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Post-exposure Anthrax Vaccination of Pregnant Women

Post-exposure Anthrax Vaccination of Pregnant Women. Lara Misegdes, PhD August 1, 2012. Overview. Vaccines Workgroup Activities Anthrax Vaccine Adsorbed (AVA) Considerations for use of post-exposure AVA in pregnant women ACIP recommendations for use of post-exposure AVA in pregnant women

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Post-exposure Anthrax Vaccination of Pregnant Women

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  1. Post-exposure Anthrax Vaccination of Pregnant Women Lara Misegdes, PhD August 1, 2012

  2. Overview • Vaccines Workgroup Activities • Anthrax Vaccine Adsorbed (AVA) • Considerations for use of post-exposure AVA in pregnant women • ACIP recommendations for use of post-exposure AVA in pregnant women • Future research

  3. Vaccines Workgroup • Ava Conlin- NHRC • Mike McNeil- ISO/NCEZID • Conrad Quinn- MVPD/NCIRD • Georgina Peacock- ONDIEH/NCBDDD • Tom Shimabukuro- ISO/NCEZID • Heather Watts- NIH • Nancy Messonnier- MVPD/NCIRD

  4. Advisory Committee for Immunization Practices (ACIP) • Provides advice and guidance to the Secretary, HHS, the Assistant Secretary for Health, and CDC Director, CDC, regarding: • The control of diseases with a vaccine licensed in the U.S.  • The most appropriate use of vaccines, including population groups and/or circumstances recommended • Structure: 15 voting members including chairperson (non-government), 30 liaison representatives, 8 ex-officio (non-voting) members • Work groups review literature, formulate recommendations to be considered by ACIP

  5. Anthrax ACIP Work Group • 35 members representing multiple stakeholders • 12 conference calls • Safety evaluations • Immunogenicity studies • Efficacy analyses • Vaccine supply information • Contemporary experience with use of AVA • Anthrax vaccine recommendations voted on in October 2008 and February 2009 • Published in MMWR in 2010

  6. ACIP Pregnancy Principles Document • Ensure recommendation development is consistent and rigorous, recommendations clear and uniform • Provides core topics, Anthrax WG reviewed: • Disease burden • Vaccination during pregnancy • Rationale, safety, immunogenicity, efficacy, timing • Vaccination during breastfeeding • Rationale, safety, immunogenicity, efficacy, timing • Alternatives to vaccination • Not reviewed by Anthrax WG: Cost effectiveness, Logistics. Future research http://www.cdc.gov/vaccines/recs/acip/downloads/preg-principles05-01-08.pdf

  7. AVA Vaccine in Pregnant and Post-partum Women Workgroup Activities • Review of existing data • 2010 Anthrax ACIP statement • Published literature on AVA in Pregnancy • Updated analysis of Vaccine Adverse Event Reporting System reports of AVA in pregnancy • Concurrence that no new data since 2010 ACIP recommendations

  8. Anthrax Vaccine Adsorbed (AVA) • Only licensed anthrax vaccine in the US • Aluminum-adjuvant, anthrax toxin ‘protective antigen’ • 1970: licensed for persons with occupational risk • 6 SQ injections (0, 2 and 4 weeks; 6, 12, and 18 months), annual boosters • 2008: FDA approved dose reduction and route change following phase 4 clinical trial • Pre-exposure schedule of 5 doses (0, 4 weeks, 6, 12, 18 months), route changed to IM • 2012: FDA approved further reduction in primary series to 3 doses (0, 1, and 6 months)

  9. Postexposure AVA • Component of PEP under an Investigational New Drug (IND) protocol • May be available under an Emergency Use Authorization (EUA) • ACIP recommendation : 3 doses at 0, 2, 4 weeks administered SQ

  10. AVA in Pregnant Women • Not a live vaccine • No biologically plausible mechanism for reproductive effect* • FDA Pregnancy Category D • Based on preliminary analysis of the Ryan, et al study • “There is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.” * Wiesen A and Littell C, JAMA 2002

  11. Issues Considered by ACIP, 2010 • Burden of disease • Immunogenicity and Efficacy • Safety (trisemester-specific issues) • Post-exposure alternatives

  12. Immunogencity and Efficacy • AVA produces robust immune response in non-pregnant adults • No AVA-specific immunogenicity or efficacy studies of pregnant or breastfeeding women • Studies of other vaccines1,2 during pregnancy do not indicate pregnancy decreases efficacy/immune response 1 Baker, et al. Immunization of pregnant women with group B streptococcal type III capsular polysaccharide-tetanus toxoid conjugate vaccine. Vaccine. 2003 Jul 28;21(24):3468-72. 2 Quiambaio, et al. Immunogenicity and reactogenicity of 23-valent pneumococcal polysaccharide vaccine among pregnant Filipino women and placental transfer of antibodies. Vaccine. 2007 May 30;25(22):4470-7.

  13. Safety: AVA and Female Fertility • Cohort study of 385 military women vaccinated pre-pregnancy* • Primary outcome = pregnancy • Did not support hypothesis that AVA results in decreased pregnancy rates or adverse fetal outcome • No evidence of miscarriage, infertility, other reproductive problems • Not powered to detect rare adverse birth outcomes *”Relationship between Prepregnancy Anthrax Vaccination and Pregnancy and Birth Outcomes Among US Army Women.” JAMA. 2002.287:12(1556-1560).

  14. Safety: Birth Defects Among Infants Born to Women Who Received Anthrax Vaccine in Pregnancy* • 37,140 infants born to vaccinated women • Utilized ICD-9 codes for birth defect diagnoses • Primary referent group = Infants born to women vaccinated during first trimester compared with all other vaccinated women • Alternative referent groups utilized *Ryan, MAK, et al. Birth Defects among Infants Born to Women Who Received Anthrax Vaccine in Pregnancy. Amer J Epi; July 2008

  15. Comparison of Primary and Alternative Models: Adjusted Odds of Birth Defects Among Infants of Military Women, by Maternal Anthrax Vaccination Status, 1998-2004.* *Ryan, MAK, et al. Birth Defects among Infants Born to Women Who Received Anthrax Vaccine in Pregnancy. Amer J Epi; July 2008

  16. Specific Birth Defects • Further explored 10 specific birth defects with >5 cases per group • Atrial septal defect (ASD) represented a statistically significant increase from the reference group in the published analysis (OR=1.38, 95% CI=1.04-1.82) • However, upon further review: • Not statistically significant upon exclusion of isolated ASD cases in preterm infants • Not statistically significant when adjustment for multiple comparisons applied. *Ryan, MAK, et al. Birth Defects among Infants Born to Women Who Received Anthrax Vaccine in Pregnancy. Amer J Epi; July 2008

  17. Assessment of Ryan, et al Data • “After review of these data and discussions with the authors of this study, ACIP concluded that AVAV is safe to administer during pregnant women but recommended that pregnant women defer vaccination unless exposure to anthrax poses an immediate risk for disease • Evidence not conclusive to associate vaccination with birth defects • Being vaccinated during first trimester may be indicative of late maternal recognition of pregnancy • May be marker for other risk factors for birth defects *Ryan, MAK, et al. Birth Defects among Infants Born to Women Who Received Anthrax Vaccine in Pregnancy. Amer J Epi; July 2008

  18. Safety of Other Inactivated Vaccines During Pregnancy • Maternal vaccination has not been established to cause birth defects • Other inactivated vaccines are recommended for use in at risk women during pregnancy • Tdap, hepatitis B, poliovirus, influenza • Studies evaluating vaccine safety during pregnancy for other vaccines1,2 1 Baker, et al.. Vaccine. 2003 Jul 28;21(24):3468-72. 2 Quiambaio, et al. Vaccine. 2007 May 30;25(22):4470-7

  19. AVA in Pregnant Women Reported to Adverse Events Reporting System, Sept 1998-June 2012 a 47 reports with gestational age information; 46/47 received vaccine during first trimester and one during second trimester

  20. Adverse events among pregnant women (N=116) Anthrax Vaccine, VAERS, Sept 1998 – June 2012* *Preliminary Results, Courtesy of Immunization Safety Office

  21. Adverse events in Infants (N=116), VAERS, Sept 1998 – June 2012* *Preliminary Results, Courtesy of Immunization Safety Office ** Reported as serious adverse event

  22. VAERS Analysis: Conclusions • Most reports (73%) did not describe an adverse event; six patients required hospitalization; no maternal or neonatal deaths • Most reports (98%) received vaccine during first trimester • Most common maternal outcome were SABs in 11 reports (10%) • No safety pattern of concern observed

  23. Alternatives to Vaccination • Antimicrobials alone only alternative in post-exposure event • Antimicrobial agents provide protection only for the duration of their utilization • Vaccination maximizes protection with: • Spore germination and outgrowth • Imperfect adherence to antimicrobials • Unvaccinated persons need antimicrobials and vaccination following exposure

  24. Summary of ACIP Discussions • The burden and severity of disease in the event of exposure may be high • No biologic plausibility for decreased immunogenicity of vaccine • No biologic plausibility for increased risk of birth defects • Available safety data are reassuring • Post-exposure alternatives to vaccination are not acceptable

  25. Use of AVA in Breastfeeding Women • No data have been collected on the use of AVA among breastfeeding women • No biologic reason suggests that breastfeeding women or infants who are breastfed have an increased risk for adverse events after vaccination. • Data from similar vaccines indicate that transfer of anti-anthrax antibodies from mother to infant through milk may occur. • Administration of other inactivated vaccines is not contraindicated in breastfeeding women

  26. 2010 ACIP Recommendations for AVA in Pregnant and Breastfeeding Women “In a pre-event setting, in which the risk for exposure to aerosolized B. anthracis spores is presumably low, vaccination of pregnant women is not recommended and should be deferred until after pregnancy. Breastfeeding is neither a precaution nor a contraindication to vaccination” “In a postevent setting that poses a high risk for exposure to aerosolized B. anthracis spores, pregnancy and breastfeeding are neither a precaution nor a contraindication to PEP. Pregnant and breastfeeding women at risk for inhalation anthrax should receive AVA and 60 days antimicrobials as described.”

  27. Other Issues • Communicating safety and importance of vaccination of pregnant women in a post-event scenario (communication subgroup) • Programmatic implications of maternal vaccination on infant vaccination (to be considered by AAP) • Should infants of vaccinated pregnant women be vaccinated and at what age? • Considerations of protection of the infant through maternal antibody transfer • No data on anthrax vaccine • Data on maternal Tdap supports maternal antibody transfer

  28. Vaccinating pregnant women with Tdap leads to higher antibody levels in infants FHA, filamentous hemagglutinin; FIM, fimbriae; PRN, pertactin; PT, pertussis toxin; a Significant at .05 level. Gall SA, Myers J, Pichichero M. Maternal immunization with tetanus-diphtheria-pertussis vaccine: effect on maternal and neonatal serum antibody levels. Am J Obstet Gynecol 2011;204:x.ex-x.ex.

  29. Infants of mothers vaccinated with Tdap (group B) have higher levels of antibody at birth and at 1 month compared to siblings born prior to maternal vaccination *Npos/N =number of positive samples/total number of available samples; % positive samples. ‡Group A: first born children, before the maternal booster dose; group B: second cohort of children, born after the maternal booster dose. PT =pertussis toxin; FHA=filamentous hemagglutinin; PRN=pertactin; CI=confidence interval. Leuridan E, et al. Effect of a prepregnancy pertussis booster dose on maternal antibody titers in young infants. Pediatr Infect Dis J. 2011 Jan 4. [Epub ahead of print]

  30. Summary of Experience with Tdap maternal vaccination • Effective maternal-infant antibody transfer after Tdap • Antibody levels higher in infants of vaccinated mothers at 1 month • Maternal antibodies are likely to provide infants protection against pertussis • In setting of anthrax exposure, vaccination could protect mothers and newborn infants • Infants immune system immature, will have lower response to antrhax vaccine compared to adults • Maternal antibody is likely most effective way to protect newborns in the short term in the setting of an anthrax exposure

  31. Future Research on AVA in Pregnant Women • DoD Studies planned or in progress (sponsored by Emergent) • Birth and infant registry analysis (Ryan et al) with updated data, exclude pre-term infants • Prospective, active registry data analysis comparing maternal/fetal outcomes (anthrax and smallpox vs smallpox alone) • Analysis of newly established pregnancy registry

  32. Thank you!

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