Lara Misegdes, PhDAugust 1, 2012
Post-exposure Anthrax Vaccination of Pregnant Women
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
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
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
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
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
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
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)
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
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
Issues Considered by ACIP, 2010 Burden of disease
Immunogenicity and Efficacy
Safety (trisemester-specific issues)
Post-exposure alternatives
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.
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).
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
Comparison of Primary and Alternative Models: Adjusted Odds of Birth Defects Among Infants of Military Women, by Maternal
Anthrax Vaccination Status, 1998-2004.*Referent Group for Maternal Vaccination
Vaccinated outside of 1st trimester (primary model) Vaccinated post-pregnancy Never vaccinated
Exposure Groups with Associated Odds Ratios and 95% Confidence Intervals
1st trimester vaccinated
1.18(0.997, 1.41)
1st trimester vaccinated
1.20(1.005, 1.43)
1st trimester vaccinated
1.20(1.02, 1.42)
Pre-pregnancy vaccinated
1.09(0.98, 1.22)
Pre-pregnancy vaccinated
1.08(0.99, 1.17)
Late-pregnancy vaccinated
0.86(0.58, 1.27)
Late-pregnancy vaccinated
0.86(0.59, 1.26)
Post-pregnancy vaccinated
1.02(0.95, 1.10)
Ever- vaccinated
1.05(0.98, 1.12)
*Ryan, MAK, et al. Birth Defects among Infants Born to Women Who Received Anthrax Vaccine in Pregnancy. Amer J Epi; July 2008
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
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
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
AVA in Pregnant Women Reported to Adverse Events Reporting System, Sept 1998-June 2012
CharacteristicNo. reports 116 Serious, n (%) 6 (5.2)Maternal age, years, median (range) 22.0 (18-47)Gestational age, wks, at time of vaccination, median (range) a
3 (1-15)
Military reports 99 (85.3%)Anthrax vaccine given alone 44 (37.9%)
a 47 reports with gestational age information; 46/47 received vaccine during first trimester and one during second trimester
Adverse events among pregnant women (N=116) Anthrax Vaccine, VAERS, Sept
1998 – June 2012*Characteristic N (%)Pregnancy-specific outcomes 16 (13.8) Spontaneous abortion * 11 (9.5)
Stillbirth (trisomy 13, multiple unspecified congenital anomalies)
1
Pre-eclampsia, pre-term delivery (29 weeks gestation) *
1
Therapeutic abortion 1
Threatened abortion, anemia 1
Vaginal Bleeding 1
*Preliminary Results, Courtesy of Immunization Safety Office
Adverse events in Infants (N=116), VAERS, Sept 1998 – June 2012*
Characteristic N (%)Neonatal outcomes: 8 (6.9)
Gaucher’s disease * * 1
Down’s Syndrome 1
Sacral teratoma & multiple vertebral & rib abnormalities 1
Pervasive developmental disorder 1 Autoimmune disorder, stuttering ** 1
Multiple infections, RSV, rotavirus, ear infections * 1
Moderate meconium 1
Infant with snorty breathing 1
No adverse events 85 (73.3)
*Preliminary Results, Courtesy of Immunization Safety Office
** Reported as serious adverse event
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
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
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
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
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.”
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
Vaccinating pregnant women with Tdap leads to higher antibody levels in
infants
Outcome Antibodies
Mother did not receive Tdap, mean (SEM) n=52
Mother received Tdap, mean (SEM) n=52
P valuea
Pearson correlation coefficient (P valuea)
PT 11.010 (1.796) 28.220 (2.768) < .001 0.158 (.055)
FHA 26.830 (4.022) 104.15 (21.664) .002 0.165 (.045)
PRN 24.700 (5.765) 333.01 (56.435) < .001 0.965 (< .001)
FIM 2/3 82.83 (14.585) 1198.99 (189.937)
< .001 0.293 (< .001)
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.
FHA, filamentous hemagglutinin; FIM, fimbriae; PRN, pertactin; PT, pertussis toxin;a Significant at .05 level.
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
GMTAnti-PT (95% CI)
(Npos/N) (%)*Anti-FHA (95% CI)
(Npos/N) (%)*Anti-PRN (95% CI)
(Npos/N) (%)*Cord blood
Group A‡ 6.1 (3.5–10.6) (12/22) (54%)
22.2 (12.9–38) (19/22) (86%)
20.3 (11.8–35) (19/22) (86%)
Group B‡ 19.0 (11.7–30.7) (21/22) (95%)
247.0 (161–379) (22/22) (100%)
278.0 (154–502) (22/22) (100%)
Infant month 1
Group A‡ 3.1 (1.6–6.0) (5/14) (35%)
10.6 (5–22) (10/14) (71%) 9.8 (5.2–18) (8/14) (57%)
Group B‡ 10.3 (6.3–16.8) (18/22) (81%)
152.1 (104–220) (22/22) (100%)
167.4 (102–274) (22/22) (100%)
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]
*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.
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
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
For more information please contact Centers for Disease Control and Prevention1600 Clifton Road NE, Atlanta, GA 30333Telephone, 1-800-CDC-INFO (232-4636)/TTY: 1-888-232-6348E-mail: [email protected] Web: www.cdc.govThe findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.
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