MaternalImmunizations:ProtectsMothers,Fetusesand

NewbornInfants

MichaelT.Brady,MDProfessorofPediatricsTheOhioStateUniversityAssociateMedicalDirectorNationwideChildren’sHospital

MaternalImmunizations:ProtectsMothers,FetusesandInfantsMichaelT.BradyMD NeitherInormyspouse/partnerhaveanyrelevantfinancialrelationshipswiththemanufacturer(s)oranycommercialproduct(s)and/orproviderofcommercialproductsorservicesdiscussedinthisCMEactivity.Idonotintendtodiscussunapproved/investigativeuseofcommercialproduct(s)/device(s)inmypresentation.

MaternalImmunizations

•  Globally-eachyear:–  600,000-800,000neonataldeathsduetoinfections.–  10-50%ofstillbirthsareestimatedtobedueto

maternal/fetalinfections.

•  Mostfatalneonatalinfections:–  Occurpriortocompletionofroutineinfantimmunization

schedulese.g.pertussis,rotavirus,meningococcus,etc. OR

–  Causedbyagentsforwhichtherearenocurrentlyapprovedvaccine,e.g.groupBstreptococcus,RSV,HSV,etc.

WHYImmunizeMothers?

MaternalImmunization

•  Potentialtoprotectmothers,fetuses,andinfantsfromvaccine-preventablediseases.

VS. •  Potentialtocauseharmtomothersand/orfetusesand/orinfantsbyadministeringvaccines.

BalancingRisksandBenefits

MaternalImmunizations

Intent:AmericanAcademyofPediatricsEthicalConsiderationsforVaccineandDrugTrialsinPregnantWomenandtheirInfants:ThePediatrician’sPerspectiveCommitteeonInfectiousDiseases(COID)CommitteeonBioethics(COB)

MaternalImmunization

•  Immuneresponsetodifferentvaccinesduringpregnancymightbeaffectedbypregnancytrimester.

•  Moststudiestodatedonotprovideanyevidencethatpregnancysignificantlyimpactsimmuneresponsestovaccinesadministeredduringpregnancy;immuneresponsesappeartobeunrelatedtomaternalage,parity,socioeconomicstatus,orbodyweight.

OmerSBNEJM376:1256-1267,2017HealyCMClinInfectDis56:539-544,2013SperlingRSObstetGynecol119:632-369,2012BakerCTVaccine21:3468-3472,2003

MaternalTransferofAntibodies

•  IgGantibodiesaretheprimaryantibodytransferredacrosstheplacenta

•  IgGantibodiesareactivelytransportedthroughtheplacentabyneonatalFcreceptor

•  IgGtransportedbyFcreceptorsonsyncytotrophoblastsofchorionicvillaebytranscytosisintofetalcirculation

MalekAAmJReprodImmunol36:248-255,1996StapletonNMImmunolRev268:253-260,2015RooopenianDCNatRevImmunol7:715-725,2007

MaternalImmunizationTransferofAntibodyfromMothertoFetus

•  IgG>>>IgM,IgA;IgE

•  IgG1>IgG2,IgG3,IgG4(mayvarybasedontrimester)

–  StreptococcalAbs:IgG2–  RSV:IgG1andIgG2

•  Maternally-acquiredantibodiesmayinhibitbothserumand

mucosalantibodiesproductioninnewborn/younginfant.

CroweJEClinicalInfectDis2001;33:1720-1727

MaternalImmunizationFactorsInfluencingMaternalTransferofAntibodies

•  Gestationalageoftheinfant.

•  Maternalantibodylevel:

–  Priorinfection(s)–  Priorimmunization(s)

•  TypeofIgclassandIgGsubclass

•  Healthoftheplacenta

TransportofMaternalAntibodiesImpactofAntigen-specificAntibodies

AntigenFetal:MaternalAbRatio

(Term)

Pertussis 0.7-1.9GroupBstrep 0.7Influenza 0.7-1.0

BahlRBullWorldHealthOrgan83:418-426,02005VictoriaCGLancet387:475-490,2016SchlaudeckerEPPlosOne8:e70867;2013

MaternalTransferofAntibodies

•  Thehalf-lifeofIgGisaffectedby:–  IgGsubclass.–  TotalIgGconcentration:higherIgGlevels→higherIgG

catabolism.–  Variesbyantigen-specificantibody.

Antigen AbHalf-lifeinInfantPertussis 30-40daysTetanus 50-daysGroupBStrep 60-days

VidorssonGIFrontImmunol5:520,2014GartyKZClinDiagLabImmunol1:667-669,1996deVoerRMClinInfectDis49:58-64,2009MunozFMVaccine20:826-837,2001

MaternalTransferofAntibodiesImpactofPrematurity

•  Pre-termbirths:5-18%ofpregnanciesglobally

•  IgGtransportacrosstheplacentastartsat26-28weeksgestation

•  Transportacrossplacentaisrestrictedatearliergestation–  28-32weeksgestation:0.5-0.6fetal:maternalratio–  Fullterm:>1.0fetal:maternalratio

•  IgG1transportismorerestrictedearlieringestationthanIgG2

VandenBergJPEarlyHumDer87:67,2011VandenBergJPPlosOne9:c94714,2014

MaternalVaccinationsandNeonatalMorbidity/Mortality

•  413,034livebirths(Tdap/influenzavs.novaccine)

– CDCVaccineSafetyDatalink(2004-2014)– 25,222infantshospitalized– 157infantdeathsinfirst6monthsoflife

•  Noassociationfoundbetweeninfanthospitalizationand/orinfantmortalityandmaternalTdaporinfluenzavaccine

MaternalImmunizationDuringPregnancyRoutinelyRecommended NotRoutinelyRecommendedin ContraindicatedinPregnancyInPregnancyinUS PregnancyinUSButAreSafe

Influenza-inactivated Anthrax(highriskonly) BCGTdap HepatitisA Influenza-live

HepatitisBJapaneseencephalitisvirus-inactivated*

HPV MMRMenACWY MMRVMenB Typhoid*PCV13 VaricellaPPSV23 ZosterPolio-IPV

Rabies(exposureorhigh-risk)Smallpox(exposure)

Yellowfever(high-risk)

*inadequatesafetydata

MaternalActiveImmunizationWhenToImmunize

•  Duetosafetyconcerns,mostvaccinesadministeredduringpregnancyarerecommendedtobegiveninthelaterhalfofpregnancy:2nd&3rdtrimesters

•  Tdapduringpregnancy*– GMTforPTandFHAarehigherwhengiven13-25wkgestationascomparedto>26weeksgestation(approximatelydouble)

*EberhardtCSClinInfectDis2016;62-829-836

MaternalAntibodiesandInterferencewithInfantImmunization

•  Passively-acquiredmaternalantibodieshavethepotentialtoaffectnotonlytheconcentrationofantibodiesproducedfollowinginfantimmunizationbutalsothequalityofantibody.

•  Passively-acquiredmaternalantibodiesdonotaffectT-cellresponsestoinfantimmunization.

•  Theimpactofpassively-acquiredmaternalantibodiesisaffectedbytheconcentrationofmaternalantibodiesatthetimeofimmunizationandtheantigencontentofthevaccine.

StegristCAVaccine21:2406-3412,2003FavoetteAnHumRepordUpdates21:119-135,2015

InitialUseofMaternalVaccines

•  Smallpoxresultsinmoreseverediseaseinpregnantwomen.

•  Smallpoxvaccinegiventopregnantwomeninlate1800s:

–  Reducedsmallpoxinmothers.–  Protectedyounginfantsfromsmallpoxearlyinlife.

•  Fetaldemisewasrare.

BurkhardtAEArchKlinMed1879;24:506.BadellMLObstetGyneol2015,125:1439-51

CurrentlyAvailableMaternalImmunizations

Tetanus:RiskFactorsandOutcomes

Mother Child

Unhygieniccareofumbilicalstump

Poorperinatalhygiene

Inadequatematerialtetanusimmunization

ThwaitesCLLancet385:362-370,2015

UnhygienicdeliveryAbortionMiscarriage

TetanusImmunizationDuringPregnancy

•  ForwomenwithnopriortetanusimmunizationpriortopregnancyWHOrecommends:– 2dosesofatetanus-containingvaccineforthe

firstpregnancy.– 1doseofatetanus-containingvaccineforeach

subsequentpregnancy(maximumof5doses).

•  Tetanusmortalitydecreasedby92%.HeolyCMClinObstetGynecol2012;55:74-86

ImpactofTetanusImmunization(2doses)onNeonatalTetanusDeaths

ThwaitesCLLancet385:362-370;2015

InfluenzaVaccine:PregnancyOutcomes

•  Influenzamorbidityisgreaterinpregnantwomen,particularlyinfluenzain2ndand3rdtrimester.1,2

•  Maternalinfluenzaincreasesriskoffetaldeath.³•  Vaccinesafety:Pregnantwomen=non-pregnant

women.⁴•  Vaccineefficacy:Pregnantwomen=non-pregnant

women.⁵•  Pregnancyoutcomes(mothers):

–  Reducedrespiratoryillness/hospitalizational.5–  Reducedstillbirths.⁵–  Reducedpretermlabor/deliveries.⁶

1.   DoddsLCMAJ2007:176:463-4682.   LouieJKNEJM2010:362:27-33.   HabergSENEJM2013;368:333-3404.   ThompsonMGClinInfectDis2014;58:449-4575.   ReganAKClinInfectDis2016;62:1221-12276.   MMWR2011;60:1193-1196

InfluenzaVaccineandNeonatalOutcomes

•  12,223pregnantwomen.

•  1958(16%)ofthesewomenreceivedseasonalinfluenzavaccine.

•  Neonataloutcomesinvaccinatedmothers:– Pre-termbirth–25%lesslikely– Low-birth-weight–27%lesslikely

LeggeA:CMAJ2014;186:E157-64

MaternalImmunizationInfluenzaVaccine:InfantOutcomes

•  Maternalinfluenzaimmunizationresultsinpassive

transferofvaccine-generatedantibodiestofetus.

•  Infantoutcomes(<6monthsofage):–  Reducedlaboratory-confirmedinfluenzainfection.¹‚²–  Reducedinfluenzaillnesses.³–  Reducedfebrilerespiratoryillnesses.¹–  80%reductionininfluenza-relatedhospitalization.²

1.   ZamanKNEJM2008;359-1555-15642.   ShakibJHPediatrics2016;137:e201523603.   EickAA.ArchPediatrAdolescMed2011;165:104-111

InfluenzaVaccine:PreventionofInfluenzaandPertussis

•  StudyinSouthAfrica:2011-2012.

•  Influenzavaccine(1062)andPlacebo(1054).

•  Efficacyininfants(reductionofinfection):– Influenza–50%– Pertussis–40%

NunesMc:NEJM2018;378:1257-58.

PertussisDuringPregnancy

•  Overallmorbidityofpertussisamongpregnantwomencomparedwithnon-pregnantwomenisnotincreased.

•  Maternalpertussisis“tiresome”bynotassociatedwithobstetriccomplicationsorpretermdelivery/disease.

MacLeanDWScottMedJ26:250-253,1981GranstromG.ScandJInfect71(Suppl):237-29,1990

ComplicationsofPertussisinInfantsUnitedStates,1997-2000

Age No. With Pertussis Hospitalizations Pneumonia Seizures Encephalopathy

< 6

Months

7,203 4,543(63%) 847(12%) 103(1%) 15(.2%)

6-11

Months 1,073 301(28%) 92(8%) 7(.6%) 1(.1%)

CDC. MMWR. 2002;51:73-76

CAPertussisCases(12/31/2010)•  9,143confirmed,probableandsuspectcases,24.3

cases/100,000

•  ThiswasthemostcasesreportedinCaliforniasince1955andthehighestincidencesince1962

•  10deaths(casefatalityrate<3months=1.6%)

–  9infants<2months;noDTaPdoses–  1prematureinfant,age2months:1DTaP–  Coughillnesscommoninparentsorsibs

Ratesofreportedpertussisbyage--California,Jan1-Aug24,2010

0

20

40

60

80

100

120

140

160

180

<6 mos 6 mos-6 years 7-9 years 10-18 years 19-64 years 65+ years

Age group

Cas

es p

er 1

00,0

00

*As of 8/24/2010

VaccineSafetyTdap:MaternalImmunization

•  Injectionsitereactions/painwerecommon

•  Noseriousadverseeventsinmothersnorinfants

•  Possibleincreaseinchorioamnionitis

CaytonJBVaccine35:4072-4078,2017MunozFMJAMA311:1760-1769,2014

PertussisImmunizationDuringPregnancy

•  BoosterdosesofTdapincreasepertussisantibodiesinpregnantwomen.

•  MaternalTdapgivenat27through30weeksgestationresultsinhighercordbloodpertussisantibodiesthanwhenTdapisadministeredat>31weeksgestation.

MunozFM:ClinInfectDis2014;59(Suppl.7):5415-27AbuRayaB:Vaccine2014:32:5787-93

EfficacyofMaternalTdap•  MaternalTdapvaccineeffectivenessinpreventingpertussisininfants:ü 91.4%infirst2monthsoflifeü 69%duringfirstyearoflife

• MaternalTdapduringpregnancyprovidedadditionalandearlierprotectionthanpre-pregnancyDTaPand/orTdapalone.

BaxterRPediatrics139:e20164091May2017AmirthalinghamGLancet384:1521-1528,2014

MaternalVaccinesStrategies

inDevelopment

ImmunityToRSVInfection•  NeutralizingantibodiesdirectedagainsttheRSVFandGproteinsaretheprimaryantibodiesassumedtoconferimmunityagainstRSVinfection.

•  •  RepeatedRSVinfectionssuggestthattheimmuneresponsefollowingnaturalRSVinfectiondoesnotprovidelife-longimmunity/protection

HallCNEJM360:588-598;2009.

PreventionofRSVinInfantsbyPassiveAntibodyTherapy

•  RSV-IGIV(RespiGam)-high-titerRSV

polyclonalIGIV

•  Palivizumab(Synagis)

•  Motavizumab(Numax)

RSVVaccines:EarlyattemptsHamperedbyAdverseEvents

•  Formalin-inactivatedRSVvaccinegiventoRSVseronegativechildren→“enhancedRSVdisease”followingnaturalexposuretoRSV.

•  Formalin-inactivatedRSVvaccine:

–  Antigensnotprocessedincytoplasm→lackofprotectiveantibodiesandCD4+helperT-cellpriming.

–  PathogenicTh2memoryresponse.–  RSVexposure→excesseosinophils,neutrophils,

monocytesandimmunecomplexdepositioninlungs.

OmerSBNEJM376:1256-1267,2017KIMHW.AmJEpidemiol89:533-434,1969FulginitiVAAMJEpidemiol89:435-448,1969AcostaPLClinVaccinImmunol23:189-195,2015

CandidateRSVVaccines

•  Liveattenuatedvirusvaccines•  Wholeinactivatedvirusvaccines•  Particle-basedsubunitvaccines•  Nucleicacidvaccines•  Gene-basedvectorvaccines

OmerSBNEJM376:1256-1267,2017

MaternalActiveImmunizationTheCaseforMaternalRSVImmunization

•  TransferofmaterialRSVAbstofullterminfantsare100%of

maternallevels.¹•  Maternally-derivedAbsdeclinerapidlybutarestilldetectable

at5-7monthsofage.²•  Maternally-derivedRSVAbsprotectagainstsevereRSVduring

first5-7monthsofage.2•  MaternalImmunizationwithananoparticleRSVvaccine:³

-Safe.-Immunogenic.-Passivetransfertofetus.-Reducedhospitalizations.

1.   ChuHYJInfectDis2014;210:1582-15892.   OcholaRPLoSOne2009;4(12):e80883.   GlennGMJInfectDis2016;213;411-422

GBS Disease in Infants Before Prevention Efforts

A Schuchat. Clin Micro Rev 1998;11:497-513.

Early-onset: 0-6 days of life

Late onset: 7-89 days of life

Rate of Early- and Late-Onset GBS, 1990-2008

Early-onset GBS

Late-onset GBS

Before national prevention policy Transition Universal screening Source: Active Bacterial Core surveillance / Emerging Infections Program

RiskFactorsforEarly-onsetGBSDisease

§  Obstetricriskfactors:§  Preterm delivery §  Prolonged rupture of membranes §  Infection of the placental tissues or amniotic fluid / fever during

labor

§  GBSinthemother’surineduringpregnancy(markerforheavycolonization)

§  PreviousinfantwithGBSdisease§  Lowmaternallevelsofanti-GBSantibodies§  Demographicriskfactors

§  African American §  Young maternal age

GroupBstreptococcalVaccines

•  Polysaccharidevaccines

•  Conjugatedpolysaccharidevaccines(incurrentclinicaltrials)

GroupBstreptococcalVaccines

•  Conjugatedpolysaccharidevaccines:– Monovalent– Trivalent(Ia,IbandIII)

•  SerotypesIa,IbandIIIcausemajorityofGBSinAmericasandEurope

•  Globally,SerotypesIIandVcauseGBSdiseaseinadditiontoIa,IbandIII.

OmerSBNEJM376:1256-1267,2017EdmundKMLancel379:547-556,2012.

GroupBStreptococcalVaccines

•  TrivalentSerotypesIa,IbandIIIVaccinehasundergonephaseIand2trials:

-Safe.-Immunogenic.- MaternalAbstransferredtonewborn.

MadhiSALancetInfectDis16:923-934,2016MadhiSAVaccine31(Suppl4):D52-D57,2013DondersGGObstetGynecol127:213-221,2016HeydermanRSLancetInfectDis16:546-555,2016BakerCVaccine21:3468-3472;2003.

51

Incidenceofmeningococcaldiseaseinchildrenaged<10years,byageandserogroup―

UnitedStates,2010-2016

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

<1 1 2 3 4 5 6 7 8 9

Casesp

er100,000

Age(years)

B CWY Unk/Other

Source:NationalNotifiableDiseasesSurveillanceSystem(NNDSS)datawithadditionalserogroupdatafromActiveBacterialCoresurveillance(ABCs)andstatehealthdepartments

52

Incidenceofmeningococcaldiseaseamonginfantsaged<1yearbyagegroupandserogroup–

UnitedStates,2010-2016

0.0

0.5

1.0

1.5

2.0

2.5

<2months 2-3months 4-5months 6-7months 8-9months 10-11months

Casesp

er100,000

Agegroup

B CWY Unk/Oth

Source:NationalNotifiableDiseasesSurveillanceSystem(NNDSS)datawithadditionalserogroupdatafromActiveBacterialCoresurveillance(ABCs)andstatehealthdepartments

MeningococcalVaccinesAvailableintheUS•  MenACWY:polysaccharidecapsuleconjugatedwithcarrierproteinformeningococcalserogroupsA,C,WandY.

•  MenB:vaccinedevelopedusingouter-membraneproteinsofmeningococcalserogroupB.

•  Safetyandefficacystudiesinpregnancyareinearlystages.

•  Sincedifferentserogroupsmightbemorerelevantinothercountries,alternatevaccinesmightbeappropriatefordifferentcountries.

MaternalImmunizationMaternalImmunizationwithPneumococcal

PolysaccharideVaccine(PPV)

•  Safe;welltolerated.

•  InfantshadhightitersofpneumococcalAbsoutto4monthsofage.

•  ResponsetoPPVininfantsat7to17weeksofageresultedinfairresponsestoafewPPVantigensbutmostwerepoor.

•  Revaccinationat3yearsofagewithPPVresultedinagoodresponsetoallPPVantigens

(noimmunetolerance).

PneumococcalVaccineDuringPregnancy

•  Pregnantwomenwhoreceivepneumococcalpolysaccharidevaccinein3rdtrimester:–  Vaccineissafeandimmunogenic.–  Transplacentaltransferofpneumococcalantibodiesrelatedstrainsinpneumococcalpolysaccharidevaccine.

– Antibodyhalf-lifeof35days.–  Breastmilkhaddetectableantibodiesuntil5

monthsofage.

ShahidNS:Lancet1995;346:1252-57MunozFM:infectDisClinNorthAm2001:15:253-271

HaemophilusInfluenzaebVaccineDuringPregnancy

•  MaternalimmunizationwithHibvaccinein3rdtrimester:–  Safeandimmunogenic.–  ConjugatevaccineresultsinbetterHibantibodylevelsinbothmotherandnewborninfantthanpolysaccharidevaccine.

–  InfantswhosemothersreceivedHibvaccineduringpregnancyhadnointerferencewithinfantresponsetoHibvaccineseries.

–  Mayplayaroleinnon-industrializedcountrieswithoutinfantHibvaccineprogram.

Mulholland:JAMA:1996;275:1182-1188Englund:Vaccine:2003;21:3455-3459Englund:PediatrinfectDisJ1997;16:1122-30Englund:JInfectDis1995;171:99-105

NeonatalHSV

•  InfantsexposednatallytoHSVwhohadhighertitersoftransplacentally-derivedHSVneutralizingantibodieshadbetteroutcomes/lowerinfectionratesthaninfantswithlowAbtiters

•  AneffectivematernalHSVvaccinecould:

– ReduceriskofacquiringaprimarygenitalHSVinfection.

– Boostmaternalantibodylevelstoprovideinfantswithhigherneutralizingantibodiesatbirth.

YeagerASInfectImmun29:532-538;1980ArvinAMRevInfectDis13(Suppl11):S953-956;1991SullenderWMJInfectDis157:164-171;1988.HargerJHJPerinatol10:16-19;1990