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

Characteristic

No. 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: cdcinfo@cdc.gov Web: www.cdc.gov

The 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.

Thank you!