Quantifying maternally derived respiratory syncytial virus specific neutralising antibodies in a birth cohort from coastal Kenya.

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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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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,c

aKenyaMedicalResearchInstitute(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

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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:

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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.

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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

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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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