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