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Update on Maternal Immunization November 7 th , 2014

Update on Maternal Immunization November 7 th , 2014. Richard H. Beigi , MD, MSc. Associate Professor & Division Director OB Specialties & Reproductive Infectious Diseases Magee- Womens Hospital of the University of Pittsburgh Medical Center. Potential COI. Research site:

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Update on Maternal Immunization November 7 th , 2014

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  1. Update on Maternal ImmunizationNovember 7th, 2014 Richard H. Beigi, MD, MSc. Associate Professor & Division Director OB Specialties & Reproductive Infectious Diseases Magee-Womens Hospital of the University of Pittsburgh Medical Center

  2. Potential COI • Research site: • Novartis Vaccine and Diagnostics: • GBS Maternal Immunization Study • Novavax Inc. • RSV Maternal Immunization Study • Sit on: • NVAC MIWG, ACIP Pertussis WG • Consultant to (& Contracts with): • NIH/NIAID, CDC, ACOG, AHRQ, BARDA • Immunization • Advocacy for pregnant women

  3. Outline • Brief Background on Immunization • Maternal Immunization • Influenza • Tdap • Ongoing policy/research considerations • Summary

  4. History • Jenner 1796 • 1st attempt to control ID through deliberate inoculation • Milkmaids –> cowpox…immune to smallpox • Inoculated susceptible persons…no smallpox • 2nd to sanitation & H20 safety • Overall disease prevention • 10 major ID’s controlled extensively • Smallpox gone • Other VPD’s nearly gone

  5. Courtesy: SA Plotkin:2006

  6. Immunization • Defined: • Immunity artificially induced &/or provided • Active vs. Passive • Active: Induce body to produce lasting defenses against infection – Vaccines – Ab (IgG) • Influenza, Hep A/B, HPV, etc. • Passive: Temporary protection given by exogenously produced/pooled Ab • VZIG, HBIG, Placental transfer, etc. • Active Immunization highly effective • Most vaccines > 80-90% effective

  7. Conceptual Basis Courtesy: SA Plotkin:2006

  8. Conceptual Basis Courtesy: SA Plotkin:2006

  9. Vaccine Safety • Numerous concerns raised • GBS, Thimerosol & Autism (multi-dose vials), Anaphylaxis….. • Storage concerns • IOM Reports • Insufficient evidence to prove causation for most vaccine-related problems • 1986 – National Childhood Vaccine Injury Act • National Vaccine Injury Compensation Program • VICP • 1990 Vaccine Adverse Events Reporting System • VAERS – 1990 (CDC+FDA)

  10. Pregnancy • No direct evidence: • Risk to fetus with any vaccine • Theoretical risk – R vs. B • But… • Most live vaccine viruses  ? Viremia • SAB risk greatest 1st tri • Avoid live virus vaccines • MMR, Varicella, LAIV, Polio • Avoided 1st tri vaccination/IG • Not evidenced based • Maternal immunization for newborn benefit • 1st 6 months of life

  11. Pregnancy Unique Time • Pregnant women motivated to improve health • Pregnancy motivates some to quit smoking • Curry. Psych of Add Behav 2001;15(2) • Frequent HC interactions: PNC • Motivated to optimize fetus/neonatal outcomes • Often preferentially over themselves • Provider input key!

  12. Maternal Immunization Success • Neonatal Tetanus • Substantial progress • 145% of total neonatal death (‘93-’03) • 82  57 countries “not eliminated” • Maternal Immunization key • WHO: Td during pregnancy • Rh Alloimmunization [Rho(D)] – 1970’s • Previous 9-10% total pregnancies affected • Now rare in Rh- women (<1% Rh- pregs) • Rubella post-partum immunization (CRS) Vandelaer J. Vaccine 2003;21 http://www.who.int/immunization_monitoring/diseases/MNTE_initiative/en/index2.html ACOG Practice Bulletin #4: Prevention of RhD Alloimunization

  13. Summary 2009 H1N1 & Pregnancy • Validated higher morbidity in pregnancy • Hospitalization, Critical Care needs • PTL/PTB • Validated higher mortality (5-13 fold) • Validated: • Importance of influenza vaccine in pregnancy

  14. Influenza Immunization • Most promise for Influenza prevention • Immunization • + VE in pregnancy (@ 65% = general population) • TIV recommended: • USA: Surgeon General 1960, 1990s : during 2nd and 3rd trimester • 2004 & ACOG: changed to any trimester, Essential PNC Element • 2005 WHO • CDC 2010: All persons > 6 mos. age • All pregnant women in any trimester • ACOG: Essential part of PNC (2004) • New ACOG CO out September 2014 • Stronger case for: • Ob Provider Recommendation • Safety data • Neonatal Benefit Thompson MG. CID 2014:58 ACOG CO #608:2014

  15. Influenzavaccination rates during pregnancy, Canada and United States, 1974-2003 *Vaccination rate was 6% during the 1976 swine flu vaccination campaign +NHIS, National Health Interview Survey Naleway AL. Epidemiol Rev 2006; 28

  16. Influenza Vaccine in Pregnancy • Ob-Gyn national: 13% get vaccine (CDC-MMWR;2005(54)) • Yeager, et. al., Am J Perinatol 1999;16:283-6 • * 71% were offered influenza vaccine accepted vaccination* • Prior to 2009 • Nationally @ 15% pregnant women • 2009 H1N1  @ 50% • Sustained @ 50% since • Healthy People 2020 Goal: 80% • CDC. MMWR 2010;59. ACOG. ObstetGynecol 2004;104 • CDC. MMWR 2011;60. • Ding H. AJOG 2011;204. CDC. MMWR 2010;59. • Internet Panel Survey, 11-2013. www.cdc.gov

  17. Influenza Vaccine Safety • IT IS SAFE • Collaborative Perinatal Project 1957-66 • NIH-sponsored longitudinal study • > 50,000 pregnant women immunized • offspring followed for 7 years and assessed for congenital malformations, learning problems, hearing loss, and cancer • 2,291 doses TIV given • No significant increase in adverse reactions in mothers or infants • 252 pregnant women who received TIV within 6 months of delivery matched with 826 unvaccinated pregnant women • No difference in pregnancy outcomes • Estimated 2 million pregnant women vaccinated in 2000-03 • No unexpected adverse events reported to VAERS. • Three miscarriages reported, not known to be causally related to vaccination • > 15-20 investigations – SAFE!! Heinonen. Int J Epidemiol 1973;2:229-35 Munoz Am J Obstet Gynecol 2005;192:1098-1106 Pool V. Am J Obstet Gynecol 2006;194:1200

  18. Influenza Vaccine in PregnancyEffectiveness and Immunogenicity • Pregnant women given TIV develop protective concentrations of anti-influenza antibodies • Maternal immunization increases the amount of antibody transmitted to infants • Limitations: • Effectiveness of vaccine in pregnant women • Exclusion from clinical trials • Studies have not included specific outcomes such as laboratory-confirmed influenza Antibody to influenza A and B in mothers and their infants following maternal immunization with TIV or TT (control) Englund et al: J Infect Dis 1993;168:647-56

  19. Transplacentally-acquired influenza Antibody and Disease in Infants • 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

  20. Mother’s GIFT Study RCT 340 moms 2004-05 Bangladesh ½ influenza vaccine, ½ pneumococcal vaccine 316 M-I pairs: - 63% flu VE for babies - 30% less ILI for babies - 36% less ILI for moms • Conclusion: Maternal vaccination benefits: moms & babies < 6 mos old • *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 Zaman et al. NEJM 2008;359

  21. Summary of Benefits

  22. Flu Maternal Immunization • NEJM 2014;371:918-31(Matflu) • South Africa • HIV + and HIV- pregnant moms: • HIV (-) • 2116 pregnant women, trivalent flu vaccine, 2011-’12 • 2x-blinded, Placebo-RCT, • Safety & efficacy: mom/baby- 24 wks after birth • PCR-confirmed influenza • Higher titers in moms/babies vaccine (p< 0.001) • VE: 48-50% (moms & babies) • SAFE

  23. Summary of Benefits

  24. Influenza Vaccine • Summary Influenza Vaccine: • Safe in pregnancy • Cont’d validation with all ongoing research • Effective (mom and baby) • Out to 6 months for neonate • ? Fetal benefits • * Strongly CE (cost-saving) • All pregnant women to receive • Ob Provider Recc Key! *Beigi et al. CID 2009;49

  25. Tdap • Tetanus, Diptheria, Pertussis • 2 Toxoids and acellular pertussis • Pertussis key • 2 Tdap Vaccines since 2005: • ADACEL (Sanofi) – licensed for ages 11-64 • BOOSTRIX (GSK) – licensed for ages 10-18 • Both licensed for: • Single-dose use to add protection against Pertussis and to replace the next booster dose of Td • Poorly control VPD

  26. Pertussis (whooping cough) • Highly contagious (80-90%) respiratory infection caused by Bordetella pertussis - 1906 isolation • Fastidious gram-negative coccobacillus • Primarily a toxin-mediated disease • Outbreaks 1st noted16th century • Aerosol droplets • Estimated 294,000 deaths worldwide 2002 • Recent outbreaks (CA, WA)

  27. Why the Increase? • Waning immunity • Whole-cell to acellular component • Better recognition, surveillance, and diagnostic capabilities • Decreased vaccine coverage rates due to vaccine concerns • Variances in vaccine potency CDC. MMWR. 2006;55(30):817-821.

  28. Pertussis trends 0-11 months of age Tanaka M. JAMA. 2003 Dec 10;290(22):2968-75.

  29. Pertussis Deaths Van Rie A. Pediatr Infect Dis J 2005;24

  30. Which Family Members? Bisgard KM, et al. Pediatr Infect Dis J. 2004;23:985-989.

  31. Cocoon Strategy • 2006 ACIP recommended Tdap immunization of caregivers of newborn infants • Mothers post-partum • Close contacts • HCWs • Cocooning programs • Postpartum women & household contacts • Labor intensive! Healy et al. CID 2011

  32. Considerations for use of Tdap in Pregnancy • Safety in mothers and newborns • Immunogenicity of Tdap in pregnancy/transplacental transfer of antibody • Interference by maternal antibodies • Programmatic considerations

  33. VAERS • Jan 1 2005-Jun 30, 2010 • 129 (1.2%) of 10,350 reports after Tdap involved administration during pregnancy • 4 (3.1%) classified as serious • No deaths • 20 (15.5%) spontaneous abortion • 6 (4.7%) gestational diabetes • 3 (2.3%) oligohydramnios • 3 (2.3%) toxemia of pregnancy • 2 (1.6%) congenital abnormality (gastroschisis, PDA) • 2 (1.6%) stillbirth • No unexpected pattern or unusual events Liang, J. ACIP February 23, 2011

  34. Maternal Tdap vaccination leads to higher Ab levels in infants

  35. Geometric mean concentrations (GMCs) and % of placental transfer of Ab (n=196) deVoer RM. Clin Infect Dis 2009 Jul 1;49(1):58-64

  36. Tdap in Pregnancy • Apparent safety • No signals, no biologic plausibility • More cost effective during pregnancy • Protects mom earlier >> protection to neonate • 2+ weeks for full Ab response • Passive Ab – neonatal protection - critical time • Remained robust in sensitivity analysis MMWR 2011;60:41

  37. Oct 2012 ACIP Tdap in Pregnancy Recommendations • Updated Recommendation • Prenatal care providers implement Tdap immunization program (tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine) for all pregnant women with EVERY pregnancy, irrespective of previous Tdap history • Guidance on Use • To maximize maternal antibody response and passive antibody transfer to infant, optimal timing for Tdap is at 27–36 wks gestation. If not previously vaccinated or given during pregnancy, administer immediately postpartum. MMWR February 22, 2013 / 62(07);131-135

  38. Efficacy Data • UK data: [CID Oct 2014 (Dabrera et al.)] • Case-control, 2012-’13, babies < 8 wks • N=113 (58,55) • PCR and/or Culture dx • Results: • 17% vs. 71% got maternal Tdap • VE: 93% (95% CI: 81-97%) • Safety data compiling: no signals noted http://www.cdc.gov/vaccines/adults/rec-vac/pregnant/whooping-cough/research-materials/research.html

  39. Current ACIP Reccs: Moniz & Beigi Hum Vaccin Immunother 2014;10 www.cdc.gov

  40. Immunization Misconceptions Prominent 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

  41. 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

  42. Barriers Cont’d • Safety Concerns • Needle issues • Don’t believe susceptible to flu/pertussis • Not normalized to OB providers • $$ • Comfort with interventions • Fear of litigation • Etc., Etc., Etc. Moniz & Beigi Hum Vaccin Immunother 2014;10

  43. Overcoming Barriers • Georgia and R.I. PRAMS • 2006-2007, X-sectional, Seasonal • 18.4% & 31.9% vaccination rates • RI: Vaccination • OR=56.6 (37.4-85.6) if HCP encouraged • MGH, 2009 H1N1 & Seasonal • 370 (53%) PP women, survey • 81% accepted both H1N1 & Seasonal • 60% desire to protect self • 60% Ob recommendation • 80% desire to protect baby Ahluwalia IB. Obstet Gynecol 2010;116 Goldfarb I. AJOG 2011;204(S)

  44. Complexity of Intervention Acceptance Moniz & Beigi Hum Vaccin Immunother 2014;10

  45. Promoting Maternal Acceptance Moniz & Beigi Hum Vaccin Immunother 2014;10

  46. National Vaccine Advisory Committee (NVAC)Maternal Immunization Working Group (MIWG) Federal Advisory Committee Recommendations for Overcoming Barriers to Maternal Immunization

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