Update on Update on Maternal Immunization Maternal Immunization November 7 November 7 th th , 2014 , 2014 Richard H. Beigi, MD, MSc. Richard H. Beigi, MD, MSc. Associate Professor & Division Associate Professor & Division Director Director OB Specialties & Reproductive OB Specialties & Reproductive Infectious Diseases Infectious Diseases Magee-Womens Hospital of the Magee-Womens Hospital of the University of Pittsburgh Medical University of Pittsburgh Medical Center Center
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Update on Maternal Immunization November 7 th, 2014 Richard H. Beigi, MD, MSc. Associate Professor & Division Director OB Specialties & Reproductive Infectious.
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Update on Update on Maternal ImmunizationMaternal Immunization
November 7November 7thth, 2014, 2014
Richard H. Beigi, MD, MSc.Richard H. Beigi, MD, MSc.Associate Professor & Division DirectorAssociate Professor & Division Director
OB Specialties & Reproductive Infectious Diseases OB Specialties & Reproductive Infectious Diseases Magee-Womens Hospital of the Magee-Womens Hospital of the
University of Pittsburgh Medical CenterUniversity of Pittsburgh Medical Center
Potential COIPotential COIResearch site: Research site:
Novartis Vaccine and Diagnostics: Novartis Vaccine and Diagnostics: GBS Maternal Immunization StudyGBS Maternal Immunization Study
Novavax Inc.Novavax Inc.RSV Maternal Immunization StudyRSV Maternal Immunization Study
Sit on: Sit on: – NVAC MIWG, ACIP Pertussis WGNVAC MIWG, ACIP Pertussis WG
Consultant to (& Contracts with): Consultant to (& Contracts with): – NIH/NIAID, CDC, ACOG, AHRQ, BARDANIH/NIAID, CDC, ACOG, AHRQ, BARDA
Immunization Immunization
Advocacy for pregnant womenAdvocacy for pregnant women
OutlineOutline
Brief Background on ImmunizationBrief Background on Immunization
PregnancyPregnancyNo direct evidence: No direct evidence: – Risk to fetus with any vaccineRisk to fetus with any vaccine– Theoretical risk – R vs. BTheoretical risk – R vs. B
But…But…– Most live vaccine viruses Most live vaccine viruses ? Viremia ? Viremia
SAB risk greatest 1SAB risk greatest 1stst tri tri
– Avoid live virus vaccinesAvoid live virus vaccinesMMR, Varicella, LAIV, PolioMMR, Varicella, LAIV, Polio
– Avoided 1Avoided 1stst tri vaccination/IG tri vaccination/IGNot evidenced based Not evidenced based
Maternal immunization for newborn benefitMaternal immunization for newborn benefit– 11stst 6 months of life 6 months of life
Pregnancy Unique TimePregnancy Unique Time
Pregnant women motivated to improve healthPregnant women motivated to improve health Pregnancy motivates some to quit smokingPregnancy motivates some to quit smoking
Curry. Psych of Add Behav 2001;15(2)Curry. Psych of Add Behav 2001;15(2)
Frequent HC interactions: PNCFrequent HC interactions: PNC
Motivated to optimize fetus/neonatal outcomesMotivated to optimize fetus/neonatal outcomes Often preferentially over themselvesOften preferentially over themselves
Substantial progressSubstantial progress 14145% of total neonatal death (5% of total neonatal death (‘‘93-93-’’03)03) 82 82 57 countries 57 countries ““not eliminatednot eliminated””
Maternal Immunization keyMaternal Immunization key WHO: Td during pregnancyWHO: Td during pregnancy
Rh Alloimmunization [Rho(D)] – 1970Rh Alloimmunization [Rho(D)] – 1970’’ss Previous 9-10% total pregnancies affectedPrevious 9-10% total pregnancies affected Now rare in Rh- women (<1% Rh- pregs)Now rare in Rh- women (<1% Rh- pregs)
Vandelaer J. Vaccine 2003;21http://www.who.int/immunization_monitoring/diseases/MNTE_initiative/en/index2.htmlACOG Practice Bulletin #4: Prevention of RhD Alloimunization
Validated:Validated:– Importance of influenza vaccine in pregnancyImportance of influenza vaccine in pregnancy
Influenza ImmunizationInfluenza ImmunizationMost promise for Influenza preventionMost promise for Influenza prevention– ImmunizationImmunization– + VE in pregnancy (@ 65% = general population)+ VE in pregnancy (@ 65% = general population)
TIV recommended:TIV recommended:USA: Surgeon General 1960, 1990s : during 2USA: Surgeon General 1960, 1990s : during 2ndnd and 3 and 3rdrd trimester trimester
– 2004 & ACOG: changed to any trimester, Essential PNC Element2004 & ACOG: changed to any trimester, Essential PNC Element
2005 WHO2005 WHOCDC 2010: All persons > 6 mos. ageCDC 2010: All persons > 6 mos. age
AllAll pregnant women in pregnant women in anyany trimester trimester
ACOG: Essential part of PNC (2004)ACOG: Essential part of PNC (2004)– New ACOG CO out September 2014New ACOG CO out September 2014
Influenza Vaccine SafetyInfluenza Vaccine SafetyIT IS SAFEIT IS SAFE– Collaborative Perinatal Project 1957-66Collaborative Perinatal Project 1957-66
NIH-sponsored longitudinal studyNIH-sponsored longitudinal study> 50,000 pregnant women immunized> 50,000 pregnant women immunizedoffspring followed for 7 years and assessed for congenital offspring followed for 7 years and assessed for congenital malformations, learning problems, hearing loss, and cancermalformations, learning problems, hearing loss, and cancer
– 2,291 doses TIV given2,291 doses TIV given – No significant increase in adverse reactions in mothers or infants No significant increase in adverse reactions in mothers or infants
– 252 pregnant women who received TIV within 6 months of delivery 252 pregnant women who received TIV within 6 months of delivery matched with 826 unvaccinated pregnant women matched with 826 unvaccinated pregnant women
No difference in pregnancy outcomesNo difference in pregnancy outcomes
– Estimated 2 million pregnant women vaccinated in 2000-03Estimated 2 million pregnant women vaccinated in 2000-03No unexpected adverse events reported to VAERS. No unexpected adverse events reported to VAERS. Three miscarriages reported, not known to be causally related to Three miscarriages reported, not known to be causally related to vaccinationvaccination
– >> 15-20 investigations – SAFE!! 15-20 investigations – SAFE!!Heinonen. Int J Epidemiol 1973;2:229-35Munoz Munoz Am J Obstet GynecolAm J Obstet Gynecol 2005;192:1098-1106 2005;192:1098-1106Pool V. Pool V. Am J Obstet Gynecol 2Am J Obstet Gynecol 2006;194:1200006;194:1200
Influenza Vaccine in PregnancyInfluenza Vaccine in PregnancyEffectiveness and ImmunogenicityEffectiveness and Immunogenicity
Pregnant women given TIV Pregnant women given TIV develop protective develop protective concentrations of anti-influenza concentrations of anti-influenza antibodiesantibodiesMaternal immunization increases Maternal immunization increases the amount of antibody the amount of antibody transmitted to infantstransmitted to infantsLimitations:Limitations:– Effectiveness of vaccine in Effectiveness of vaccine in
pregnant womenpregnant women– Exclusion from clinical trialsExclusion from clinical trials– Studies have not included Studies have not included
specific outcomes such as specific outcomes such as laboratory-confirmed influenzalaboratory-confirmed influenza
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80001000012000140001600018000
ELIS
A Un
its
ControlH1N1
ControlH3N2
ControlB
H1N1 H3N2 B
Mother delivery Infant delivery Infant 2 mo
Antibody to influenza A and B in mothers and their infants Antibody to influenza A and B in mothers and their infants following maternal immunization with TIV or TT (control)following maternal immunization with TIV or TT (control)
Englund et al: J Infect Dis 1993;168:647-56
▀ Correlation between level of cord blood antibody and age at time of influenza A/H3N2 infection, suggesting protective effect (26 infants), Puck, et. Al., J Infect Dis 1980;142:844-9
▀ Infants of mothers with antibody to influenza A/H1 had delayed onset and decreased severity of influenza disease (39 mother-infant pairs), Reuman et al, PIDJ 1987;6:398-403
Transplacentally-acquired influenza Transplacentally-acquired influenza Antibody and Disease in InfantsAntibody and Disease in Infants
Transplacentally-acquired influenza Transplacentally-acquired influenza Antibody and Disease in InfantsAntibody and Disease in Infants
MotherMother’’s GIFT Studys GIFT Study
Conclusion:Conclusion: Maternal vaccination benefits: moms & babies < 6 mos old Maternal vaccination benefits: moms & babies < 6 mos old*NNT: 5 maternal vaccinations to prevent 1 case ILI in mom or infant*NNT: 5 maternal vaccinations to prevent 1 case ILI in mom or infant*NNT: 16 maternal vaccinations to prevent 1 proven flu illness in infant*NNT: 16 maternal vaccinations to prevent 1 proven flu illness in infant
RCT 340 moms 2004-05 Bangladesh½ influenza vaccine, ½ pneumococcal vaccine
316 M-I pairs: - 63% flu VE for babies - 30% less ILI for babies - 36% less ILI for moms
2 Toxoids and acellular pertussis2 Toxoids and acellular pertussis– Pertussis key Pertussis key
2 Tdap Vaccines since 2005: 2 Tdap Vaccines since 2005: – ADACEL (Sanofi) – licensed for ages 11-64ADACEL (Sanofi) – licensed for ages 11-64– BOOSTRIX (GSK) – licensed for ages 10-18BOOSTRIX (GSK) – licensed for ages 10-18– Both licensed for: Both licensed for:
Single-dose use to add protection against Pertussis Single-dose use to add protection against Pertussis and to replace the next booster dose of Tdand to replace the next booster dose of Td
– No unexpected pattern or unusual eventsNo unexpected pattern or unusual events
Liang, J. ACIP February 23, 2011
Maternal Tdap vaccination Maternal Tdap vaccination leads to higher Ab levels in leads to higher Ab levels in
infantsinfants
Geometric mean concentrations Geometric mean concentrations (GMCs) and % of placental (GMCs) and % of placental
transfer of Ab (n=196)transfer of Ab (n=196)
Antigen Maternal serum GMC (95%CI)
Cord Serum GMC (95% CI)
Placental transfer %
PT 9.9 (8.6-11.3) 16.2 (14.2) 164
FHA 21.5 (18.6-24.8) 34.8 (30.1-40.1) 162
PRN 13.5 (11.7-15.6) 17.1 (15.2-20.5) 131
deVoer RM. Clin Infect Dis 2009 Jul 1;49(1):58-64
Tdap in PregnancyTdap in Pregnancy
Apparent safetyApparent safety– No signals, no biologic plausibilityNo signals, no biologic plausibility
More cost effective during pregnancyMore cost effective during pregnancy– Protects mom earlier >> protection to neonateProtects mom earlier >> protection to neonate
2+ weeks for full Ab response2+ weeks for full Ab response
– Passive Ab – neonatal protection - critical timePassive Ab – neonatal protection - critical timeRemained robust in sensitivity analysisRemained robust in sensitivity analysis
MMWR 2011;60:41
Oct 2012 ACIP Tdap in Pregnancy Oct 2012 ACIP Tdap in Pregnancy RecommendationsRecommendations
Updated RecommendationUpdated Recommendation– Prenatal care providers implement Tdap immunization Prenatal care providers implement Tdap immunization
program (tetanus toxoid, reduced diphtheria toxoid and program (tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine) for all pregnant women with acellular pertussis vaccine) for all pregnant women with EVERY EVERY pregnancy, irrespective of previous Tdap historypregnancy, irrespective of previous Tdap history
Guidance on UseGuidance on Use– To maximize maternal antibody response and passive To maximize maternal antibody response and passive
antibody transfer to infant, optimal timing for Tdap is at antibody transfer to infant, optimal timing for Tdap is at 27–36 wks gestation27–36 wks gestation. If not previously vaccinated or . If not previously vaccinated or given during pregnancy, administer immediately given during pregnancy, administer immediately postpartum.postpartum.
MMWR February 22, 2013 / 62(07);131-135
Efficacy DataEfficacy Data
UK data: [UK data: [CID Oct 2014 (Dabrera et al.)CID Oct 2014 (Dabrera et al.)] ] – Case-control, 2012-’13, babies Case-control, 2012-’13, babies << 8 wks 8 wks– N=113 (58,55)N=113 (58,55)– PCR and/or Culture dxPCR and/or Culture dx– Results: Results:
17% vs. 71% got maternal Tdap17% vs. 71% got maternal Tdap
VE: 93% (95% CI: 81-97%)VE: 93% (95% CI: 81-97%)
Safety data compiling: no signals notedSafety data compiling: no signals notedhttp://www.cdc.gov/vaccines/adults/rec-vac/pregnant/whooping-cough/research-materials/research.html
Immunization MisconceptionsImmunization MisconceptionsProminent with Flu Vaccine
Broughton, Beigi, et . Al. Obstet Gynecol 2009;114 Poor OB office staff knowledge & acceptance of flu vaccine - 1/3 don’t believe in vaccines - 36% think not safe in pregnancy, 65% recc to ob patient
What is the Flu Vaccine ?What is the Flu Vaccine ?Trivalent Inactivated Vaccine – TIV/QIV
- Flu Shot- 2 A’s + 1-2 B
Live-Attenuated Vaccine –LAIV- Flu Mist- Same strains
February each Year- Experts meet to select upcoming strains for next yr
Barriers Cont’dBarriers Cont’d
Safety ConcernsSafety Concerns
Needle issuesNeedle issues
Don’t believe susceptible to flu/pertussisDon’t believe susceptible to flu/pertussis
Not normalized to OB providersNot normalized to OB providers
$$$$
Comfort with interventionsComfort with interventions
Fear of litigation Fear of litigation
Etc., Etc., Etc. Etc., Etc., Etc.
Moniz & Beigi Hum Vaccin Immunother 2014;10
Overcoming BarriersOvercoming Barriers
Georgia and R.I. PRAMS Georgia and R.I. PRAMS – 2006-2007, X-sectional, Seasonal 2006-2007, X-sectional, Seasonal
““Research on vaccines and antimicrobials in Research on vaccines and antimicrobials in pregnancypregnancy””
Multidisciplinary: FDA, NIH, Industry, Academia Multidisciplinary: FDA, NIH, Industry, Academia
Delineated paradigm & recommendations for Delineated paradigm & recommendations for vaccine/antimicrobial trials in pregnancyvaccine/antimicrobial trials in pregnancy
SummarySummary
Influenza VaccineInfluenza Vaccine– High risk group, Safe, Neonatal protection High risk group, Safe, Neonatal protection – Fetal Protection, CE (Cost-Saving)Fetal Protection, CE (Cost-Saving)– Ob-GynOb-Gyn’’s: 13% in pregnancy 2008 s: 13% in pregnancy 2008
Improvement seen nationally (40-50%) 2013Improvement seen nationally (40-50%) 2013
Much room for growth (80% - HP 2020)Much room for growth (80% - HP 2020)
– Direct OB provider recommendation KEYDirect OB provider recommendation KEY