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ContentsI. Introduction ............................................................................................................................. 441

II. General principles for the immunization of PLHIV ........................................................... 442

III. Use of vaccines and immunoglobulins ................................................................................ 443 1. Liveattenuatedvaccines.................................................................................................. 443 1.1. BCGvaccine........................................................................................................... 443 1.2. Choleravaccine(CVD103-HgR)........................................................................... 444 1.3. Measles,mumpsandrubellavaccines................................................................... 444 1.4. Oralpoliovirusvaccine........................................................................................... 445 1.5. Rotavirusvaccine.................................................................................................... 445 1.6. Typhoid(Ty21a)vaccine......................................................................................... 445 1.7. Varicellavaccine..................................................................................................... 445 1.8. Yellowfevervaccine............................................................................................... 446 2. Killedorinactivatedvaccines.......................................................................................... 446 2.1. Choleravaccine(WC/rBs)...................................................................................... 446 2.2. Diphtheria,tetanusandpertussisvaccines............................................................. 447 2.3. Haemophilus influenzaetypebvaccine.................................................................. 447 2.4. HepatitisAvaccine.................................................................................................. 447 2.5. HepatitisBvaccine................................................................................................. 448 2.5.1. RecommendedscheduleforhepatitisBvaccinationinpatientsinfected withHIV...................................................................................................... 449 2.5.2. ResponsetohepatitisBvaccination............................................................ 449 2.5.3. RecommendedmonitoringofHIV-infectedpatients

afterHBVvaccination................................................................................. 449 2.6. Influenzavaccine..................................................................................................... 450 2.7. Meningococcalvaccine........................................................................................... 450 2.8. Pneumococcalvaccine............................................................................................ 450 2.8.1. Pneumococcalpolysaccharidevaccine........................................................ 450 2.8.2. Pneumococcalconjugatevaccine................................................................ 451 2.9. Inactivatedpoliovirusvaccine................................................................................ 451 2.10.Rabiesvaccine......................................................................................................... 452 2.11.Tick-borneencephalitisvaccine.............................................................................. 452 2.12.Typhoidvaccine(Vipolysaccharide)...................................................................... 453 2.13.Otherkilledantigens............................................................................................... 453 3. Useofimmunoglobulins.................................................................................................. 454 3.1. HepatitisBimmunoglobulin................................................................................... 454 3.2. Humannormalimmunoglobulin............................................................................. 454 3.2.1. HepatitisA.................................................................................................... 454 3.2.2. Measles........................................................................................................ 455 3.3. Humanrabiesimmunoglobulin............................................................................... 455 3.4. Tetanusimmunoglobulin......................................................................................... 455 3.5. Varicella-zosterimmunoglobulin............................................................................ 456

Annex 1. Summary of immunization recommendations for people immunocompromised due to HIV/AIDS .................................................................................. 457

Annex 2. WHO classification of HIV-associated immunodeficiency in infants and children ................................................................................................................ 458

Annex 3. Rabies vaccines ............................................................................................................ 459

Annex 4. Glossary ....................................................................................................................... 460

References .................................................................................................................................... 463

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ImmunIzatIon of PeoPle lIvIng wIth hIv and PeoPle at RIsk of hIv InfectIon

I. Introduction

ThisprotocolisbasedontheglobalWHOrecommendationsforvaccinatingpeoplewhoareHIV-infected.Atthesametime,itreflectstheepidemiologicalsituationandimmunizationprogrammeprioritiesoftheWHOEuropeanRegion.Thisprotocoldivertsfromglobalrecommendationsre-garding the use of bacille Calmette-Guérin (BCG) vaccine, oral poliovirus vaccine (OPV) andmeasles-containingvaccines (MCVs) includingmeasles,mumpsand rubella (MMR)vaccine. Italsoprovidesadditionalrecommendationsonthevaccinesandimmunoglobulinsusedoutsidetheroutinenationalimmunizationprogrammes.

ThisprotocolisdesignedprimarilyforHIV/AIDSclinicians.Itisrecommendedasabasisforde-velopingnationalrecommendationsthattakeintoaccountlocalepidemiologicalsituations.

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hIv/aIds tReatment and caRe clInIcal PRotocols foR the who euRoPean RegIon

II.GeneralprinciplesfortheimmunizationofPLHIV

AsHIVinfectionresultsinaprogressivedeteriorationoftheimmunesystem,therehasbeencon-cernthatsomevaccinescouldresultinsevereadverseeventsinHIV-infectedindividuals.

Sincenoimmunobiologicalproductiscompletelysafe,generalrecommendationsforvaccinatinginfants,childrenandadultsarebasedon:• thecharacteristicsofimmunobiologicalproducts• scientificknowledgeoftheprinciplesofactiveandpassiveimmunization• theepidemiologyofinfection• theriskandbenefitsofachievingoptimalprotectionagainstinfectiousdisease.

Untilfurtherresearchcanclearlydefinetherisksandbenefits,administrationofcertainvaccinestopeoplelivingwithHIV(PLHIV)shouldberestrictedoradministeredwithcautionafterathoroughriskassessmentbyexpertsinclinicalandpreventivemedicine.

Thetermsvaccinationandimmunizationareoftenusedinterchangeably.Vaccinationdenotesthephysicalactofadministeringanimmunobiologicalproduct(avaccineortoxoid)toapersonandrefers toactive immunization.“Immunization” isamore inclusive termdenoting theprocessofinducingorprovidingimmunityartificially,anditcanbeactiveorpassive.

GeneralprinciplesforvaccinationofPLHIVareasfollows.• Killedorinactivatedvaccinesdonotrepresentadangertoimmunocompromisedpeopleand

generallyshouldbeadministeredasrecommendedforotherpeople.• Live-virusor live-bacteriavaccinessuchasBCG,oralpoliovirus, typhoid(Ty21a),varicella

andyellowfevervaccinesmayposearisktoHIV-infectedpeople,whoshouldnotbegiventhemwithoutcarefulconsiderationoftherisksandbenefits,giventheirindividualstageofHIVdiseaseandlevelofimmunesuppression.

Forfurtherinformation,pleaserefertosectionIIIbelowforvaccine-specificconsiderationsandtoAnnex1forasummaryofrecommendations.

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1BCGvaccine;diphtheria,tetanusandpertussis(DTP)vaccine;OPV;MMRvaccine;hepatitisBvaccine;andHiBvaccine.2ItshouldbenotedthatthesafetyinformationonadministrationofcertainvaccinestoPLHIVislimited,andthatcountriesareencouragedtoreportanyencounteredadverseeventsfollowingimmunization(AEFIs)totheirpharmacovigillanceorAEFIsurveillancesystems,keepinginmindthatsomeAEFIsmayoccurwithlargelatencyinPLHIV.3Forclinicalstaging,refertoProtocol1,Patient evaluation and antiretrovital treatment for adults and adolescents,Annex2,andProtocol11,Paediatric HIV/AIDS treatment and care,Annex1.

III.Useofvaccinesandimmunoglobulins

Generalaspectsofimmunogenicityofvaccinesshouldbetakenintoconsiderationwhenimmuniz-ingPLHIVagainstvaccine-preventablediseases.• Althoughthecapacity tomountbothcellularandhumoral immuneresponsestartsdeclining

afterbirthinHIV-infectedneonates,mostchildrenstillhaveanimmuneresponsecapacitydur-ingthefirsttwoyearsoflife.Studiesoftheimmunogenicityofimmunizationprogrammeswithrecommendedvaccines1haveshownsatisfactoryseroconversionratesintheearlystagesofHIVinfection.Eachvaccinehasitsownseroconversionrate,someofwhichcanbefoundinthissec-tion.However,theproportionofrespondersdecreaseswithprogressionfromHIVinfectiontoAIDS(1).

• SymptomaticHIV-infectedchildrenandadultshavesuboptimalimmunologicresponsestovac-cines (1–5).The response toboth liveandkilledantigensmaydecreaseas theHIVdiseaseprogresses(1).However,theresponsetohigherdosesofvaccineandthepersistenceofantibod-iesinHIV-infectedpatientshavenotbeensystematicallyevaluated.Althoughhigherdosesormorefrequentboostersmaybeconsideredforsuchpatients,firmrecommendationscannotbemadeatthispoint.

Specificconsiderationsfor thesafety2andefficacyof individualvaccinesand immunoglobulinsincludetheepidemiologyoftheparticulardiseaseandthepatient’slevelofimmunosuppression.

Thedegreetowhichapatientisimmunocompromisedshouldbedeterminedbyaphysician,usingtheWHOclinicalstagingsystem3and/orage-specificCD4countsandpercentages(seeAnnex2).

1. Live attenuated vaccines

1.1. BCG vaccineBCGvaccineprotectschildrenyoungerthan2againstdisseminatedandseveretuberculosis(TB),includingTBmeningitisandmiliaryTB.BCGhaslittleornoeffectinreducingthenumberofadultcasesofpulmonarytuberculosis.

ItisnotknownifHIVinfectionreducestheprotectionconferredbyBCGinchildren.ThereissomeevidencethatconversiontoapositivetuberculintestafterBCGis lessfrequent inHIV-infectedchildren(6),butthesignificanceofthisfindingisnotclear.Therehavebeencasereportsoflocalcomplications anddisseminatedBCG infection, evenyears after vaccinatingHIV-infected chil-dren.However,prospectivestudiescomparingBCGimmunizationinHIV-infectedanduninfectedinfantshaveshownnodifferenceinriskforcomplications(6).ThereneedstobeclosermonitoringforadverseeventsinareasofhighHIVprevalence,withspecificeffortstodistinguishBCGinfec-tionfromTB(7).

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UntilfurtherresearchcanclearlydefinetherisksandbenefitsofBCGvaccination,itshouldbere-strictedtoasymptomaticchildren(duetoitspotentialtocausedisseminateddisease)whoareathighriskoftuberculosisinfection(8, 9),whichinturndependonthelocalprevalenceofTB.4Wheretheriskishigh,thepossiblebenefitsofBCGimmunizationoutweighthepossibledisadvantages.

1.1.1. Recommendations

• WhereTBincidenceislow,5BCGshouldnotbeadministeredtoHIV-infectedchildren,regard-lessoftheirclinicalstageorimmunodeficientstatus.Inallotherareas,BCGvaccinationshouldberestrictedtoHIV-positivechildrenwhoareasymptomatic.ChildrenwithsymptomsofHIVinfectionshouldnotreceiveBCGvaccine.

• BCGisnotrecommendedforadolescentsandadults,includingthosewithHIVinfection,be-causeithaslittleornoeffectinreducingthenumberofadultcasesofpulmonarytuberculosis(6).

• TBpreventivetherapyshouldbestronglyrecommendedforPLHIVthoughttobeinfectedwithMycobacterium tuberculosisandatriskofdevelopingTB(forfurtherinformation,pleaserefertoProtocol4,Management of tuberculosis and HIV coinfection).

1.2. Cholera vaccine (CVD 103-HgR)


• Live,attenuatedoralcholeravaccine(usingCVD103-HgRstrain)iscontraindicatedinHIV-infectedpeopleduetoinsufficientsafetydata(11).

• ThekilledWC/rBscholeravaccineistherecommendedvaccineforHIV-infectedpeople(seesectionIII.2.1.belowforcholeravaccineWC/rBs).

1.3. Measles, mumps and rubella vaccines (MMR, MR, M and R vaccines6)HIV-infected asymptomatic children or children with signs of mild immunosuppression shouldroutinelyreceiveMMRandothermeasles-containingvaccines(MCVs), thesameasnon-infect-edchildren.Itisimportanttorememberthatimmunogenicityofmeaslesvaccineisdecreasedifthevaccineisadministeredinaperiodlessthansixmonthsafterhumannormalimmunoglobulin(HNIg)administration.

Although studies amongbothasymptomatic and symptomaticHIV-infectedpatients immunizedwithMMRvaccineandotherMCVshavenotdocumentedanyseriousorunusualadverseevents(1),theyarenotrecommendedforPLHIVwithevidenceofsevereimmunosuppression.Thelackofarecommendationisprimarilydueto:• areportofapneumoniacasefollowingmeaslesvaccineinanindividualwithsevereHIV-re-

latedimmunosuppression(12);• other evidence indicatingadiminishedantibody response tomeaslesvaccinationamong se-

verelyimmunocompromisedpeople(13);and• evidencelinkingmeaslesvaccineviralinfectiontosubsequentdeathinatleastsixseverelyim-

munocompromisedpeople(14).


• MMRandotherMCVsshouldnotbeadministeredtoPLHIV,eitherchildrenoradults,whoshowevidenceofsevere immunosuppression.Severe immunosuppressionisdefinedasCD4<200 cells/mm3 in adults and children ≥5 years, for severe immunosuppression in childrenyoungerthan5years,seeAnnex2(15–17).

4ItshouldbenotedthatevenamongcountrieswithagenerallylowprevalenceofTB,theremaybehighprevalenceingivensubpopulations,makingasubnationalpolicydesirable.5CountriesintheWHOEuropeanRegionwithacrudenotificationrateof<20per100000populationaredefinedaslow-incidence(10).6MMR:measles,mumpsandrubella;MR:measlesandrubella;M:measles;R:rubella.

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• MMRandotherMCVsshouldbeconsideredforHIV-infectedpatientswhoareasymptomaticormildlyimmunosuppressed,aspertheroutinenationalschedule.

• For infantswithhighriskofexposure tomeaslesvirus,anadditionaldoseofsingle-antigenmeaslesvaccineadministeredat6–11monthsofageisrecommended,followedbyafirstdoseofroutineMMRoranothermeasles-containingvaccine(MCV)atage12monthsorolder(withaminimumintervalof1monthbetweendoses).

• HIV-infectedsymptomaticpatientswhoareexposedtomeaslesshouldreceiveHNIgregardlessoftheirpriorvaccinationstatus(seesectionIII.3.2.1belowforfurtherinformationonHNIg).

• Healthysusceptibleclosecontactsofimmunocompromisedpeople(includingPLHIV)shouldalsobevaccinated.

1.4. Oral poliovirus vaccine (OPV)AlthoughasymptomaticHIV-infectedchildrenmaybevaccinatedwithOPV(1, 18),datashowthatadministrationofOPVtochildrenwithcongenitalimmunodeficiencycanresultinsevere,progres-siveneurologicalinvolvement(paralyticdisease)(19–22).Therefore, inactivatedpoliovirusvac-cine(IPV)isrecommendedforbothsymptomaticandasymptomaticchildren(seesectionIII.2.9belowforIPV).

Inaddition,personsimmunizedwithOPVcanshedvaccinevirusintotheirenvironmentforuptoonemonth,consequently,HIV-positiveindividualsshouldhavelimitedcontactwithpersonsvac-cinatedwithOPV.IfOPVisinadvertentlyadministeredtoahouseholdmemberorotherclosecon-tact7ofanHIV-infectedindividual,regardlessofpriorimmunizationstatus,closecontactbetweenthemshouldbeavoidedforonemonthpost-vaccination.

1.4.1. Recommendation

• OPVshouldnotbeadministeredtoPLHIV,eitherchildrenoradults,regardlessoftheirimmu-nodeficiencystatus,ortomembersoftheirhouseholdorotherclosecontacts.

1.5. Rotavirus vaccine1.5.1. Recommendation

• RotavirusvaccineshouldnotbeadministeredtochildreninfectedwithHIVregardlessoftheirimmunodeficiency status, untilmore scientific evidence can clarify the safety and immuno-genicityprofileinHIV-infectedchildren.

1.6. Typhoid (Ty21a) vaccineWhileliveattenuatedtyphoidvaccine(usingtheTy21astrain)canbeadministeredtoHIV-infectedasymptomaticindividualswithoutriskaslongastheCD4cellcount>200cells/mm3,parenteralinactivatedvaccineistheoreticallyasaferalternative(23).


• Ty21avaccineshouldnotbeadministered toPLHIV,eitherchildrenoradults, regardlessoftheirimmunodeficiencystatus.

1.7. Varicella vaccineAlthougharecentsmallstudyindicatednoseriousadverseeventsfor10HIV-infectedchildren(24),peoplewithmoderateorseverecellularimmunodeficiencyresultingfromHIV,includingthosedi-agnosedwithAIDS,shouldnotreceivevaricellavaccine.However,childrenwithasymptomaticormildlysymptomaticHIVinfectionandaCD4cellcount≥25%shouldreceivethevaccineat12–15monthsofageorlater,withaseconddose4–8weeksafterthefirst.VaricellavaccineshouldnotbeadministeredtoHIV-infectedchildrenwithCD4cellcount<25%becauseofthepotentialdis-seminationofviralinfection(23).

7DefinedassomeonewhoriskstransmittinglivepoliomyelitisvaccinevirustoanHIV-infectedpersonthroughfaecalororalcontact.

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HIV-infectedchildrenandadultswhoaresusceptibletovaricella-zostervirus(VZV)–includingthosewhohavenohistoryofchickenpox(primaryvaricella infection), thosewhohaveshingles(recurrentinfection)andthosewhoareseronegative–shouldavoidexposuretopeoplewithchick-enpoxorshingles.

Susceptiblehouseholdcontacts(especiallychildren)ofPLHIVshouldbevaccinatedwithvaricellavaccineiftheyhavenohistoryofchickenpoxandareseronegativeforHIV,sothattheywillnottransmitthevirustotheirHIV-infectedcontactsthatmaybesusceptibletoVZV(14).

1.7.1 Recommendations

• VaricellavaccineshouldnotbeadministeredtoHIV-infectedadults,regardlessoftheirimmu-nodeficiencystatus,ortoHIV-infectedchildrenwithmoderateorsevereimmunosuppression.

• VaricellavaccinationshouldberestrictedtochildrenwithasymptomaticormildlysymptomaticHIVinfection(CD4levels≥25%).

• SusceptiblehouseholdcontactsofPLHIVshouldbevaccinatedtopreventpossibletransmissionofVZV.

1.8. Yellow fever vaccineYellow fevervaccinevirusposes a theoretical riskof encephalitis toHIV-infectedpeople,whoshouldthusnotbegivenit.Yellowfever isendemicto33countries inequatorialAfricaand11countriesinSouthAmerica.Iftraveltosuchanareaisnecessary,patientsshouldbeadvisedontherisks,instructedinmethodsofavoidingmosquitoesandsuppliedwithvaccinationwaiverlettersbytheirphysicians.Sometravelclinicsmaydecidewhetherornottoadministerthevaccineonthebasisofaperson’sCD4cellcount.

PeoplewhoareknowntobeHIV-infectedandwhocannotavoidpotentialexposuretoyellowfevervirusshouldbeofferedthechoiceofvaccination.Vaccineesshouldbemonitoredforpossiblead-versereactions.SincevaccinationmaybelesseffectiveforHIV-positivepeoplethanforHIV-nega-tivepeople,measuringneutralizingantibodyresponsesbefore travelmaybeconsidered.Familymembersofimmunosuppressedpeoplemayalsobevaccinatedagainstyellowfeveriftherearenocontraindications(25).

1.8.1 Recommendation

• YellowfevervaccineshouldnotbeadministeredtopeopleinfectedwithHIV,eitherchildrenoradults,regardlessoftheirimmunodeficiencystatus,unlessbenefitsexceedrisks.

2. Killed or inactivated vaccinesKilledorinactivatedvaccinesdonotpresentadangertoimmunocompromisedpeopleandgeneral-lyshouldbeadministeredasrecommendedforotherpeople(17).Frequently,theimmuneresponseofimmunocompromisedpeopletokilledandinactivatedvaccineantigensisnotasgoodasthatofimmunocompetentpeople;higherdosesormorefrequentboostersmayberequired,althoughevenwiththesemodifications,theimmuneresponsemaybelessthanoptimal.

2.1. Cholera vaccine (WC/rBs)Avaccineconsistingofkilledwhole-cellVibrio choleraeO1combinationwitharecombinantB-subunitofcholeratoxin(WC/rBs)hasbeenshowntobesafeeveninpregnancyandduringbreast-feeding,andwelltoleratedbyHIV-positiveindividuals.

Givenorallyaccordingtoatwo-doseschedule,10–14daysapartinducesinitialprotectionin86%ofthevaccinees.Onaverage,thevaccineconfers50–60%protectionforatleast3years.TherehavebeennospecificreportsofWC/rBsvaccineefficacyinHIV-positiveindividualspub-lishedtodatebutarecentstudyconducted inMozambiquedemonstratedpromisingresults ina

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populationinwhichapproximately25%wereHIV-positive.DurationofimmunityisunknowninHIV-infectedpeople.HIV-infectedadultswithCD4counts<100cells/mm3maybeexpected torespondpoorlytoimmunization,whereasthosewithCD4counts>100cells/mm3showimprovedresponsesafter twodoses (26).Theseobservations indicateapotentialbenefitofvaccination inthosewithearlyandmoderatelyadvancedclinicalHIVdisease(27).


• VaccinationshouldbeconsideredforselectedHIV-infectedpeopleiftheyareduetotraveltohighlyendemicareas,fallinoneoftheriskgroups(long-termtravellersandforthosewhodrinkuntreatedwater,eatpoorlycookedorrawseafood,orliveinunsanitaryconditionsindisease-endemicareas).

• Owingtoitslowefficacyandshortdurationofprotection,useofoldparenteralvaccine(basedoninactivatedphenol-killedwhole-cellV.choleraeO1)isnotrecommended,althoughthisvac-cineisstillproducedinsomecountries(28).

2.2. Diphtheria, tetanus and pertussis vaccines (DTP, DTaP, DT, TT and Td8)


• ForchildreninfectedwithHIV,irrespectiveoftheirimmunestatus,DTP(andDT)vaccineisindicatedonthesamescheduleanddosageasfornon-HIV-infectedchildren,includingtheuseoftheacellularpertussisform(DTaP)forboostersortheprimaryseries.

• TTandTdvaccinescanbeadministeredtoHIV-infectedadultsirrespectiveoftheirimmunestatus,usingthesamescheduleanddoseasfornon-HIV-infectedadults(25).

• SpecialattentionshouldbepaidtovaccinatingIDUswithTTorTdtopreventtetanuswheretherearenoneedleorsyringeexchangeprogrammes.

2.3. Haemophilus influenzae type b (HiB) vaccine Ingeneral,childrenolderthan2yearsdonotneedHiBvaccination,duetoage-dependentsuscepti-bilitytothedisease(11).Insomepeopletheorganismcausesaninvasiveinfection.Theexactmodeofinvadingthebloodstreamisunknown,butpreviousviralormycoplasmalinfectionoftheupperrespiratorytractmaybeacontributingfactor.Thebacteriaspreadviathebloodstreamtodistantsitesinthebody,themeningesinparticular.HIV-infectedchildrenandadultsareatincreasedriskforinvasiveHiBdiseaseduetoimmunosuppressionandshouldthereforebevaccinated.

Individualpatientriskforthediseaseandbenefitsfromvaccinationshouldbeconsideredbeforedecidingwhethertovaccinate.Insomesettings,theincidenceofHiBdiseasemaybehigheramongHIV-infectedadultsthannon-HIV-infectedadults(29, 30).


• PreviouslyunvaccinatedHIV-infectedindividualsolderthan2yearswhoareatriskforinvasiveHiBshouldbegivenatleastonedoseofvaccine.

• Immunocompromisedchildrenshouldbevaccinatedwiththesamedosageandscheduleasim-munocompetentchildren.

2.4. Hepatitis A vaccineTheriskofdevelopingsymptomaticillnessfollowinghepatitisAvirus(HAV)infectionisdirectlycorrelatedtoage.Inchildrenyoungerthan6,HAVinfectionisusuallyasymptomatic,whilesymp-tomaticdiseaseoccursmorecommonlyamongadults. InfectionwithHAVinduces lifelong im-munity. In areasof lowendemicity, hepatitisAusuallyoccurs as single cases amongpeople in

8DTP:diphtheriaandtetanustoxoidsandpertussisvaccine;DTaP:diphtheriaandtetanustoxoidsandacellularpertussisvac-cine;DT:diphtheriaandtetanustoxoids(forpaediatricuse);TT:tetanustoxoid;Td:tetanusanddiphtheriatoxoids(foradultuse).

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high-riskgroupsorasoutbreaksinvolvingasmallnumberofpeople.Inareasofhighendemicity,mostpeopleareinfectedwithHAVwithoutsymptomsduringchildhood.Incountriesofloworin-termediateendemicity,adultdiseaseisseenmoreoften,andhepatitisAmayrepresentasubstantialmedicalandeconomicburden.

HepatitisAvaccineishighlyimmunogenic.Morethan95%ofadultswilldevelopprotectivean-tibodieswithinfourweeksofasingledose.Amongchildrenandadolescents,morethan97%willbeseropositivewithinamonthofthefirstdose.Inclinicaltrials,allrecipientshadprotectivelevelsofantibodiesaftertwodoses.Therefore,post-vaccinationtestingisnotindicated.TestingmethodssufficientlysensitivetodetectlowHAVantibodyconcentrationsaftervaccinationarenotapprovedforroutinediagnosticuse(14).

Dataconcerningthelong-termpersistenceofantibodyandofimmunememoryarelimitedbecausethecurrentlyavailablevaccineshavebeenunderevaluationforlessthan12years.Theneedforboosterdoseswillbedeterminedbyfuturesurveillancestudies(31).


HepatitisAvaccination(onedosewithabooster6–12monthslater)isstronglyrecommendedforpeopleatriskforHAVinfectionoritscomplications,irrespectiveoftheirHIVorimmunestatus.Riskgroupsinclude:• peoplewithchronicliverdisease;9

• menwhohavesexwithmen(MSM);• drugusers;10

• peoplewithclotting-factordisorders;• peoplewithoccupationalriskofinfection(e.g.somelaboratoryworkers);and• people≥1yearoldfromnon-endemiccountrieswhoare travellingtocountrieswithhighor

intermediateriskofHAVinfection.11

2.5. Hepatitis B vaccineWhile therearenodataregardingHIV-infectedchildrenand thedurationofprotectionaffordedbyHBVvaccine,availabledataforuninfectedchildrenshowthatvaccine-inducedantibodylevelsdeclinewithtime(14).Nevertheless,immunememoryremainsintactformorethan15yearsfol-lowingimmunizationinbothadultsandchildren.Adultsandchildrenwithnormalimmunestatusdonotrequireboosterdoses,norisroutineserologicaltestingindicated,exceptforchildrenofhepa-titisBsurfaceantigen(HBsAg)-positivemothers,whoshouldbetestedforHBsAgandhepatitisBsurfaceantibody(HBsAb)afterthethirddose.Ifthesurfaceantibodylevelis<10mIU/ml,theentirethree-vaccineseriesshouldberepeated.TestingforHBVcoreantibodiesinthesechildrenisdiscouragedbecausepassivelyacquiredmaternalantibodiesmaybedetectableupto24monthsofage.Theneedforboosterdosesafterlongerintervalswillcontinuetobeassessedasadditionalinformationbecomesavailable.12

9SusceptiblepeoplewithchronicliverdiseaseareatincreasedriskoffulminanthepatitisAshouldtheybecomeinfected.HIV-infectedpeoplewithevidenceofchronichepatitisCorhepatitisBdiseaseshouldbevaccinatedwithhepatitisAvaccine(14).10HAVispresentinthebloodattheonsetoftheillnessandhasonrareoccasionsbeentransmittedbytransfusion;thevirusismoreeasilyspreadinareasofpoorsanitationorpersonalhygiene,conditionscommonamongdrugusers(14, 23, 32).11Vaccinate2–4weeksbeforedeparture.AreasofhighorintermediateriskincludeallareasoftheworldexceptCanada,theUnitedStates,westernEuropeandScandinavia,Japan,NewZealandandAustralia(33).12Onlyforhaemodialysispatientsshouldtheneedforboosterdosesbeassessedbyannualtestingforantibodylevels;boosterdosesshouldbeprovidedwhenantibodylevelsgobelow10mIU/ml.

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• HepatitisBvaccinationisrecommendedforadultsatincreasedriskforhepatitisBvirus(HBV)infection,irrespectiveoftheirHIVorimmunestatus,including:

o MSM; o heterosexualswithmultiplepartners, o sexuallytransmittedinfection(STI)patients; o sexworkers; o sexualpartnersandhouseholdcontactsofHBVcarriers; o IDUs; o prisoninmates,bothmaleandfemale; o peopleonhaemodialysis (although thehepatitisBvaccine is lesseffective in them, it is

recommendedforallsusceptiblehaemodialysispatients);and o healthcareworkers.13

• HepatitisBvaccinationisrecommendedforallinfantsatbirthandallchildrentoage18,irre-spectiveoftheirHIVorimmunestatus.Variousschedulesincludeorexcludeneonates,butallhavethesameeffectiveness.

2.5.1.1. Recommended schedule for hepatitis B vaccination in patients infected with HIV

HIV-infectedpatientslackingHBVinfectionmarkersorHBsAgnegativemarkersshouldbevac-cinated.• HepatitisBvaccinationshouldstartwiththeconventionaldose(20µgatMonths0,1,2and12

orMonths0,1and6)forpatientswithCD4count>500cells/mm3.• PaediatricdosageofhepatitisBvaccineis10µg.• InpatientswithCD4count200–500cells/mm3,anintensivescheduleisrecommended(20µg

atMonths0,1,2and12)(34).• Patientswhodonotrespondtothefirstcycleshouldreceiveboosterdosesoranewvaccination

cyclewith40µg.• PatientswithCD4counts<200cells/mm3whoarenotonantiretroviraltreatment(ART)should

firstreceiveART.Vaccinationshouldbedeferreduntilaclinicallysignificantimmunereconsti-tutionhasbeenachieved,preferentiallyaftertheCD4cellcounthasincreased>200cells/mm3.

2.5.1.2. Response to hepatitis B vaccination

• TheresponsetothevaccineisdependentontheCD4countatthetimeofvaccination,andmaybereducedinpatientswithaCD4count<500cells/mm3.

• AfterthehepatitisBvaccinationschedulehasbeencompleted,theresponserateis87%inHIV-positivepatientswithCD4count>500cells/mm3,andonly33%inpatientswithCD4count200–500cells/mm3(35).

• HepatitisCvirus(HCV)/HIVcoinfectionmaybeassociatedwithimpairedresponsestohepa-titisBvaccine,withfewerHBsAbtitresafterthethirdvaccinationthaninHIVmonoinfection.

2.5.1.3. Recommended monitoring of HIV-infected patients after HBV vaccination

• HBsAbtitreshouldbemonitoredfourweeksaftertheendoftheHBVvaccinationschedule,andboostervaccinationorrevaccination(1–3additionaldoses)shouldbeconsideredforpatientswhodonotdevelopprotectiveantibodies(HBsAb<10mIU/ml).However,theimmunogenicityofhigherdosesofvaccineisunknown,andfirmrecommendationsondosagecannotbemadeatthistime(15).

• Peoplewhofail toseroconvertaftervaccinationandremainatriskofHBVinfectionshouldbeannuallymonitoredforserologicalmarkersofHBV(HBsAgandHBcAb(hepatitisBcoreantibody)).

13Riskisoftenhighestduringtrainingperiods;therefore,itisrecommendedthatvaccinationbecompletedduringtraininginschoolsofmedicine,dentistry,nursing,laboratorytechnologyandotheralliedhealthprofessions(14).

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• PeoplewhofailtodevelopdetectableHBsAbaftersixdosesshouldbetestedforHBsAg.• PeoplewhoarefoundtobeHBsAg-positiveshouldbecounselledaccordingly.• Vaccinenon-responderswhoareHBsAg-negative shouldbe considered susceptible toHBV

infectionandshouldbecounselledregardingprecautionstopreventitandtheneedtoobtainhepatitisBimmunoglobulin(HBIg)prophylaxisforanylikelyparenteralorsexualexposuretoHBsAg-positiveblood.

2.6. Influenza vaccine14

Influenzamayresultinseriousillnessandcomplicationsforpeoplewhoareimmunocompromised.Vaccinationcanresultinprotectiveantibodylevelsinmanyimmunocompromisedrecipients(36).


• AlthoughthereiscurrentlylittleinformationregardingthefrequencyandseverityofinfluenzainPLHIV(37),vaccinationisrecommendedforallPLHIVbeforetheannualinfluenzaseason.

• TheantibodyresponsetovaccinemaybelowinpeoplewithadvancedHIVdisease;however,ithasnotbeenshownthataboosterdoseimprovestheirimmuneresponse(38).

2.7. Meningococcal vaccine

2.7.1 Recommendation

• Routineimmunizationwithmeningococcalvaccinecontainingappropriateserotypes15 isrec-ommendedforalltravellers,regardlessofHIVstatus,toareaswithepidemicmeningococcaldisease (32), and for those in high-risk groups, including peoplewith terminal complementcomponentdeficienciesandanatomicorfunctionalasplenia(39).

2.8. Pneumococcal vaccineTwotypesofpneumococcalvaccineareavailable:pneumococcalpolysaccharidevaccine(PPV)andpneumococcalconjugatevaccine (PCV).Pneumococcalvaccine is recommended foruse inpeoplewithchronicillnessesspecificallyassociatedwithincreasedriskofpneumococcaldiseaseoritscomplications,suchasconditionsassociatedwithimmunosuppression,includingHIVinfec-tion(40).

2.8.1. Pneumococcal polysaccharide vaccine (PPV)

Morethan80%ofnon-HIV-infectedhealthyadultswhoreceivePPVdevelopantibodiestoitssero-typeswithin2–3weeks.Elevatedantibodylevelspersistforatleastfiveyearsinhealthyadults,butfallmorequicklyinpeoplewithcertainunderlyingillnesses,includingHIVinfection.

2.8.1.1. Recommendations

• OnedoseofPPVshouldbeadministeredroutinely,irrespectiveofHIVandimmunestatus,to: o everyonewhoisolderthan65; o immunocompetentpeoplewhoareolderthan216andhavechronicillness(cardiovascular

disease, pulmonary disease, diabetes, alcoholism, cirrhosis or cerebrospinal fluid leaks);and

o immunocompromisedpeople(includingPLHIV)17whoareolderthan2andareatriskforpneumococcaldisease.

14SinceliveinfluenzavaccineiscontraindicatedinPLHIV,inactivatedinfluenzavaccineshouldbeused.15Themeningococcalvaccineshouldcoverserotypescausingmeningococcaldiseaseepidemicsintherelevantgeographicalarea.MeningococcalserogroupsA,BandCarefoundworldwide;serogroupYisfoundinsomepartsoftheUnitedStates;serogroupAisfoundinthe“Africanmeningitisbelt”fromSenegaltoEthiopia;serogroupW125isfoundinSaudiArabia.16Inchildren<2yearsold,antibodyresponsewithPPVtomostserotypesisgenerallypoor.17 Including (in addition toPLHIV)peoplewith splenicdysfunctionor absence (fromeitherdiseaseor surgical removal),Hodgkindisease,lymphoma,multiplemyeloma,chronicrenalfailure,nephriticsyndrome(atypeofkidneyfailure)orotherconditionsassociatedwithimmunosuppression(suchasorgantransplantation).

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• PPVisrecommendedinHIV-infectedadultswithCD4countof>200cells/mm3andarestableonHAART.

• WhenCD4countis<200cells/mm3vaccinationmaybeconsideredforthosewithanincreasedriskforthedisease;however,itmaybelesseffectiveasimmuneresponseisdecreased.OnceHAARThasbeenadministeredandimmunefunctionrestoredsothatCD4countincreasesto>200cells/mm3,revaccinationshouldbeconsidered.

• Ifvaccinationstatusisunknown,patientswithHIVinfectionandotherswithimmunosuppres-sion(includingthosereceivinglong-termsystemiccorticosteroids)shouldbevaccinated(41).

• Routinerevaccinationofimmunocompetentpeopleyoungerthan65isnotrecommended.• People65andoldershouldbegivenaseconddoseiftheyreceivedthevaccinemorethanfive

yearspreviouslyandwereyoungerthan65atthetime.PLHIVandotherswhoareimmunocom-promisedandathighestriskshouldbegivenaseconddoseafterfiveyears.

• Revaccinationisalsorecommendedforchildrenvaccinatedatage2orolderwhoareathighestriskforseriousinfection,andforthosewithcertainunderlyingillnessesthatmakethemlikelytoexperiencearapiddeclineinpneumococcalantibodylevels.Theseconddoseshouldbead-ministered3–5yearsafterthefirst,thoughthereisnouppertimelimitforrevaccinationafter5years.

2.8.2. Pneumococcal conjugate vaccine (PCV)

PCVhasbeenshowntobeimmunogenicininfantsandchildren,includingthosewithHIVinfec-tion, regardlessof immunestatus.After fourdosesofPCV,virtuallyallhealthy infantsdevelopantibodiestoallserotypesinthevaccine.18

2.6.2.1 Recommendations

• Forinfants,dosesareroutinelygivenat2,4and6monthsofage,andaboosterdoseisrecom-mendedat12–15monthsofage.

• Unvaccinatedchildren7–11monthsold,includingthosewithHIV,shouldreceivetwodosesofPCV6–8weeksapart,followedbyaboosteratage12–15months.

• Unvaccinatedchildren12–23monthsoldshouldreceivetwodosesofPCV,6–8weeksapart.• Unvaccinatedhealthychildren24–59monthsoldshouldreceiveasingledoseofPCV.• Children24–59monthsoldwithHIVinfection,sicklecelldisease,asplenia,chronicillnessor

immunocompromisingconditionsshouldreceivetwodosesofPCV6–8weeksapart.Inordertoimprovetheboostereffect,onedoseofPPV6–8weeksafterthelastPCVdoseisrecom-mended.

• PCVisnotroutinelyrecommendedforchildrenolderthan5,regardlessofHIVstatus.• Revaccinationafteranage-appropriateprimaryserieswithPCVisnotcurrentlyrecommend-

ed.• Children2andolderwhoreceiveaprimaryseriesofPCVshouldalsohavePPV6–8weeks

afterthelastdoseofPCV.

2.9. Inactivated poliovirus vaccine (IPV)


• Inordertopreventtransmissionofvaccineand/orvaccine-derivedpoliovirusestoPLHIVIPVshouldbeadministeredtothefollowingpeoplewhenpolioimmunizationisindicated:

o infantsandchildreninfectedwithHIVregardlessoftheirimmunestatus; o householdmembersorotherclosecontacts;and o nursingpersonnelinclosecontactwithPLHIV.

18Presently,therearenotmuchdataforPLHIVresponsetoPCV,otherthanfromSouthAfricaandsmallerstudiesintheUnitedStates.

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• ForunvaccinatedHIV-infectedadultsatincreasedriskofexposuretopoliovirus(suchastraveltoapolio-endemiccountry),aprimaryseriesofIPVisrecommended(25).

2.10. Rabies vaccineTwomaintypesofrabiesvaccineareinuse:nervetissue(Semple-type)vaccineandmoderncell-derivedvaccine.

ImmunocompromisedHIV-infectedpeoplemightnotdevelopsufficientimmunologicalresponse,as immunity depends upon theCD4+T-cell-dependent neutralizing antibody response to theGprotein.


• Rabiesvaccinesareusedforpost-exposureprotectionandpre-exposureimmunogenicity.Ra-biesvaccinesarenotcontraindicated forHIV-infectedpeopleandshouldbeadministered ifindicated(seeAnnex3).

• Ifpost-exposuretreatmentmustbegiventoimmunocompromisedHIV-positivepatients,intra-muscularvaccineandrabiesimmunoglobulinaremandatory,alongwithserologicalmonitoringoftheantibodyresponses(seesectionIII.3.3belowonrabiesimmunoglobulin).

• Peoplewhohavedemonstratedlessthan0.5IU/mlneutralizingantibodytitresafter4–5dosesofrabiesvaccineoverfourweeksshouldreceiveadditionaldosestoachievetherequiredlevel(23),asrabiesantibodytitres>0.5IU/mlarerequiredforprotection.

2.11. Tick-borne encephalitis vaccineTick-borneencephalitis, causedby tick-borneencephalitisvirus, infectionsoccur inmanypartsof Europe (Albania,Austria, Croatia, the Czech Republic, Denmark, Estonia, France (Alsace),Germany,Hungary,Latvia,Lithuania,Norway,Poland,theRussianFederation,Slovakia,southernandcentralSweden,Switzerland),correspondingtothedistributionofthetickreservoir.Thedis-easehasbeenknownbyseveralnames,includingRussianspring-summerencephalitis(RSSE),FarEasternencephalitisandcentralEuropeanencephalitis(CEE)(42).

Generallyrisktotheaveragetravellertoaffectedcountriesissmall.Infectionsarerelatedtoeitherleisureactivities suchashiking,walkingandhunting,orworking inagricultureand forestry inwarm,ruralorforestedpartsofendemicregions.Peopleatriskofinfectionincludeforesters,wood-cutters,farmers,militarypersonnel,laboratoryworkersandtouristswhocamp,huntandundertakefield-workinrural,forestedareas.

Pre-exposureprophylaxisisavailablewiththewholevirusinactivatedvaccines.Thestandardvac-cinationscheduleconsistsof2dosesgivenover4–12weeksapart,followedbyathirddose9–12monthslater.Inimmunocompetentadults,therateofseroconversionafter3dosesis85–100%.Forthoseatrisk,boostingisrecommendedevery3years.Therapidschedules19haveshownsimilaref-ficacyinhealthyindividualsandarepracticalfortravellers.WhethertherapidvaccinationscheduleiseffectiveinHIV-infectedpersonsisunknown.

OnlytwopublishedstudieshaveinvestigatedtheimmunogenicityofvaccinationinHIV-infectedpatients.ThesestudiessuggestthatthevaccineislessefficaciousinHIV-infectedindividualsthanthosenotinfectedwithHIV,particularlywithaCD4count<500cells/mm3.Althoughafour-dosevaccinationschedulegivenat0,1,2and9–12monthsmay improve responses inHIV-infectedpeople,evidenceinsupportofthisstrategyremainslimited(11).

19ForFSMEImmun:2doses14daysapartasprimarycourseandfollowedbyathirddose9-12monthslater;forEncepur:3dosesondays0,7and21asprimarycourseandfollowedbyafourthdose12-18monthslater.

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• ImmunizationshouldbeconsideredforHIV-infectedpeoplewhointendtowalk,camporworkinheavilyforestedregionsofaffectedcountriesduringlatespringorsummerwhentheticksaremostactive,particularlyifstayinginareaswithheavyundergrowth.

• Thevaccineisalsorecommendedforexpatriateswhoseprincipalareaofresidenceisinanareawheretick-borneencephalitisisendemic.

• EitherthestandardortherapidvaccinationschedulemaybeconsideredforHIV-infectedpeoplewithaCD4count>400cells/mm3.

• InHIV-infectedindividualswithaCD4count<400cells/mm3,serologicaltestingmaybecon-sideredonemonthaftertheseconddose.

• Incaseofaninadequateantibodyresponse,twofurthervaccinedosesshouldbegiven,oneim-mediatelyandoneat9–12monthsafterthefirstdose.

• Intheabsenceofserologicaltesting,a4-dosevaccinationschedule(0,1,2and9–12months)shouldbeadoptedtoimproveresponserates(11).

• TheboosterrecommendationisthesameforHIV-infectedindividualsasforimmunocompetentpeople.

• Due to the possibility of reduced responses to vaccination in immunocompormisedHIV-in-fected individuals, the importance of protective clothing and insect repellent use should beemphasized.

2.12. Typhoid vaccine (Vi polysaccharide)HIV-infectedpeopleare at increased riskof infectionwithSalmonella species. In addition, im-munodeficiencypredisposes patients to bacteraemia, antibiotic resistance, relapsingdisease andpersistentinfection(11).

AparenteralkilledvaccinecomposedofpurifiedVipolysaccharide(from S. typhi)hasbeenshowntobemoderately(50–80%)effective(43),withonedoseadministeredsubcutaneouslyorintramus-cularly.Thevaccineconfersprotection7daysafterinjectionforatleast2years.Forpersonsatrisk,boostingisrecommendedevery3years.


• Owingtolowefficacyandhighratesofassociatedadverseevents,useofold,heatinactivatedwholecelltyphoidvaccineisnotrecommended,althoughthisvaccineisstillproducedinsomecountriesmainlyforeconomicreasons(43).

• Althoughnotrequiredforinternationaltravel,vaccinationwiththeVipolysaccharidevaccineisrecommendedforallHIV-infectedpeoplewhoareduetotraveltoareasinwhichthereisarecognizedriskofexposureandwhowillbeintimatewithadocumentedcarrier.

• Onedoseofthevaccineshouldbegivenatleast2weeksbeforetheexpectedexposure.• Abooster is recommendedevery3years in thosewhoremainat risk, this intervalmightbe

consideredtobereducedto2years,iftheCD4countis<200cells/mm3,astyphoidvaccinesarenot100%protectiveandresponsesmaybefurtherreducedinPLHIV.

• Travellersshouldbeadvisedtofollowstrictfoodanddrinkprecautions.

2.13. Other killed antigensOthervaccinescontainingkilledantigens,includingJapaneseencephalitis,plagueandanthrax,donotposearisktoPLHIV,regardlessoftheirimmunologicalstatus.


• ThesevaccinesshouldbeusedinthesamemannerasfornonHIV-infectedpeople.

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3. Use of immunoglobulins

3.1. Hepatitis B immunoglobulin (HBIg)TemporaryimmunitymaybeobtainedusingHBIgforpost-exposureprophylaxis.HBIgisusedforpassiveimmunizationof:• newborninfantsofHBsAg-positivemothers;• peoplehavingpercutaneous,mucousmembraneorsexualexposuretoHBsAg-positivebloodor

bodyfluids;and• livertransplantpatients.


• Immunocompromisedpeople,includingPLHIV,shouldreceiveHBIgforthesameindicationsandinthesamedosesasimmunocompetentpeople.

• Asarule,HBIgshouldbeusedasanadjuncttohepatitisBvaccine.AllcandidatesforHBIgarebydefinitioninahigh-riskcategoryandshouldthereforebeconsideredforaconcurrenthepatitisBvaccineseries.

• ThepeopleforwhomHBIgisindicatedinclude: o prematureinfantswhoareborntoHBsAg-positivewomenandwomenwithunknownHB-

sAgstatus,andwhoshouldreceiveimmunoprophylaxiswithhepatitisBvaccineandmayreceiveHBIg20atorshortlyafterbirth;

o infantsborntoHBsAg-positivemothers,preferablywithin12hoursofbirthbutatadiffer-entsitefromthehepatitisBvaccination;

o HBsAg-negativepeoplewhodonotrespondtoHBVvaccine,andwhoshouldbecounselledonpreventingHBVinfectionandtheneedforHBIgprophylaxisagainstanypossibleparen-teralexposuretoHBsAg-positiveblood;

o susceptiblesexualcontactsofpeoplewithacuteHBVinfection,within14daysofthelastsexualcontact;21

o unvaccinated infantswhosemothersorprimarycaregivershaveacuteHBVinfection, inwhichcasethefirstdoseofthehepatitisBvaccineseriesshouldalsobegiven;22and

o peoplewhoarehouseholdcontactsofpeoplewithacuteHBVinfectionandwhohavebeenexposedtothebloodoftheinfectedperson(forexample,bysharingatoothbrushorrazor),inwhichcasetheyshouldalsobegiventhefirstdoseofthehepatitisBvaccineseries.23

3.2. Human normal immunoglobulin (HNIg)

3.2.1. Hepatitis A


• ForthepreventionofhepatitisA,24HNIgshouldbeadministeredinthesamewaytobothimmu-nocompromisedandimmunocompetentpeopleandforthesameindications(25).ConcurrentadministrationofHNIgandhepatitisAvaccinedoesnotappeartosignificantlyinfluencetheformationofprotectiveantibodies(23).

• HNIgisindicatedtopreventhepatitisAinthefollowinggroupsofpeople: o peopletravellingtohigh-riskareaslessthanfourweeksafteraninitialdoseofhepatitisA

vaccineshouldreceiveHNIgatadifferentsitefromthehepatitisAvaccination;

20Theprotectionagainstperinatallyacquiredinfectionachievedbyimmediate(within24hours)hepatitisBvaccinationisnotsignificantlyimprovedbytheadditionofHBIg(44).21Ifthelastsexualcontactwasmorethan14daysprior,hepatitisBvaccinationshouldbeinitiated,althoughtheamountofprotectionaffordedbypost-exposureprophylaxisgiventhislateisnotknown.HBIgisnotrecommendedinthissituation.22HBIgisnotneededforinfantswhohavereceivedorarescheduledtoreceiveaseconddoseofvaccine.23RoutinehepatitisBvaccinationshouldalsobeconsideredfornonsexualhouseholdcontactswithoutbloodexposure,espe-ciallychildrenandadolescents.24TopreventHAVinfection,administrationofHNIgisrecommendedbeforeorwithintwoweeksofHAVexposure.LateradministrationofHNIgoftenonlyattenuatestheclinicalexpressionofHAVinfection.

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o childrenyoungerthan1travellingtohigh-riskareasshouldreceive0.02–0.06ml/kg,de-pendingonlengthofstay,sincehepatitisAvaccineisnotapprovedforchildrenyoungerthan1;

o peopleexposedtoHAVwhohavenotpreviouslyreceivedhepatitisAvaccine,whoshouldbegivenHNIgassoonaspossiblewithintwoweeksofexposure;

o peopleinclosecontactwithapersonwhohashepatitisA; o staffandchildrenatchildcarecentreswhereahepatitisAcasehasbeendiagnosed;and o peopleincertaincommon-sourceexposuresituations(forexample,patronsofafoodestab-

lishmentwithanHAV-infectedfoodhandlerwheretheriskoftransmissionisdeterminedtobehigh).

• PeoplewhoreceivedadoseofhepatitisAvaccineatleastonemonthbeforeanexposuredonotneedHNIg.

3.2.2. Measles


• For immunocompromisedpeople(including thosewithHIVinfection),HNIg is indicated topreventmeaslesfollowingexposure.

• Ifimmediateprotectionagainstmeaslesisrequiredforimmunocompromisedpatientswithcon-traindicationsformeaslesvaccination,includinginfantsyoungerthan1,passiveimmunizationwithHNIg0.5ml/kgofbodyweight(maximumdose15ml)shouldbeadministeredintramus-cularlyassoonaspossibleafterexposure.

• ExposedsymptomaticHIV-infectedpatientsshouldreceiveHNIgregardlessoftheirpreviousvaccinationstatus,asmeaslesvaccinemaynotbeeffectiveinsuchpatientsandthediseasemaybesevere.

• ForimmunocompromisedpeoplereceivingHNIgformeaslesprophylaxis,measlesvaccinationshouldbedelayedforsixmonthsfollowingHNIgadministration.

3.3. Human rabies immunoglobulin (HRIg)


• Immunocompromisedpatients,includingthosewithHIVinfection,shouldreceiveHRIgforthesameindicationsandinthesamedosesasimmunocompetentpatientsdo.

• HRIgis indicatedforCategoryIIIcontact(singleormultiple transdermalbitesorscratches,contaminationofmucousmembranewithsalivafromlicks),alongwith thefirstdoseof therabiesvaccineseries.

• HRIgtreatmentisnotnecessaryforpeoplevaccinatedagainstrabieswhohavedemonstratedneutralizingantibodytitresofatleast0.5IU/ml(twointramusculardosesofacell-derivedvac-cineseparatedbythreedaysaresufficientforsuchcases).

• If post-exposure treatment must be given to an immunocompromised HIV-infected person,HRIgismandatory,alongwiththefirstdoseofanintramuscularrabiesvaccineseries.

• Inaddition,theantibodyresponsesshouldbemonitoredserologically.Forfurtherdetails,seeAnnex3.

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3.4. Tetanus immunoglobulin (TIg)


• TIgisrecommendedforpeoplewithtetanusandtopreventtetanusininadequatelyimmunizedpeoplewithwoundsorotherconditionsassociatedwithtetanus,regardlessoftheirHIVandim-munestatus.TIgneutralizescirculatingunboundtetanustoxin.Itdoesnotaffecttoxinthathasreachedthenervoussystem.

• DosageisthesameforPLHIVasforothers.• Forthetreatmentoftetanus,asingleintramusculardoseof3000–5000unitsisgenerallyrecom-

mendedforchildrenandadults.• IndicationsforTIgare: o woundsthatareneithercleannorminorinpeoplewhohavehadnomorethantwoprior

dosesofTd toxoid (vaccine)orwhohaveanuncertainhistoryofTIg immunization,Tdtoxoidsshouldalsobeadministered;25

o anyinjuryotherthanacleanminorwound,incombinationwithacontraindicationforteta-nustoxoid;or

o symptomsconsistentwithtetanusdisease.• Intravenousimmunoglobulin(IgIV)containstetanusantitoxinandmaybeusedifTIgisnot

available.

3.5. Varicella-zoster immunoglobulin (VZIg)ThemostimportantuseofVZIgisforpassiveimmunizationofneonatesandsusceptibleseverelyimmunocompromisedpeople,includingPLHIV,aftersignificantexposuretochickenpoxorzoster.ImmunocompromisedpatientswhoareexposedtovaricellaandreceiveVZIgmayhavelowerratesofcomplicationsandinfections.TherisksofVZIgappeartobenegligible,thoughthecostcanbesubstantial.


• Forprophylaxisofchickenpox,susceptibleHIV-infectedchildren(thosewhohavenohistoryofchickenpoxorshinglesorwhohavenodetectableVZVantibodies)shouldbeadministeredVZIgassoonaspossiblewithin96hoursafterclosecontactwithchickenpoxorshingles.

• VZIgisalsorecommendedforVZV-susceptibleHIV-infectedpregnantwomenwithin96hoursafterexposuretoVZV.Iforalaciclovirisused,VZVserologyshouldbeperformedsothatthedrugcanbediscontinuedifthepatientisseropositiveforVZV(25).

25Earlydosesoftoxoiddonotinduceimmunity,butonlyprimetheimmunesystem.TheTIgprovidestemporaryimmunitybydirectlyprovidingantitoxin,ensuringthataprotectivelevelofantitoxinisachievedevenifanimmuneresponsehasnotyetoccurred.

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Annex1.Summaryofimmunizationrecommenda-tionsforpeopleimmunocompromisedduetoHIV/AIDS

Table 1. Summary of immunization recommendations for people immunocompromised due to HIV/AIDSa

Vaccine/Disease Infants and childrenb Adults Non-routine immunization

Anthrax — — Useifindicated

BCG Contraindicated/considerc — Contraindicated

Cholera (CVD 103-HgR) — — Contraindicated

Cholera (WC/rBs) — — Useifindicated

DTP/DTaP/DT Recommended — —Hepatitis A — — Useifindicated

Hepatitis B Recommended Useifindicated —

HiB Recommended Considerd —

Influenzae — — Useifindicated

IPV Recommended — Useifindicated

Japanese encephalitis — — Useifindicated

Meningococcal — — Useifindicated

MMR/MR/M/R Recommended/considerf Considerf —

OPV Contraindicated — Contraindicated

Plague — — Useifindicated

Pneumococcal — — Useifindicated

Rabies — — Useifindicated

Rotavirus — — Contraindicated

Tick-borne encephalitis — — Useifindicated

TT/Td Recommended Recommended —

Typhoid (Ty21a) — — Contraindicated

Typhoid, inactivated — — Useifindicated

Varicella — — Contraindicated/considerg

Yellow fever — — Contraindicated

Recommended:thevaccineiseitherrecommendedaspartoftheroutineschedule,orHIVimmunosuppressionindicatesitsuse.Use if indicated:immunosuppressionisnotacontraindicationunlessotherwiseindicated.Contraindicated:HIVimmunosuppressionisanabsoluteorrelativecontraindicationtotheuseofthevaccine.Consider:thedecisiontousethevaccineshouldincludeconsiderationoftheindividualpatient’sriskofdiseaseandthelikelyeffectivenessofthevaccine.—:notapplicableaRoutineandnotroutineimmunizationschedulesdifferfromcountrytocountry.bCutoffageforinfants,childrenandadultsanddosagediffersaccordingtovaccine.Checknationalimmunizationpoliciesorpackageinsert.cRefertospecificconsiderationsforBCGvaccineinsectionIII.1.1.dRefertospecificconsiderationsforHiBvaccineinsectionIII.2.3.eNotethatliveinfluenzavaccinesarecontraindicated.Ifinfluenzavaccineisindicated,useaninactivatedone.fRefertospecificconsiderationsforMMRvaccineinsectionIII.1.3.gRefertospecificconsiderationsforvaricellavaccineinsectionIII.1.7.

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Annex2.WHOClassificationofHIV-associatedimmunodeficiencyininfantsandchildren

Table 2. Classification of HIV-associated immunodeficiency

Classification of HIV associated immunodeficiency

Age-related CD4 values≤11 months

(%)12–35 months

(%)36–59 months

(%)≥5 yearsa

(cells/mm3)

Not significant >35 >30 >25 >500

Mild 30-35 25-30 20-25 350-499

Advanced 25-29 20-24 15-19 200-349

Severe <25 <20 <15 <200or<15%aIncludingadolescentsandadults.Source:WHO(16).

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Annex3.RabiesvaccinesPre-exposurerabiesvaccinationmaybeperformedwithanyofthemoderncell-derivedvaccinesandisrec-ommendedforanyoneatriskforexposuretorabiesvirus.Traditionally,thisrecommendationincludes:• laboratorystaff• veterinarians• animalhandlers• wildlifeofficerswithfrequentexposuretopotentiallyinfectedanimals• visitorstohighlyrabies-enzooticareas26whomaybeexposedtorabieshosts.27

Thepre-exposurescheduleofmoderncell-derivedrabiesvaccinesrequiresintramusculardosesof1mlor0.5ml,dependingonthevaccine,givenonDays0,7and28.28Theindicationforpost-exposurevaccina-tionwiththesevaccines(withorwithoutrabiesimmunoglobulin)dependsonthetypeofcontactwiththerabidanimal.29Dependingonvaccinetype,thepost-exposurescheduleprescribesintramusculardosesof1mlor0.5mlgivenas4–5dosesoverfourweeks.Forrabies-exposedpatientswhohavepreviouslyunder-gonecompletepre-exposurevaccinationorpost-exposuretreatmentwithcell-derivedrabiesvaccines,twointramusculardosesofacell-derivedvaccineseparatedbythreedaysaresufficient.Rabiesimmunoglobulintreatmentisnotnecessaryinsuchcases.Thesamerulesapplytopeoplevaccinatedagainstrabieswhohavedemonstratedneutralizingantibodytitresofatleast0.5IU/ml.

Thehumandiploidcellrabiesvaccineisregardedasthegoldstandardforcell-derivedrabiesvaccines.30TheWHOrequirementisapotencyofatleast2.5IUperintramusculardoseforallcell-derivedvaccines.Despitetheuseofpotent,moderncell-derivedvaccines,aboutonefailureinonemillionpost-exposuretreatmentsdoesoccur.Carefulanalysesshowthatsuchfailuresarealmostalwaysassociatedwithseverelesionsonorneartheheadand/orinappropriateadministrationofthetreatment.

Acompletepost-exposuretreatmentusingnervetissuevaccinesinvolvesaprolongedandpainfulimmuniza-tioncourseofupto23injections.Furthermore,protectivepotencynervetissuevaccinesareinferiortomod-erncell-derivedvaccines.Obviously,thesevaccinesarenotrecommendedforpre-exposureimmunization.

26Morethan2.5billionpeopleliveinregionswhererabiesisendemic,inAfrica,AsiaandSouthAmerica.Itisestimatedthateachyearatleast50000peoplediefromrabies,andthatmorethan10millionreceivepost-exposurevaccination.Childrenaged5–15yearsareatparticularrisk(23).27Accordingtoage-stratifiedstudiesofincidence,thoseatgreatestriskareprobablychildrenlivinginrabies-enzooticregionsofthedevelopingworld(23).28Majorvaccinemanufacturersrecommendoneboosterdoseafteroneyear,andtoensureprotectioninpeopleatcontinuedrisk,boostervaccinationseveryfiveyears,orideally,atintervalsdictatedbyregulartestingforrabiesantibodies(titres>0.5IU/mlrequiredforprotection).29ThetypesofcontactareCategoryI:touchingorfeedinganimals,orlicksontheskin;CategoryII:nibblingofuncoveredskin,minorscratchesorabrasionswithoutbleeding,orlicksonbrokenskin;andCategoryIII:singleormultipletransdermalbitesorscratches,orcontaminationofamucousmembranewithsalivafromlicks.ForCategoryI,notreatmentisrequired;forCategoryII,immediatevaccinationisrecommended;andforCategoryIII,immediatevaccinationandadministrationofrabiesimmunoglobulinarerecommended,inadditiontoimmediatewashingandflushingofallbitewoundsandscratches.30Othercell-derivedrabiesvaccinesareverocellandpurifiedchickembryocellvaccines.Noclinicallyimportantdifferenceswereobservedwhenthesevaccineswereevaluatedtogetherwithhumandiploidcellvaccinesinstudiesonbothpost-exposureprotectionandpre-exposureimmunogenicity(23).

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Annex4.GlossaryActive immunity isusuallypermanentprotectionproducedbyaperson’sownimmunesystem.Onewaytoacquireactiveimmunityistohavethenaturaldisease.Ingeneral,oncepatientsrecoverfrominfectiousdiseases,theywillbeimmunetothosediseasesfortherestoftheirlives.

Antibodiesareproteinsthatareproducedbytheimmunesysteminresponsetospecificantigens,therebyhelpingthebodyfightinfectionandforeignsubstances.

Antigensaresubstances,foreigntothebody,thatstimulatetheproductionofantibodiesbytheimmunesys-tem.Antigenscaneitherbelive(suchasvirusesandbacteria)orinactivated.

Anantitoxinisasolutionofantibodies(forexample,diphtheriaantitoxinandbotulinumantitoxin)derivedfromtheserumofanimalsimmunizedwithspecificantigens.Antitoxinsareusedforconferringpassiveim-munityandfortreatmentandareusuallypermanent.

Anasymptomatic HIV-infected personisonewithaconfirmedHIVdiagnosisbutwithnoclinicalsignsorsymptomsoftheinfection,correspondingtoWHOClinicalStage1.(Forstaging,seeProtocol1,Patient evaluation and antiretrovital treatment for adults and adolescents,Annex2, andProtocol11,Paediatric HIV/AIDS treatment and care,Annex1).

Acontraindication isaconditioninarecipient thatgreatly increases thelikelihoodofaseriousadversereaction that could seriouslyharm the recipient. Ingeneral,vaccines shouldnotbeadministeredwhenacontraindicatedconditionispresent.

Animmune responseisthedefencethattheimmunesystemdevelopsagainstantigens.Itusuallyinvolvestheproductionofproteinmolecules,antibodies(orimmunoglobulins),andofspecificcells(alsoknownascell-mediated immunity)whosepurposeistofacilitatetheeliminationofforeignsubstances.

Theimmune systemisacomplexsystemofinteractingcellswhoseprimarypurposeistoidentifyforeignsubstancesreferredtoasantigens,andtodefenditagainstinfection,diseaseandotherforeignsubstances.Thebody’simmunesystemnaturallyproducesantibodiesinthisdefenceprocess.

Immunityistheabilityofthehumanbodytotoleratethepresenceofmaterialindigenoustothebodyandtoeliminateforeignmaterial.Thisdiscriminatoryabilityprovidesprotectionfrominfectiousdisease,sincetheimmunesystemidentifiesmostmicrobesasforeign.Immunitytoamicrobeisusuallyindicatedbythepresenceofanantibodytothatorganism.Immunityisgenerallyveryspecifictoasingleorganismorgroupofcloselyrelatedorganisms.Therearetwobasicmechanismsforacquiringimmunity,activeandpassive.

Immunoglobulin (Ig)isasterilesolutioncontainingantibodiesfromhumanblood,alsoknownashumannormal immunoglobulin (HNIg), immune serum globulin (ISG) or gamma globulin (IgG). Ig is used topreventthespreadofsomediseasesamongpeoplewhoareinclosecontactwitheachother.Intendedforintramuscularadministration,itisprimarilyindicatedforroutinemaintenanceofimmunityamongcertainimmunodeficientpeopleandforpassiveimmunizationagainstmeaslesandhepatitisA.IgdoesnottransmithepatitisBvirus,HIVorotherinfectiousdiseases.

Immunizationisaninclusivetermdenotingtheprocessofinducingorprovidingimmunityartificiallybyadministeringanimmunobiologicalproduct.Immunizationcanbeactiveorpassive.Active immunizationistheproductionofantibodyorotherimmuneresponsesthroughtheadministrationofavaccineortoxoid.Passive immunizationistheprovisionoftemporaryimmunitybytheadministrationofpreformedantibod-ies,suchasimmunoglobulinsandantitoxins.

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Immunologic memoryispersistentprotectionformanyyearsafteraninfection.Followingexposureoftheimmunesystemtoanantigen,certaincells(memoryB-cells)continuetocirculateintheblood(andalsointhebonemarrow)formanyyears.Uponexposuretotheantigen,thesememorycellsbegintoreplicateandproduceveryrapidlytore-establishprotection.

Immunosuppression is thesuppressedimmunestatusofanindividualcausedbydiseases(suchasHIV/AIDS,congenitalimmunodeficiency,leukaemia,lymphomaorgeneralizedmalignancy)ordrugs(suchasalkylatingagents,antimetabolitesorradiationtherapy).ThelevelofimmunosuppressioncanbemeasuredbyCD4countorbyCD4percentageoftotallymphocytes.

Inactivated vaccinescanbecomposedofwholevirusesorbacteria,orfractionsofeither.Fractionalvac-cinesareeitherprotein-basedorpolysaccharide-based.Protein-basedvaccinesincludetoxoids(inactivatedbacterial toxins)andsubunitorsubvirionproducts.Mostpolysaccharide-basedvaccinesarecomposedofpurecell-wallpolysaccharidefrombacteria.Conjugatepolysaccharidevaccinesarethoseinwhichthepoly-saccharideischemicallylinkedtoaprotein.Thislinkagemakesthepolysaccharideamorepotentvaccine.Vaccineantigensmayalsobeproducedbygeneticengineeringtechnology.Theseproductsaresometimesreferredtoasrecombinantvaccines.

Intravenous immunoglobulin (IgIV)isaproductderivedfrombloodplasmafromadonorpoolsimilartotheIgpool,butpreparedsoitissuitableforintravenoususe.IgIVdoesnottransmitinfectiousdiseases.Itisprimarilyusedforreplacementtreatmentinprimaryantibody-deficiencydisordersandforthetreatmentofKawasakidisease, immunethrombocytopenicpurpura,hypogammaglobulinaemiainchronic lymphocyticleukaemia,andsomecasesofHIVinfection.

Live attenuated vaccinesareproducedbymodifyingadisease-producing(“wild”)virusorbacteria inalaboratory.Theresultingvaccineorganismretainstheabilitytoreplicateandproduceimmunity,butitusu-allydoesnotcauseillness.

Passive immunity isprotectionbyproductsproducedbyananimaloranotherhumanand transferred totherecipient,usuallybyinjection.Passiveimmunityoftenprovideseffectiveprotection,butthisprotectionwanesovertime,usuallyafewweeksormonths.

Specific immunoglobulinsarespecialpreparationsobtainedfrombloodplasmafromdonorpoolsprese-lectedforhighantibodycontentagainstaspecificantigen(forexample,hepatitisBimmunoglobulin,vari-cella-zosterimmunoglobulin,rabiesimmunoglobulinortetanusimmunoglobulin).LikeIgandIgIV,thesepreparationsdonottransmitinfectiousdiseases.

Asymptomatic HIV-infected person isapersonpresentingwithsignsandsymptomsofHIVinfection.Mild,advancedandsevereHIVdiseasecorrespondstoWHOClinicalStages2,3and4,respectively(seeAnnex2andtheannexesmentionedunder“asymptomaticHIV-infectedperson”above).

Atoxoidisamodifiedbacterialtoxinthathasbeenmadenon-toxicbutretainstheabilitytostimulatetheformationofantitoxin.

Vaccinationisthephysicalactofadministeringanyimmunobiologicalagent(vaccine,toxoidorimmuno-globulin)toapersontoproduceactiveimmunity.

Vaccineisasuspensionoflive(usuallyattenuated)orinactivatedmicroorganisms(e.g.bacteria,virusesorrickettsiae)or fractions thereof,administered to induce immunityandprevent infectiousdiseasesor theirconsequences.Somevaccinescontainhighlydefinedantigens(suchasthepolysaccharideofHaemophilus influenzatypeborthesurfaceantigenofhepatitisB);otherscontainantigensthatarecomplexorincom-pletelydefined(forexample,killedBordetella pertussisorliveattenuatedviruses).Vaccinesinteractwiththe

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immunesystemandoftenproduceanimmuneresponsesimilartothatproducedbythenaturalinfection,butdonotsubjecttherecipienttothediseaseanditspotentialcomplications.Vaccinesproduceimmunologicalmemorysimilartothatacquiredbyhavingthenaturaldisease.

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