbanruralsettings

In February 2010, during a visit to Delhi, detailed discussionswere heldwith keypersonsintheimmunizationunitoftheMinistryofHealthaswelltheIndianCouncil

15

for Medical Research (ICMR). The immunization unit recognized the value ofvaccinationbutindicatedthatthereareotherprioritiesthatthecentralgovernmentisengaged in rightnowand that thereareno immediateplans to include typhoidvaccines within their national immunization programme. On the issue ofsurveillance, the ministry was looking to other agencies or partners to initiatesurveillance.

WhentheissuewasbroachedtoICMRtoinitiateafewselectcentersaroundIndiaas study sites to look at typhoid burden, ICMR did not think it was its coreresponsibilityandfeltthatsurveillanceisacentralgovernmentactivity.

Delhi state introduced ViPS since 2004 as part of its routine immunizationprogrammebut targeting children aged 2 to 4 year olds. The vaccine is deliveredthrough thesameservice infrastructureas routine immunizationandbynowtheyarereachingabout300,000childrenannually.DelhiStatehasapopulationinexcessof20millionpeople.

Delhiwasencouragedtoconductareviewoftheimpactoftheprogramme,butthewouldneedassistance.WeexploredpossibilitieswithNational InstituteofCholeraandEntericDiseases(NICED),Kolkata,whowerepartnerswithIVIinconductingtheViPS effectiveness trial in Kolkatta [Sur et al. A Cluster‐Randomized EffectivenessTrial ofVi TyphoidVaccine in India.NEngl JMed, 361;4: July 23, 2009].Althoughthey showed some interest, no specific steps have been taken to carry out theevaluation.

Followingthe2004Tsunami,theUnionTerritoryofPondicherrycarriedoutamasscampaign with ViPS vaccine targeting about 17,000 under five children as apreventive campaign against potential typhoid outbreak. There were no cases oftyphoidreportedinthewakeofTsunami.

SriLanka

SriLankahasalonghistoryofusingthewholecelltyphoidvaccine,targetedmainlyathealthworkersandknownhighriskareas.Howevertheuseof thisvaccinewasdiscontinued in the early 1990's due to its severe adverse events followingimmunization. In recent years Sri Lanka has restarted the programme with ViPSvaccineinhighendemicareas

TheincidencerateoftyphoidfeverinSriLankais11.48per100,000populationsin2009.Butthisdistributionisuneventhroughoutthecountry.Thehighestincidencerate 90.56/ 100,000 population has been reported from Vavuniya District, thenfromMannarDistrict(140.76/100,000).Themediumlevel incidencereportedfromJaffna (98.27/100,000), Nuwara Eliya (27.21/100,000) and Puttlam Districts(10.32/100,000).

ThevaccinationwithViPSisrecommendedbytheSriLankanMOHtothosedeemedathigh risk in areas known for typhoidoutbreaks.High risk groups includehealthworkers, food handlers, people living in typhoid endemic areas where water andsanitation facilities are considered poor or inadequate, etc. For 2010 they haveprocured 200,000 doses of ViPS and distributed to 20 districts with generalguidelinesontheriskgroupstobevaccinated.

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2.0 WESTERNPACIFICREGION

China TyphoidisendemictomanyChineseProvinces,particularlyinthesouth,south‐east,

and south‐western part of the country. Typhoid vaccine,mainly Vi polysaccharidehadbeenusedinChinaformanyyears.

InJune2010,incollaborationwithIVIandtheGuangxiCentersforDiseaseControland Prevention (GXCDC), organized a workshop in Guilin where representativesfrom four provinces and one autonomous region of China, two vaccine Chinesevaccine manufacturers, National CDC, and National Institute for the Control ofPharmaceutical andBiological Products (NICPBP)were represented, in addition toparticipantsfromIVI,WHOandBill&MelindaGatesFoundation.Themainobjectiveoftheworkshopwastolearnabouttyphoidvaccinationandtheimpactithashad,and the most recent available data and the trend in the disease epidemiologyfollowingtheuseofViPSvaccineintheseprovinces

Typhoid vaccination is not part of the national immunization programme and,therefore, the vaccine is not available free as the ones on the national EPIProgrammelist.Thevaccine issoldbythelocalCDCandtheaveragecost isaboutUS$1perdoseofViPS.

Common strategies employed are school‐age vaccination in high risk areas,vaccination of food handlers, outbreak response, and high risk focused regularimmunizationcampaigns.

Althoughcoveragevariedacrossandwithinprovinces,thevaccinehasproventobeeffective in reducing typhoid incidence to very low level and, also, seems to beeffectiveincurtailingtransmissionduringoutbreaks

However, in recentyears the rise in the incidenceofparatyphoidhascomplicatedboth theepidemiologyof thediseaseandthemeasurementof the impactofViPSvaccinationagainstS.Typhi

Wherevaccinesarenotavailablefree,priceisanimportantdeterminantofuptakeastheonesinmostneedofthevaccinesareoftentheoneswhocanafforditleast.

Fiji Fiji, a South Pacific island nation, consists of over 350 islands and islets, ofwhich

approximately 100 are inhabited, but themajority of the population (about 87%)resides on the two main islands‐ Vanua Levu and Viti Levu. In 2007 Fiji had apopulationof837,271[http://www.statsfiji.gov.fj/Census2007/ census07_index2.htm] with an approximate birth cohort of 20,000. Of the total population about 25%resideontheislandofVanuaLevuandtheremainingmainlyonVitiLevu;thecapital,Suva,inalsoonthisisland

Typhoidisknowntobeendemicinmanypartsofthecountry.Ina2006study,WHOestimatedthatFijihasanincidenceoftyphoidofbetween136and1000casesper100,000populationperyear,whichisoneofthehighestratesreportedintheWorld.Inrecentyearsthegeographicalareawheretyphoid isreportedisexpandingfromthehistorical'hotspot'intheNorthandcasesarenowroutinelyreportedinpartsofWesternandCentral/EasternDivision.FollowingcycloneTomas inMarch2010,anincrease in notifications of typhoidwas reported and, by end of July 2010, there

17

were110casesreportedfor2010comparedwith58forthesametimeperiodlastyear.

DiscussionswereinitiatedwithWHOcountryofficetowardsthelatterhalfof2009about instituting a regular typhoid control programme. Even a draft vaccineintroduction plan was developed and circulated for discussions. Then early 2010,cycloneTomas, aCategory IV Storm,broughtdestructionanddisease in itswake.Suddenlytyphoidcontrolbecameanurgentmatter.

With support from AusAID the Government of Fiji decided to vaccinateapproximately 70,000 people aged above two years with the ViPS vaccine. Theoutbreakresponsewastargetedmainlyforthosepopulationsresidingintheknownhighendemicspotsaswellashighriskareasfromwherecaseswerebeingreportedregularly. By the end of July 2010, more than 40,000 people were alreadyvaccinated

InAugust,ameetingwasconvenedbytheGovernmentofFijiincollaborationwiththeWHOCountryOffice.ExpertswereinvitedfromWHOHQ,WPRO,CDC(US)andthe InternationalVaccine Institute (IVI).After a two‐and‐half daysofmeeting, thefollowingrecommendationsweremadefortyphoidvaccinationinFiji:

o tocompletethepresent70,000targetedimmunizationwithViPSvaccine[theMoHiskeentoexpandthemasscampaigntoreachmorepeopleifadditionalresourcescanbefound),

o introduceasingledoseViPSatschoolentry,andpossiblyarepeatdoseafterthreeyearsoratprimarylevelexitasoptions.

o Immunizeallhealthcareworkersandhospitallaboratoryworkers,o RegularImmunizationforfoodhandlerso MaintainasmallstockpileofViPSvaccinetorespondtooutbreaks,o tocontinuethesurveillanceactivityinthethreelaboratoriesthatare

alreadyinvolvedindoingbloodandstoolculturefromsuspectcasesoftyphoid.Itwasemphasizedthatkeepingupthesurveillanceatthesamelevelandqualityisimportantsothatafterafewyears,aproperimpactassessmentofthevaccineispossible

Theproposalwillbevettedbythegovernmentanddonoragents.Fiji,therefore,canmostlikelybeoneofthecountriestohavearegulartyphoidvaccinationprogrammeaspartorEPIwork.

3.0 EasternMediterraneanRegion Pakistan

AlongandextensivediscussionwasheldwiththeWHOPakistanCountryOfficeontyphoid and typhoid vaccination. Brief meeting was also held with a few seniorgovernmentfiguresattheGAVIForuminHanoi.

Although typhoid is considered a public issue, there isn't the kind of urgency orpressure to do anything immediately. This is partly because there is no donorfunding to support it. And further, the national 5‐year development plans for thecycle 2012‐2017 is already finalized and budget envelopes for various sectorsdecided; typhoid control programme cost is not included and, by the timediscussionswereinitiatedtowardsendof2009,itwastoolate(Iwastold)

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Following the DOMI typhoid project in Karachi, Pakistan, there was a concertedeffort towards a school based vaccination strategy in Sindh and Punjab. Severalmeetingswere held in Islamabad, Lahore and Karachi and expressions of interestobtainedfromtheMinistriesofHealthinPunjabandSindhforpilotprojectsinthecitiesofFaisalabadandKarachi.However,lackofdonorfundingwasaproblemandinterestwanedwiththechangeingovernments.

Asastartingpoint,itwasplannedtoincludediscussionsontyphoidattheNationalImmunizationTechnicalAdvisorymeetinginDecember2009.Thatgotpostponedtoearly2010,andthenitneverhappened.Thenthefloodscame.

Further, it was clear that without donor support, it is unlikely that PakistanGovernment will make any specificmoves towards a typhoid control programmethatincludesvaccinesaspartofthepackage

SimilartotheprograminNepal,VIVAInitiativehascommencedapilotintroductionof Vi polysaccharide vaccine utilizing a cross‐subsidization scheme. The programtargets 240,000 students in two townships of Karachi using public healthinfrastructure. The program will also examine the viability and sustainability ofcross‐subsidization scheme where students in high‐fee private schools will bevaccinatedforaminimaluserfee,whichistobedepositedinthevaccinerevolvingfund to support financing the typhoid vaccination program for public schools andmadrassahs.

4.0 EuropeanRegion TheKyrgyzRepublic

The former Soviet states in Central Asia, namely Uzbekistan, Tajikistan and theKyrgyzRepublic,areknown tohaveperiodic largeoutbreaksof typhoid.AmongstthemtheKyrgyzRepublichavelongexpressedaninteresttoexplorethefeasibilityofvaccination(withTy21aasthepreferredchoice)tocontrolandpreventtyphoid.The International Vaccine Institute had provided technical assistance to initiate apilotprojectandaproposalwasdeveloped.However,nofundingsupportcouldbemobilizedandtheplandidnotproceedanyfurther.

AdiscussionwasheldwiththeWHORegionalOffice inCopenhagenandtheWHOCountryOfficetodevelopaplanofactiontopushthis forward,and itwasagreedthat a visit fromWHOHQwould be a useful first step.Unfortunately before thatcouldtakeplace,politicalturmoilrockedthecountryintouncertainty.

It would be only reasonable that no further actions can be taken till normalcyreturnstothecountry.

Othercountries in the same regionhavenotexpressedany interest,but thatalsomaybebecausenoeffortsweremadetoreachouttothem.

5.0 THEAFRICANREGION

Enquiring through the Regional Adviser for Immunization in the Africa Region, itappears thatnocountry inAfricahasexpressed interest in typhoidvaccinationonany significant scale except Kenya who has initiated a programme of vaccinatingfood handlers in schools. Although many countries have reported confirmed

19

outbreaksoftyphoidtherehasneverbeenanyseriousattempttodefinebetterthediseaseburdenoftyphoidinAfrica,atleasttillnow.

No serious efforts were made to follow up with countries on their interest intyphoidas itwasknownthatamulti‐countrysurveillancesystemwasbeingput inplacebytheInternationalVaccineInstitutewhich,inthenearfuture,willgeneratebetterdataontyphoidforAfrica.

The Division of Vaccines & Immunization, Ministry of Public Health & Sanitation,Kenya,hasbegunatyphoidvaccinationprogramtargetingfoodhandlersinboardingschools nationwide. There are 2,422 boarding schools in Kenya for primary‐agechildrenandineachinstitution,thereareestimated20staffhandlingfoodforthem.Intheinitialyear,theyplannedtocover967oftheseschoolsin61districtswithin7provinces. They have procured approximately 20,000 doses of Vi polysaccharidevaccineforthisprogramandplanningtocompletethevaccinationwithin2010.

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ANNEXIII

UPDATEONTHEDEVELOPMENTOFNEWTYPHOIDANDPARATYPHOIDVACCINES1

This Appendix was prepared by Professor Myron M. Levine of the Center for VaccineDevelopmentoftheUniversityofMarylandSchoolofMedicine,Baltimore,Maryland,withinputfrom Dr. LindaMartin and Dr. Allan Saul of the Novartis Vaccines Institute of Global Health,Siena,ItalyandDr.JohnD.ClemensoftheInternationalvaccineInstitute,Seoul,Korea.1.Impetustodevelopnewtyphoidandparatyphoidvaccines.Whereas parenteral Vi andoral Ty21a, the second generation typhoid vaccines, are verywelltoleratedandconferuponvaccinated subjectsamoderate levelofprotectionagainst typhoidfever, each nevertheless suffers from some drawbacks. For example, although Vi is able toprovidemoderateprotectionafteradministrationof justasingledose,givingadditionaldosesdoes not further boost the titers of serum IgG Vi antibody; rather Vi behaves like a T‐independent antigen that does not elicit immunologic memory. Consequently, protectionconferredbyVidoesnotextendbeyondthreeyears.[1]Withsomeotherpurifiedunconjugatedpolysaccharide vaccines, such as meningococcal C and A and polyvalent pneumococcalpolysaccharide vaccines, repetitive administration to subjects leads to B cell depletion andattainment of lower antibody levels than are seen following the initial administration of thepolysaccharide.[2‐4] Heretofore, there are insufficient data available to concludewhether ornotthishappenswithVi. The main drawback of Ty21a is the need to administer three spaced doses to achieve themoderate level of long‐lived protection that this vaccine can elicit. In many situations indeveloping countries, this requirement to administer three doses constitutes an impedimentthatmakesmass vaccinations, as in community or school‐based campaigns, logisticallymorecomplexthanmassvaccinationwithasingle‐dosevaccine.Fortunately, immunologic knowledge and advances in biotechnology have allowed a thirdgeneration of new typhoid vaccines to be prepared that overcome the drawbacks of Vi andTy21a.Thesenewvaccinesaredescribedbrieflybelow. Thenewvaccines includemuchmoreimmunogenicattenuatedstrainsthatserveassingle‐doseliveoralvaccines.Thenewvaccinesalso includeparenteral conjugate vaccines consistingofVi polysaccharide covalently linked todifferent carrier proteins. The new Vi‐based parenteral conjugate vaccines aim to stimulateimmunologicmemoryandtoelicitlonger‐livedantibodylevelsofhigheraffinityandavidityandtherebytoachieveahigherlevelofprotectionandsustainitlongerthanwithunconjugatedVi.Since Ty21a does not express Vi, it confers long‐term protection by immunologic responsesotherthanserumViantibody.TherearenolicensedvaccinestoprevententericfevercausedbyS.ParatyphiAorS.ParatyphiB. This is a notable gap in the public health armamentarium, since S. Paratyphi A carrying astableR factorplasmidencoding resistance tomultiple antibiotics is rapidly emerging inAsia.

1 Contributed by Professor M. Levine

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Thus,S.ParatyphiAisaprobleminendemicareas[5,6]likeSouthandSoutheastAsiaandalsoamongtravellers[7]fromindustrializedcountrieswhovisitendemiccountries.2.Newgenerationtyphoidandparatyphoidvaccinesunderdevelopment

2.1. Typhoidvaccines 2.1.1.Attenuatedstrainsassingle‐doseoralvaccines.SeveralnewstrainsofSalmonellaTyphi

havebeengenetically‐engineeredtocontainpreciseattenuatingmutations. AssummarizedinTable1,fouroftheseengineeredstrainshavebeensuccessfullytestedinPhaseIandIIclinicaltrialsandhavebeenshowntobewelltoleratedandimmunogenicafteringestionofjustasingleoraldose.ThesestrainswereallderivedfromvirulentwildtypeparentstrainTy2,whichisalsotheparentofTy21a.Theselivestrainsremainoralvaccinecandidatesthatcouldeventuallybebroughttolicensureifindustrialpartnerschosetomakethenecessaryinvestments.

Theliveoralvaccinecandidatesinclude:

• strainM01ZH09,withdeletionmutationsinaroCandssaV(acomponentofthetypeIIIsecretionsystemencodedbySalmonellapathogenicityisland‐2)[8‐10];

• strainTy800,deletedinphoP/phoQ[11];• strainCVD908‐htrA,withdeletionmutationsinaroC,aroDandhtrA[12,13];• strain CVD 909, a further derivative of CVD 908‐htrA that constitutively expresses Vi

capsularpolysaccharide.[14,15]

2.1.2. Parenteral Vi conjugate. BoosterdosesofpurifiedVidonot raiseantibody titersoverthoseelicitedbyasingledoseofvaccine;i.e.,immunologicmemorydoesnotoccur.Toremedythis, Vi polysaccharide has been conjugated to various carrier proteins. The first conjugatevaccine to undergo extensive clinical testing was a product in which Vi was linked torecombinantexotoxinAofPseudomonasaeruginosa inanattempttoconferT‐cell‐dependentpropertiesupontheViantigen,includingtheinductionofimmunologicmemory.Inchildrenandadults in endemic areas booster doses of Vi conjugate vaccine clearly increase the titers ofantibodyoverthoseelicitedbyaprimingdose.[16‐18]Arandomized,controlledfieldtrialofViconjugate in children immunized at ages 2‐4 years in the Mekong Delta of Vietnamdemonstrated91.5%(CI,77‐97%)vaccineefficacyover27monthsofactivesurveillance[17]and82% efficacy (CI, 22‐99%) during an additional 19months of follow‐up that utilized a passivesurveillancesystem.[18]Despite the highly impressive field results cited above, the Vi conjugate based on use ofrecombinantexotoxinAasacarrierdidnotprogress indevelopmentandwasnotadoptedbyanyvaccinemanufacturer. Accordingly, severalgroupshavedevelopedalternativeconjugatesthatutilizeothercarrierproteinstolinktoVi.Onesuchconjugate(PedaTyph®manufacturedbyBio‐MedP)thatutilizesVilinkedtotetanustoxoidisalreadylicensedinIndiaonthebasisofalimited amount of safety and immunogenicity data.[19,20] Another tetanus toxoid‐basedconjugateisbeingdevelopedbyBharatBiotech.ShantaBiotechandtheInternationalVaccineInstitute are developing a conjugate that utilizes diphtheria toxoid as the carrier protein,[21]while the Novartis Institute of Global Health has initiated clinical trials with a conjugateconsistingofVilinkedtoCRM197.[22]

22

2.1.3. Immuneresponsetothenewgenerationtyphoidvaccines2.1.3.1. Single‐dose live oral typhoid vaccine candidates. As discussed above, several liveattenuated S. Typhi strains have been developed using recombinant DNA technology. AmongthecandidatesthathavebeenevaluatedinPhaseIandIIclinicaltrialsareM01ZH09,[9,10,23,24]Ty800,[11]CVD908‐htrA,[12,13]andCVD909.[15]Oralimmunizationofadultvolunteerswiththesevaccinestrainselicitedgut‐derivedIgAASCandserumIgGandIgAantibodiestoS.TyphilipopolysaccharideOantigen.IntheclinicaltrialswithCVD908‐htrA,CMIresponseswerealsointensivelystudied.CVD908‐htrAelicitedrobustCMIresponsesincludingS.Typhi‐specificCD4+TcellswiththecapacitytoproduceTh1‐typecytokines(i.e.,IFN‐γandTNF‐αintheabsenceofinterleukin4[IL‐4]and[IL‐5]),aswellasCD8+cytotoxicTcellsthatkillS.Typhi‐infectedtargetcells.[25] Immunizationwith CVD 909 also elicited a wide array of CMI responses similar tothose induced by CVD 908‐htrA.[26] Further studies of these responses revealed that oralimmunization with attenuated S. Typhi strains elicits diverse S. Typhi‐specific IFN‐γ‐secretingCD4+andCD8+Tcentralmemory(TCM)andTEMsubsetsthatexpress,ornot,integrinα4/β7.Thus,thesecellsareabletomigratetothegut(iftheyexpressα4/β7)orsecondarylymphoidtissues(ifthey express integrin).[27] Taken together, these results provide strong evidence for thecontentionthatmemory/effectorBandTcells recirculate inhumans.However, thestudies tocharacterize these cells are only just beginning. Lymphoproliferative responses and IFN‐γproductionwerealsoobservedinsubjectsimmunizedwithM01HZ09.[10]In clinical studies conducted in the US and Vietnam, M01Z09 was well tolerated andimmunogenicinchildren5‐14yearsofage,aswellasinadults.[9,10,23,28]Collectively,theseresults illustrate the wide range of effector responses that can be elicited by a singleimmunizationwith thenewgenerationof attenuatedS. Typhi vaccine strains in different agegroups,allofwhicharebelievedtoplayimportantrolesinprotection.

2.1.3.2. Vi conjugate. Most of the serologic data that demonstrates the enhancedimmunogenicity of Vi conjugates over purified unconjugated Vi polysaccharide vaccine comefrompublicationsofclinical trialswiththeVi‐rEPAconjugate inaseriesofclinicalstudiesthatincludedadultsandlivingintheUSandinendemicareasandchildrenlivinginendemicareas.Children of school age and pre‐school age from endemic areas who received the Vi‐rEPAconjugatevaccinehadincreasedlevelsofViIgGantibodiescomparedwiththosewhoreceivedthe unconjugated Vi polysaccharide vaccine.[16,17] The immunogenicity of the Vi conjugatewas shown tobedosage‐dependent,withhigherdosesofVi‐rEPA inducinghigher levelsofViIgGantibodies.[29]Adoseof25µgofViasVi‐rEPAwasrecommendedforimmunizationof2‐5yearold children. Thisdose induced the strongest serum IgG responses from the threedosestested(5,12.5and25µg)andconferredprotectionforat least4‐years.[18] TheViantibodieselicitedbytheconjugatevaccinearelong‐lasting,reflectingthelong‐livedprotection.Atapoint42monthsafterchildren2‐5yearsofagehadbeenvaccinated, thegeometricmeanantibodylevelwas3.66EU(interquartilerange,2.2–5.8EU)comparedtoageometricmeanof0.80EUin childrenof the sameagewhohad receivedplacebo42monthsearlier (interquartile range,0.30 – 2.26 EU).[18] Preliminary data from ongoing long‐term follow up studies in adultssuggest Vi IgG antibody levelsmay remain elevated (> 7‐fold over baseline) for as long as 10yearsaftervaccination.

ItisexpectedthatserologicalresponsedatawillbeavailablesoonfromclinicaltrialswithotherViconjugatevaccinesthatutilizecarrierproteinsotherthanrEPA.

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2.1.3.3. Vi polysaccharide entrapped in a cross linked protein matrix. One biotechnologycompanyispreparingforPhaseIclinicaltrialsaparenteraltyphoidvaccinethatconsistsoflargeaggregates of a matrix of CRM197 mutant diphtheria toxin protein chemically cross linked byglutaraldehyde with Vi polysaccharide embedded within the matrix. Although there is noevidence that the Vi is covalently linked to the protein (but is rather simply physicallyentrapped), inpre‐clinicalstudiestheresultantVi‐proteinmatrixappearstoelicit immunologicmemory like a Vi conjugate vaccine. These polysaccharide/protein matrix aggregates areselectivelysizedtoincludelargermoietiesthatexceedinsizethediameterofvirus‐likeparticles.

2.2.0 ParatyphoidAvaccines2.2.1 LiveoralvaccinecandidatesHeretofore, only one live oral S. Paratyphi A vaccine candidate, CVD 1902, is known to be inclinicaltrials(Table3).CVD1902,whichharborsindependentlyattenuatingdeletionmutationsinguaBAandclpXiscurrentlycompletingadose‐escalatingPhaseIclinicaltrialinwhichgroupsof subjects ingest 106, 107, 108 or 109 colony forming units, or placebo to assess the safety,preliminaryimmunogenicity,excretionpatternandtransmissibilityofthelivevaccine.

OtherS.ParatyphiA livevaccinestrainshavebeenevaluated inpre‐clinical studies inanimalsbuthavenotenteredclinicaltrialsinhumans.[30]2.2.2.ParatyphiAconjugatevaccinecandidatesSeveralpublicsectorresearchgroupsandcompaniesthatareworkingonViconjugatevaccinesagainsttyphoidfeverhaveannouncedtheirintentiontodevelopcompanionconjugatevaccinestopreventdiseasecausedbyS.ParatyphiA.Thegoalwillbeabivalentvaccinetopreventthetwomaincausesofentericfever.IneachinstancethesamecarrierproteinasisusedintheViconjugate will be used to link the O polysaccharide of S. Paratyphi A (Table 4). Heretofore,results of only one set of clinical trialswith two prototype S. Paratyphi A conjugates utilizingtetanustoxoidasthecarrierproteinhavebeenreported.[31]

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Table1.Single‐doseliveoraltyphoidvaccinesunderdevelopment

Vaccinestrain Mutatedgenes Phaseofdevelopment Developers

M01HZ09 aroC,ssaV PhaseII Emergent

Ty800 phoP/phoQ PhaseII Celldex

CVD908‐htrA aroC,aroD,htrA PhaseII CenterforVaccineDevelopment,UniversityofMaryland(previouslyinconjunctionwithMedeva)

CVD909 aroC,aroD,htrA.Ptac‐tviA PhaseII CenterforVaccineDevelopment,UniversityofMaryland

Table2.ParenteralViconjugatevaccinesandaVipolysaccharideproteinmatrixvaccineunderdevelopment

CarrierproteintowhichViislinked(orcross‐linked)

Developers Phaseofdevelopment

Tetanustoxoid(PedaTyph®)

BioMed(P) LicensedinIndia

CRM197 NovartisVaccinesInstituteofGlobalHealth

PhaseI

Tetanustoxoid BharatBiotech ?

Diphtheriatoxoid ShantaBiotechandtheInternationalVaccineInstitute

Pre‐clinical(PhaseIplanned,Q22011)

PseudomonasaeruginosarecombinantexotoxinA

U.S.NIH PhaseIII

CRM197matrixinwhichViisentrappedratherthancovalentlylinked

Matrivax PhaseIplannedforQ42011

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Table3.LiveoralparatyphoidAvaccinesinclinicaltrials

Vaccinestrain Mutatedgenes Phaseofdevelopment

CVD1902 guaBA,clpX PhaseI

Table4.ParatyphoidAconjugatevaccinesthatareinclinicaltrialsorarebeingpreparedforclinicaltrials

CarrierproteinlinkedtoS.ParatyphiAOpolysaccharide

Developer Phaseofdevelopment

Tetanustoxoid USNIH PhaseI

CRM197 NovartisVaccinesInstituteofGlobalHealth

Pre‐clinical

Tetanustoxoid BharatBiotech ?

Diphtheriatoxoid InternationalVaccineInstitute

Pre‐clinical(PhaseIplanned,Q22011)