JPediatr(RioJ).2015;91(2):108---110
www.jped.com.br
EDITORIAL
Pneumococcal
conjugate
vaccine
and
changing
epidemiology
of
childhood
bacterial
meningitis
夽
,
夽夽
Vacina
pneumocócica
conjugada
e
variac
¸ão
da
epidemiologia
de
meningite
bacteriana
infantil
Shabir
A.
Madhi
a,baMedicalResearchCouncil,RespiratoryandMeningealPathogensResearchUnit,Johannesburg,SouthAfrica
bDepartmentofScience,NationalResearchFoundation:VaccinePreventableDiseases,FacultyofHealthScience,Universityof
theWitwatersrand,Johannesburg,SouthAfrica
Sincetheinclusion ofHaemophilus influenzatypeb (Hib) conjugatevaccine(HibCV)intochildhoodimmunization pro-grams,therehasbeenvirtualeliminationofHibmeningitis in high- and low-income countries.1,2 This resulted from
immunizationofyoungchildren, whichnotonlyconferred directprotectionagainstinvasiveHibdiseaseamong immu-nizedchildren,butalsoindirectprotectionofunvaccinated individuals,due totheinterruptionof transmissionofthe bacteriumwithincommunitiesthroughtargetedvaccination of young children.3 Subsequentto HibCVimmunization of
children,Streptococcuspneumoniaeemergedastheleading causeofbacterialmeningitisinmostcountries,albeit sec-ondtoNeisseriameningitidis(32%)insomecountries,such asBrazil.4ThestudybyHiroseetal.,publishedinthisissue
oftheJournal,suggeststhatfurtherchangesinthe epidemi-ologyofchildhoodmeningitis inBrazil arelikelytooccur, since the introduction of the 10-valent polysaccharide-Protein-Dproteinconjugatevaccine(PCV10)intothepublic immunizationprogram in March of 2010.5 Usingthe
Noti-fiable Diseases Information System on reported cases of pneumococcalmeningitisfortheBrazilianstateofParaná,
DOIoforiginalarticle:
http://dx.doi.org/10.1016/j.jped.2014.07.002
夽 Pleasecitethisarticleas:MadhiSA.Pneumococcalconjugate
vaccineandchangingepidemiologyofchildhoodbacterial
meningi-tis.JPediatr(RioJ).2015;91:108---10.
夽夽
SeepaperbyHiroseetal.inpages130---5.
E-mail:shabirm@nicd.ac.za
Hirose etal.document areduction by approximately60% in the incidence of pneumococcal meningitis and a 76% reductionin the incidenceof deathdue topneumococcal meningitisinchildren youngerthan2years.This occurred within two-years of introducing PCV10 into the public immunization program ofBrazil; the authors performed a comparisonwiththepre-PCV10era.
Althoughtheseobservationsareencouraging,itis impor-tanttointerpretthefindingsinthecontextofthelimitations and possiblebiases thatareinherent topassive reporting systems,includingvariabilityincompletenessandaccuracy ofcaptureofcasesovertime.Thiscouldinadvertentlybias thefindingsfromecologicalstudies usingsuch administra-tivedatabases,eitherthroughoverestimationoftheimpact ofPCV(shouldreportinghavebeensuboptimalfollowingPCV introduction)orunderestimationofitseffect(shouldthere havebeenenhancedreportingofcasesinthepost-PCVera). Onewayofaddressingthislimitationistoanalyseforother diseasesrecordedinsuchsystems,whicharelesslikelyto havebeenaffectedbytheinterventionunderinvestigation andwhichthemselvesarenotsubjecttotemporalchanges. In this regard, it would have been useful to analyse the trendsinincidenceofothercausesofbacterialmeningitis, suchasGroupBStreptococcus(GBS),whichalthoughmainly affectinginfants<3monthsofage,isexpectedtoremain largelyunchanged.6,7Sucha‘‘dummy’’analyseswouldhelp
toverifythestabilityindocumentationofbacterial menin-gitis casesinthe reportingsystem.Similarly, reportingon thetrendsofincidencebyvaccine-serotypeandnon-vaccine serotype (excluding thosefor whichtherecould be
cross-http://dx.doi.org/10.1016/j.jped.2014.11.001
Pneumococcalconjugatevaccineandchangingepidemiology 109
protection or are known to be associated with temporal variability)wouldfurtherstrengthen theinterpretationof the current results. In contrast, trends in meningitis due toNeisseriameningitidiswouldhavebeen lessusefulasa ‘‘dummy’’variableanalysis,asitissubjecttonatural tem-poralchangesandcouldalsobeaffectedbyintroductionof vaccinesrecentlydevelopedagainstthisbacterium.
Also,although thecurrent study details theproportion of pneumococcal meningitis cases that were due to the PCV10-serotypes prior to the PCV10 era (58%) and dur-ing the PCV10-era (46%), the results were not analyzed specificallyinrelationtovaccineserotype-specificchanges in incidence of meningitis, possibly due to the fact that serotypingwasonlyperformedin<50%ofisolates. Further-more,the study isunlikely tohave hadsufficient number ofcasesofmeningitisbyindividualserotypestodetermine whethertherewasuniformprotectionagainstallserotypes, or whether the changes were specific tosome serotypes, such as 1 and 5. These serotypes could undergo natural year-on-year incidencefluctuation. Serotype 1 in particu-lar is a major cause of pneumococcal meningitis in some settings;8althoughincludedinPCV10(andPCV13),itcould
haverapidlydeclinedduetonaturalfluctuationsinits inci-dence,whichwasonlycoincidentallytemporallyrelatedto PCVintroduction.
As such, whilst the decline in incidence of pneumo-coccal meningitis that was temporally related to PCV10 childhoodimmunizationinthisecologicalstudyispromising, the results need to be corroborated by additional vac-cineeffectivenessstudiesinthesamesetting.Suchstudies have recently been forthcoming from Brazil, including a multi-centred case-control study on invasive pneumococ-cal disease (IPD) that included meningitis cases.9 In the
latterstudy,Dominguesetal.reportedthatPCV10 immu-nization usingthe threedose primaryseries(at 2,4, and 6monthsofage)andaboosterdoseatage12monthswas associated witha 84% reduction(95% CI:66-92) in PCV10 serotype IPD and notably also a 78% reduction (95% CI: 41-92) in vaccine-related serotypes (6A and 19A), whose immunologicalcross-reactivityhadbeenreportedfrom ear-lierimmunogenicitystudies.10ThisindicatesthatthePCV10
formulation effectively prevented IPD due to at least 12 serotypes,includingserotype19A(VE:82%;95%CI:11-96). Serotype19Apreviouslyemergedasamajorserotypethat caused ‘‘replacement disease’’following theintroduction of the 7-valent polysaccharide-CRM197 protein conjugate
vaccine (PCV7) intoimmunizationprogramsof some high-incomecountries,whichwaslargelyduetoclonalexpansion of pre-existing antibiotic-resistant strains.11 Additionally,
clonal expansion of other non-PCV7 serotypes, including serotypes 1, 3,7F,22F, and33F, wereobserved in United KingdomfollowingPCV7immunization.12 Theeffectiveness
of PCV10 againstIPD is further corroboratedby a cluster randomizedcontroltrialofPCV10undertakeninFinland,in whichvaccineefficacywas100%forthe3+1dosingschedule and93%foratwo-doseprimaryseriesfollowedbyabooster dose.13
Despite the limitations of the study by Hirose et al., the results are nevertheless consistent with the impact thatPCV7childhoodimmunizationhadonvaccine-serotype meningitisinhigh-incomecountries.Arecentreviewonthe effect of PCV7 on pneumococcal meningitis in European
andNorthAmericancountriesdemonstratedreductions of vaccineserotypemeningitisof59%withinoneyearof intro-duction in the United States, and of up to100% in some countriesamongtheagegroupstargetedforvaccination.14
Inaddition, many studies reporteda declinein incidence ofvaccine-serotype meningitisamongtheagegroups that were not targeted for vaccination. In the United States, this decline among PCV unvaccinated age-groups was of slightly lower magnitude (59% to 65% reduction) com-pared to that observed in children younger than 1 year (83% reduction) ten years following PCV7 introduction.15
This reflects some ongoing transmission of the vaccine-serotypes even in countries such as the United States, andpossiblyalagin indirectprotectionmaterializing rel-ativeto thedirect effectamong theage groups targeted for vaccination. Similarly to HibCV, the indirect effect of PCV immunization of children, who are the main age group reservoir of pneumococcal colonization and source of transmission in communities, is related to vaccination reducingtheirrisk of acquiringvaccine-serotype nasopha-ryngealcolonization.16 Consequently, thereisinterruption
of the transmission of vaccine-serotypes in the commu-nityandreducedacquisitionoftheseserotypesevenamong unvaccinatedindividuals,thusprotectingthemfrom devel-oping IPD (including meningitis).3 Although the study by
Hiroseetal.didnotanalyzetheeffectofchildhoodPCV10 immunizationontheincidenceofpneumococcalmeningitis amongPCV-unvaccinatedagegroups,thefindingsby Ham-mittet al., fromKenya, supportthat PCV10 (similarly to PCV7 and PCV13) result in indirect communityprotection againstpneumococcalcolonization(andconsequentlylikely againstdisease).17
Despitethesuccessinreducingtheincidenceof pneumo-coccalmeningitis,itremainedaleadingcauseofbacterial meningitisintheUnitedStates(58%)sevenyearsfollowing PCV7 introduction, albeit being second toGBS in those< 18years.7Also,thecasefatalityproportionof
pneumococ-calmeningitishasremainedunchangedintheUnitedStates andintheUnitedKingdomintheeraofPCVimmunization (14%to16%),7,12,18aswell asinthestudybyHiroseetal.,
when comparing the pre-PCV (31%) to the PCV-era (19%, p=0.25). Furthermore, a high rate (63%) of neurological sequelae among children surviving pneumococcal menin-gitis persists, regardless of whether it was due to PCV7 vaccine-serotypes.18 As further reductions in
pneumococ-calmeningitisareexpectedsincethetransitionfromPCV7 tothePCV13formulationinmanycountries,theincidence ofpneumococcal meningitis is likelyto declinefurther in countries where PCV13 (or PCV10) vaccination has been widelyimplemented.Thischangeisalreadybeingobserved intheUnitedStates,withinoneyearoftransitioningfrom PCV7toPCV13forimmunization,withafurther57% reduc-tionobservedin IPDdue toPCV13serotypes comparedto the era of PCV7 utilisation.19 The reduction in
pneumo-coccal meningitis was, however, lower than the decrease observedinvaccine-serotypebacteremia,pneumonia,and mastoiditis.19 With the further decline in pneumococcal
meningitis, it is expectedthat GBS will now become the leadingcauseof bacterial meningitisin the UnitedStates among the pediatric population, albeit concentrated in infants youngerthan 3 months.7 Although atrivalent GBS
110 MadhiSA
phaseIIclinical studies,20 the targetfor suchavaccine is
theimmunizationofpregnantwomen,aimedatincreasing thetransplacentaltransferofcapsularantibodytothefetus; thisissubsequentlyexpectedtoprotectyounginfantagainst GBS(group Bstreptococcal)meningitis andother invasive GBSdisease.21
Although pneumococcal meningitis is among the least commonformsofseverepneumococcaldisease,itremains adiseasewithhighproportionsoffatalityandneurological sequelae.ThePCV vaccineshavenowbeen establishedto preventvaccine-serotypemeningitis.Consideringthehigher incidenceofpneumococcal diseaseand muchhigher mor-tality associated with pneumococcal meningitis (35%) in childrenfromlow-incomecountries,22expeditingthe
intro-duction of PCV into all low-middle incomecountries in a cost-effectiveandsustainablemannershouldbeprioritized.
Funding
Theauthorhasreceivedgrantfundingandbeen aclinical trialiston studies onPCV; hehas alsoreceived honoraria forparticipatingonspeakersbureauandadvisoryboardsof GlaxoSmithKlineandPfizer.
Conflicts
of
interest
Theauthordeclaresnoconflictsofinterest.
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