Nyiro, JU; Sande, C; Mutunga, M; Kiyuka, PK; Munywoki, PK;
Scott, JA; Nokes, DJ (2015) Quantifying maternally derived
respira-tory syncytial virus specific neutralising antibodies in a birth cohort
from coastal Kenya. Vaccine, 33 (15). pp. 1797-801. ISSN
0264-410X DOI: https://doi.org/10.1016/j.vaccine.2015.02.039
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ContentslistsavailableatScienceDirect
Vaccine
jo u rn al h om ep a g e :w w w . e l s e v i e r . c o m / l o c a t e / v a c c i n e
Quantifying
maternally
derived
respiratory
syncytial
virus
specific
neutralising
antibodies
in
a
birth
cohort
from
coastal
Kenya
Joyce
U.
Nyiro
a,∗,
Charles
Sande
a,
Martin
Mutunga
a,
Patience
K.
Kiyuka
a,
Patrick
K.
Munywoki
a,
J.
Anthony
G.
Scott
a,b,
D
James
Nokes
a,caKenyaMedicalResearchInstitute(KEMRI)—WellcomeTrustResearchProgramme,CentreforGeographicMedicineResearch-Coast,Kilifi,Kenya bLondonSchoolofHygieneandTropicalMedicine,London,UK
cSchoolofLifeSciences,UniversityofWarwickandWIDER,Coventry,UK
a
r
t
i
c
l
e
i
n
f
o
Articlehistory:
Received15October2014
Receivedinrevisedform2January2015 Accepted16February2015
Availableonline26February2015 Keywords:
Vaccinedesign
Respiratorysyncytialvirus Maternalantibody Birthcohort Neutralisation Rateofdecay
a
b
s
t
r
a
c
t
Background:Severerespiratorysyncytialvirus(RSV)diseaseoccurspredominantlyinchildrenunder 6monthsofage.ThereisnolicensedRSVvaccine.Protectionofyounginfantscouldbeachievedby amaternalvaccinetoboosttitresofpassivelytransferredprotectiveantibodies.Dataontheleveland kineticsoffunctionalRSV-specificantibodyatbirthandovertheearlyinfantperiodwouldinformvaccine productdesign.
Methods:Fromabirthcohortstudy(2002–2007)inKilifi,Kenya,100participantswererandomlyselected forwhomcordbloodand2subsequent3-monthlybloodsampleswithinthefirstyearoflife,were available.RSVantibodiesagainsttheA2strainofRSVwereassayedandrecordedasthelogarithm(base 2)plaquereductionneutralisationtest(PRNT)titre.Analysisbylinearregressionaccountedfor within-personclustering.
Results:Thegeometricmeanneutralisationantibodytitrewas10.6(SD:1.13)atbirthwithalog-linear decayoverthefirst6monthsoflife.Theestimatedrateofdecaywas−0.58(SD:0.20)log2PRNTtitreper
monthandahalf-lifeof36days.Therewasnosignificantinteractionbetweencordtitreandrateofdecay withage.Meancordtitresroseandfellinapatterntemporallytrackingcommunityvirustransmission. Conclusions:Inthisstudypopulation,RSVneutralisingantibodytitresdecayapproximatelytwo-fold everyonemonth.Therateofdecayvarieswidelybyindividualbutisnotrelatedtotitreatbirth.RSV specificcordtitresvaryseasonally,presumablyduetomaternalboosting.
©2015TheAuthors.PublishedbyElsevierLtd.ThisisanopenaccessarticleundertheCCBYlicense (http://creativecommons.org/licenses/by/4.0/).
1. Background
SevereRSVdiseaseoccursprimarilyininfancyand
predomi-nantlyamongchildren1–5monthsofage[1].Globally,RSVdisease
mayberesponsiblefornearly200,000deathsperyearinyoung
childrenand99%ofthesedeathsoccurinlowincomecountries[2].
AnannualrateofhospitalisationwithRSVassociatedpneumonia
of1–2per100forchildreninthefirstyearoflifehasbeenreported
inaruralcommunityinCoastalKenya[1,3].
∗ Correspondingauthor.Tel.:+254417522063;fax:+254417522390. E-mailaddresses:jnyiro@kemri-wellcome.org,jnyiro2005@yahoo.com
(J.U.Nyiro),csande@kemri-wellcome.org(C.Sande),
mmutunga@kemri-wellcome.org (M. Mutunga), pkiyuka@kemri-wellcome.org
(P.K.Kiyuka),pmunywoki@kemri-wellcome.org(P.K.Munywoki),
Ascott@kemri-wellcome.org(J.A.G.Scott),jnokes@kemri-wellcome.org(D.J.Nokes).
PreventionofRSVdiseaseisprimarilytargetedtowardsyoung
infants[4],forwhichtwovaccinestrategiesareappropriate:first,
tovaccinateinfantsattheearliestagewhenabletodevelopa
pro-tectiveimmuneresponsewithminimalreactogenicity,andsecond,
toboostthelevelofRSV-specificantibodiesinpregnantwomen
beforedeliverytoextendthedurationofprotectiveantibodiesin
earlyinfancy[5–7].
Thereisevidencewhichsupportstheideathatmaternalspecific
RSVantibodiesprovideprotectionfromRSVdisease[7,8].Glezen
etal.demonstratedthatinfantsbornwithhigherlevelsofantibody
developinfectionatalaterage,andinfantsinfectedinthe
pres-enceofmoderatelevelsofserumantibodyhavemilderillnesses
thaninfantsinfectedwithlowerorundetectablelevelsofantibody
[7].Acase-controlstudyinruralMozambiqueshowedthathigh
levelsofantibodiesofmaternaloriginwereassociatedwith
pro-tectionagainstRSVdisease[5].Arandomiseddoubleblindplacebo
controlledtrialamongprematureinfantsandinfantswith
bron-chopulmonarydysplasiashowedthatmonthlyprophylaxiswith
http://dx.doi.org/10.1016/j.vaccine.2015.02.039
1798 J.U.Nyiroetal./Vaccine33(2015)1797–1801
Palivizumab(ahumanisedmonoclonalIgGantibody)was
associ-atedwitha55%reductioninhospitalisationasaresultofRSV[9].In
addition,therearedatathatsuggestadefinedlevelofneutralising
antibodywhichprotectsagainstRSVdisease[10].
The success of a maternal RSV vaccinationstrategy will be
governedbythedegreetowhichavaccinewillboostlevelsof
pro-tectiveantibodiestransferredbythemothertotheinfantandby
therateatwhichthoseantibodiesdecay.Inthisstudyweprovide
baselinedatanecessarytoevaluatevaccinepotential.Specifically,
inabirthcohortofinfantsfromKilifiinKenya,weestimatethe
meanofandvariationinRSVneutralising(i.e.functional)antibody
innewborncordblood,anditsrateofdecayinrelationtostarting
titre.
2. Methods
2.1. Studysiteandpopulation
ThisstudywasconductedattheKenyaMedicalResearch
Insti-tute(KEMRI)—WellcomeTrustCollaborativeResearchProgramme,
inKilifi,coastalKenya[11].Between1999and2007,abirthcohort
study[12,13]wasconductedtoinvestigatesusceptibilityto
inva-sivepneumococcaldiseaseamongchildrenaged0to23months.
Thisstudywasanaturalhistory study,withnointervention,in
whichcordand3monthlybloodsampleswerecollectedforeach
participant.
Thecurrentstudyusedarchivedserumsamplesofchildrenwho
wereparticipantsoftheKilifiBirthCohort(KBC)studyandwho
wereresidentsoftheKilifiHealthandDemographicSurveillance
System(KHDSS).Characteristicsofthisstudypopulationhavebeen
describedbefore[11,12,14].
Approximately6000KBCstudyparticipantswererecruitedin
thematernitywardandatthematernalandchildhealthclinicat
KilifiDistrictHospital(KDH).Arandomsampleof100participants
fromtheKBCstudy,recruitedfromtheKDHmaternityward,were
selectedfromthestudydatabaseregardlessofRSVdisease.Each
selectedparticipanthadatleast3bloodsamples(specifically,acord
bloodandtwofollowupsamples)eachseparatedbyapproximately
3months.
ThetemporalpatternofcasesofRSVassociatedsevere
pneumo-niawasderivedfromcontinuoussurveillanceofchildrenunder5
yearsofageadmittedtoKilifiDistrictHospital,Kilifi,whichserves
theKHDSSpopulation[1,15]. AnRSVepidemicwasempirically
definedtobeginwhenatleast10%oftestedsampleswereRSV
pos-itiveorwiththeobservationofatleast2casesofRSVinfectionper
weekineachof2consecutiveweeksandweredefinedtocontinue
aslongastheseconditionsweresatisfied,withtherequirement
thatanepidemicmustlastfor≥4weeksaspreviouslydefined[1].
Thesedatawereusedtocomparewiththetemporalpatternofcord
titres.
TheKenya NationalEthicalReviewCommitteeapproved this
study.
2.2. Laboratoryprocedures
Archivedserumsampleshadbeenstoredat−80◦C.Thetitre
of RSV neutralising antibodies was determined by a plaque
reductionneutralisationtest(PRNT)asdescribedpreviously[16].
Themethodincorporateda step in whichserum sampleswere
incubatedat56◦Cinawaterbathfor30mintoinactivate
com-plementcascade proteins. Thedilution of a test serum sample
required to induce 50% neutralisation of a known titration of
RSVA2viruswasdeterminedusingtheSpearmanKarbermethod
[16].
2.3. Statisticalanalyses
DataanalysiswasconductedusingSTATAversion11.2(College
Station,Texas).Thelaboratorydataweremergedwitharchived
datafromtheKBCandKHDSSdatabasesforanalysis.SamplePRNT
titreswerelogarithmicallytransformed(base2)forallstatistical
analyses.Thetitreofcord,firstandsecondsamplesforan
individ-ualweredefinedasTC,T1andT2,respectively.Tooffsetbiasonthe
rateofdecayarisingfromRSVinfection,weappliedthefollowing
criteria.ForindividualswithT1≥TC,allresultsforthatindividual
wereexcluded,andforindividualswithT2≥T1theresultfor
sam-pleT2wasexcluded.Inaddition,allsamplescollectedatages≥7m
afterbirthwereexcludedduetotherebeingfewinnumberandof
wideagerange(7–11m)andahighlikelihoodthatthemeasured
antibodywouldbeactiveratherthanpassive.Therateofdecayof
RSVspecificlog2PRNTtitresfrombirthto<7monthsoflifewas
determinedbysimplelinearregression,accountingforclustering
oftitresforsamplesfromthesameindividualusingtheprocedure
forHuber–Whitesandwichestimator.Possibleinteractionbetween
cordantibodytitreandrateofdecayofmaternalantibodieswas
testedusingthemodelwithindividualscategorisedbyquartileof
titreatbirth.Agedependenceintherateofdecayofantibodytitres
wasevaluatedbycomparingmodelfitsusinglinearandquadratic
termsforage.TheWaldtestwasusedtoevaluatethesignificance
ofremovalofvariablesinnestedmodels.Toevaluatetheeffectof
infectionontheantibodylevels,therateofdecayofthose
partic-ipantswithatleast2samplescollectedwithinanRSVepidemic
wasestimatedandcomparedtothatofparticipantswithatleast
2samplescollectedoutsideanRSVepidemic.Atwosamplet-test
wasusedtocomparethelevelsofneutralisingantibodiesandthe
meanoftheratesofdecaybetweensamplescollectedwithinand
outsideanRSVepidemicandbetweenbinarycovariatesfor
birth-weight(lowbirthweight<2.5kg)measuredusingaweighingscale
atbirthandgestationperiod(premature<37weeks)basedondate
oflastmenstruationorbyclinicalevaluation.
3. Results
A total of 300 samples from 100 cohort participants were
selected.For8individuals,thesecondfollow-upsample(T2)was
notavailable,therefore,292sampleswerescreenedforRSV
spe-cific neutralising antibodies. Applying the exclusion criteria as
describedintheMethods,18additionalsampleswereremoved(9
sampleswithT2≥T1and9samples≥7months),leaving274
sam-plesfrom100participants(76with3samples,22with2samples
and2with1sample)foranalysis.
Thefrequencydistributionoflog-transformedPRNTtitresfor
cordbloodsampleswasapproximatelynormal(Fig.1)withmean
concentration10.6(95%ConfidenceInterval(CI)10.3–10.7,
vari-ance1.28)andmedianof10.6(InterquartileRange(IQR)9.95–11.4,
10thpercentile8.87log2PRNT).Themeanbirthweightinkilograms
oftheparticipantsinthisstudywas2.89kg(SD:0.49)and19%were
bornwithlowbirthweight<2.5kg(mean:2.16;SD:0.21).Only63
participantshad dataongestationalperiod.Themeangestation
periodinweekswas38.6(SD:3.16).Ofthe63individuals with
gestational data,15(24%) wereborn prematurely i.e. <37weeks
(mean34.4;SD:2.48).Therewasasignificantdifferenceinthecord
bloodneutralisingantibodyconcentrationsamongthelowbirth
weight,9.9log2PRNTcomparedtothenormalweight10.7log2PRNT
(P=0.02,t=−2.37)andbetweenpremature,9.8log2PRNTandnot
premature,10.9log2PRNT(P=0.002,t=−3.18).
Thedistributionoflog-transformedPRNTtitresbyageisshown
inFig.2,withthebestfitlinearregressionmodel(agerange0–<7m)
givinganaveragereductionpermonthinlog2PRNTof−0.58(95%CI:
N=100 Mean =10.6 Percentile 25% 9.9, 75% 11.4 0 .1 .2 .3 .4 .5 Frequency 8 9 10 11 12 13 log2 PRNT
Fig.1. FrequencydistributionofmaternallytransferredRSVspecificantibodies (log2transformedPRNTtitres)atbirthfor100infantsborninKilifi,Kenya.The overallmean(variance)andupperandlowerquartiletitres(log2PRNT)areshown.
10.2 and10.7). Theestimatedrateof decayfor participantsfor
whomallsampleswerecollectedwithinanRSVepidemic(n=48;
Samples=98)was−0.56log2PRNTpermonth(95%CI:−0.66and
−0.46)whilethosewhosesampleswereallcollectedoutsidean
RSVepidemic(n=31;Samples=66)was−0.67log2PRNTpermonth
(95%CI: −0.81 and −0.53). Thedifference in therates of decay
betweenthosewithinanRSVepidemicandoutsideanepidemic
wasnotstatisticallysignificant(P=0.19,t=−1.32).Theestimated
rateofdecayforsamplescollectedinchildrenunder4mofagewas
−0.64log2PRNTpermonth(95%CI:−0.70and−0.58).Weexplored
possibleage-dependenceintherateofdecayofantibodytitreby
fit-tingaquadratictermforageintheregressionmodel.Theestimate
hadasignificantresult(WaldtestP=0.001)andwasnot
consid-eredfurther,sincetheplotsforthetwomodelsappearedsimilar
withapredictedstartingtitreof10.5log2PRNT.Thedifferentrates
ofdecaywiththeircorrespondinghalflifeandmeandurationare
detailedinTable1.
ResultsofregressionanalysisoftherateofdecayofRSV
anti-bodiesbyageandbyquartileatbirth(i.e.cordtitre)isalsoshown
inFig.2.Therewasnoevidencethatslopevariedbyquartile,i.e.no
evidenceofaninteraction(Waldtestcomparingmodelswithage
andcordtitrewithorwithoutinteraction,P=0.70.).
ThedistributionofindividualratesofdecayofRSVPRNTtitres
(shownin Fig.3)isunimodalwithmean−0.58 (i.e.half lifeof
q4
q2 q1 q3
Mean decay rate
4
6
8
10
12
Neutralising titre (log2)
0 2 4 6 8 age (months) q4 q3 q2 q1
Fig.2. ThedecayinPRNTtitre(logbase2transformed)overthefirst6months oflifeforabirthcohort,Kilifi,Kenya,withbestfitlineardecaymodelforall sam-ples(mean)andforeachquartilecordlevel(q1–q4)assumingafixedrateofdecay (−0.58log2PRNTtitrepermonth).
Table1
Therateofdecay,meandurationandHalf-lifefordifferentcategoriesofinfantsin aKilifiBirthCohort.
Category Rateofdecay
(log2PRNT/month) Meanduration indays Half-lifein days Overall −0.58 52 36 Withinepidemic −0.56 54 37 Outsideepidemic −0.67 45 31 <4months −0.64 47 32 >4months −0.51 59 41 Std dev.= 0.20 Percentile 25% 0.44, 75% 0.68 Mean=0.58 0 10 20 30 Frequency 0 .5 1 1.5
Rate of decay (-log2 PRNT per month)
Fig.3.Ahistogramofthedistributionofindividualratesofdecayshowingthe
overallmean(standarddeviation;inter-quartilerange),−log2PRNT/month.
36days),variance0.04,andIQR−0.44–0.68,i.e.25%ofthesample hadahalflifeofmaternalantibodiesof≥48≤31days.
Analysisofcovariatesontherateofdecayshowedno statisti-callysignificanteffectonunderweight<2.5kgvsnormalweight >2.5kg(log2PRNTpermonth−0.62vs−0.57;P=0.32)and
pre-maturebirthvsfullterm(log2PRNTpermonth−0.66vs−0.55;
P=0.06).
Furtheranalysisofthecordneutralisationtitresby distribut-ingthem againstdateofcollectionand overlayingwithweekly RSV casesadmittedtoKilifiDistrictHospitalisshownin Fig.4.
Theresultssuggestthatchildrenbornattheendandfirst
quar-terafteranRSVepidemichave highertitresofRSV neutralising
Fig.4. Dynamicsofcordtitresbytimeandtransmissionintensity.Greysymbols denoteindividualcordtitresbydateofbirth,blacksquaremarkersthemeancord titrebyquarter(95%CI),andtheverticalbarsshowthenumberofRSVIFATpositive paediatricsevereorveryseverepneumoniaadmissionstoKilifiDistrictHospital 2002–2008.
1800 J.U.Nyiroetal./Vaccine33(2015)1797–1801
antibodies10.8log2PRNT(SD:1.06)relativetochildrenbornmid
inter-epidemicandattheearlystageoftheepidemic10.0log2PRNT
(SD:1.01)(P=0.043,t=−2.09).
4. Discussion
RSVisamajorcauseofsevererespiratorydiseaseamonginfants
under6monthsofage[1].Studieshavefoundthatinfantsborn
withhighlevelsofRSVspecificmaternalantibodiesareafforded
a degree of protection against the development of severe RSV
associatedpneumoniaduringthefirstmonthsoflifewhentherisk
ofseverediseaseisgreatest[8,17].Hence,maternalvaccination
toboostprotectivespecificantibodiesinearlyinfancyrepresents
a plausible disease prevention strategy for RSV. A number of
maternalvaccines based on theRSV F protein are now
under-development[18] (http://www.clinicaltrials.gov/ct2/show/study/
NCT01905215).Thisstudywasundertakentodefinethebaseline
characteristics of maternal RSV neutralising antibody transfer
anddurationinsupportofthematernalvaccinationintervention
strategy (
http://sites.path.org/vaccinedevelopment/respiratory-syncytial-virus-rsv/vaccine-development/).
Inalowincomepredominantlyruralpopulationweestimated
ameanconcentrationofcordneutralisingantibodylevelof10.6
log2PRNT.Theseresultsareslightlylowercomparedtothosefound
inarecentstudyconductedinBangladesh[19].However,other
studiesreportedneutralisingantibodytitreslowerthanour
esti-mates[20,21].Wealsofoundthat,thecordantibodylevelisrelated
tobirthweightandgestationalperiod;whicharesomeofthe
fac-torsreportedtoinfluencetransplacentalantibodytransfer [22].
Thisindicatesthatinfantsbornpriorto28weeksarelesslikely
togainantibodylevelssinceRSVspecificantibodiesdonotreadily
crosstheplacentabeforethe28thweekofgestation.
Weidentifiedtherateofdecaytobe−0.58log2PRNTpermonth
inthefirst6monthsoflife,indicatingahalflifeof36days.Since
therateofdecaymightbeaffectedbyRSVtransmissionwe
com-paredratesforindividualswhosesampleswerecollectedwithin
or outside of RSV epidemic periodsand founda faster rate of
decay(−0.67log2PRNTper month;half-life31d)for thelatter,
thoughthedifferencewasnotstatisticallysignificant.However,
wealsonotedthat therateof decayinthose under4mofage
inthetotalsample(wherematernalantibodiesarehighest and
leastlikelytobeinfluencedbytransmission)wasrelativelyhigh
(−0.64log2PRNT/month).Thus,weconcludethattherateofdecay
ofRSVspecificmaternalneutralisingantibodiesisbetween−0.58
and−0.67log2PRNTtitrespermonth,i.e.withaveragehalf-lifeof
36–31days.
ThelevelofspecificRSVneutralisingantibodyrequiredto
pre-ventdiseaseisnot preciselyknown,butindirectestimatesof a
protectivethresholdarereportedas6and7.5log2PRNT[10,20].
Our studysuggests thevast majority of individuals to beborn
withtitresabovethisthreshold,andfurthermore,thatover50%
ofindividualsremainsoforaround5–6m.Theindicationisthat
raisinglevelsofcordRSVantibodybymaternalvaccinationabove
themedian levelidentified inthis studywouldprovide
protec-tiontomostinfantsoverthefirst5–6moflifedeemedtobethe
mostcriticalforlife-threateningRSVdisease.Clearly,morework
isrequiredtoestimatedirectlythelevelofprotectiveneutralising
antibodies.
Ourfindingsalsoindicatethattherateofdecayofmaternally
derivedneutralisingantibodiesisindependentofstarting(cord)
level. This result is of significance since it suggests a constant
increaseinbenefitfromboostingtitres,i.e.foreachdoublingrise
inantibodyanincrease induration abovea putativeprotective
thresholdofaround50days.Thismeans, atheoreticalRSV
vac-cinewhichincreasesmaternalantibodytitresbyapproximately4
fold,wouldshifttheagefrequencycurveofRSVdiseasetotheright
byabout100days.TheaboveassertionassumesthatcordRSV
anti-bodyboostedbyamaternalvaccinewoulddecayatthesamerate
ascordantibodyofthesamelevelpassivelytransferredfromthe
motherintheabsenceofvaccination.
Furthermore,althoughbasedonasmallsamplesize,wefind
some evidence for an inverse relationship between population
level neutralising antibodytitres (inferred fromcord sera) and
populationlevelvirustransmission.RSVspecificneutralising
anti-bodiesdeclineintheabsenceofexposureandincreasefollowing
anincreaseinvirustransmissionatpopulationlevel.Assuggested
byStensballe,thisimpliesthatadeclineinherdimmunitymay
establishtheconditionsnecessaryforthespreadofthevirus[20].
Ourstudyhasanumberoflimitations.Theresultsare
appropri-atetoasingleruraldevelopingcountrypopulation.Futurestudies
wouldbeofusetoprovidecomparativedatainsub-SaharanAfrica,
intheIndian sub-continent,and inbothurbanand rural
popu-lations. The level and duration of maternal antibodymay also
varyaccordingtoconcurrentmaternalinfectionssuchasHIVand
malaria,whichareallimportantfactorswhichthisstudywasnot
designedtoinvestigate.Measurement errorindetermining
ges-tational ageand hence thepravelenceof prematurity couldbe
addressedin futurestudiesthrough useofstandard ultrasound
procedures.RSVinfectsveryearlyinlifeandtheinfluenceof
trans-missionontheestimatedrateofdecayisproblematic.Wehave
takenstepstoremove theeffectofRSV infectiononestimating
theratesofdecayanddeterminedarealisticrangewithinwhich
therealratelies.However,thereremainsthepossibilitythatearly
infectionsinthepresenceofmoderatetohightitrematernal
anti-bodymightnothavebeendetected.Analysisofcordlevelinrelation
toprevalentRSVgroupwithinapopulationhasnotbeen
under-taken.Finally,neutralisationassaysarefrequentlybasedonRSVA2
virus(withoutcomparisonwithotherstrainsoralternativegroup)
andnotstandardisedbetweenlaboratoriesandthis complicates
comparisonofresultsbetweenstudiesindifferentlocations.
5. Conclusions
Theresultsofthisstudyprovidepreciseestimatesofthelevel
anddurationofmaternalRSVneutralisationantibodytransferfor
aruraldevelopingcountrypopulation.Similarstudiesarerequired
inarangeofsettings.Interpretationoftheseresultsrequiresbetter
understandingoftherelationshipbetweenthelevelofRSV-specific
neutralisingantibodyandprotectionfrominfectionanddisease,
andthecapabilityofmaternalvaccinestoboostspecificRSV
pro-tectiveantibodiesinrelationtoexistingantibodylevels.
Authors’contributions
JUNdesigned,implementedthestudy,performedinitial
analy-sisanddraftedthemanuscript.
CSprovidedtraininginperformingneutralisationassays,data
analysisandreviewedthemanuscript.
MMperformedneutralisationassays.
PKperformedneutralisationassays.
PMconducteddataanalysisandreviewedthemanuscript.
JAS designed the birth cohort study and reviewed the
manuscript.
DJNdesignedthestudy,conducteddataanalysisandreviewed
themanuscript.
Conflictofintereststatement
DJNhasreceivedresearchsupportfromGlaxoSmithKline. All
Acknowledgements
We thankallthestudyparticipantsfortheircontributionof
studysamples.Wearegratefultofield,laboratoryanddata
man-agementstaffoftheKEMRIWellcomeTrustResearchProgramme
forcollectionandstorageofthesamplesanddataretrieval,and
specificallythesupportofLilianMwango.Finally,weacknowledge
thefundingsupportfromPATH[Grantref:R.LFJN.3003];andthe
WellcomeTrust[077092],[084633].Thispaperispublishedwith
thepermissionoftheDirectorofKEMRI.
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