Update on
Maternal Immunization
November 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
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
Outline
Brief Background on Immunization
Maternal Immunization
Influenza
Tdap
Ongoing policy/research considerations
Summary
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
Courtesy: SA Plotkin:2006
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
Conceptual Basis
Courtesy: SA Plotkin:2006
Conceptual Basis
Courtesy: SA Plotkin:2006
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)
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
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!
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
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
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
Influenza vaccination rates during pregnancy,
Canada and United States, 1974-2003
Authors, year (reference)
Population
Study
Period
Source of
Vaccine Data
Vaccination
Rate (%)
Neuzil et al., 1998 (11)
Medicaid population,
United States
1974-1993
Medicaid
database
<0.1
Mullooly et al., 1986 (10)
Managed care organization,
United States
1975-1979
Medical
record review
<1*
Black et al., 2004 (18)
Managed care organization,
United States
1997-2002
Vaccine
Registry
7.5
Munoz et al., 2005 (19)
Clinic population, United
States
1998-2003
Clinic
Database
3.5
Silverman & Greif, 2001 (35)
Hospital-based survey of
postpartum women, United
States
2000
Self-report
8
Tuyishime et al., 2003 (44)
Hospital-based survey of
postpartum women, Canada
2002
Self-report
2
NHIS,+ 2003 (34)
Population-based telephone
survey, United States
2003
Self-report
12.8
*Vaccination
+NHIS,
rate was 6% during the 1976 swine flu vaccination campaign
National Health Interview Survey
Naleway AL. Epidemiol Rev 2006; 28
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. Obstet Gynecol 2004;104
CDC. MMWR 2011;60.
Ding H. AJOG 2011;204. CDC. MMWR 2010;59.
D. Internet Panel Survey, 11-2013. www.cdc.gov
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
Influenza Vaccine in Pregnancy
Effectiveness and Immunogenicity
– Effectiveness of vaccine in
pregnant women
– Exclusion from clinical trials
– Studies have not included
specific outcomes such as
laboratory-confirmed influenza
ELISA Units
Pregnant women given TIV
develop protective
concentrations of anti-influenza
antibodies
Maternal immunization increases
the amount of antibody
transmitted to infants
Limitations:
Antibody to influenza A and B in mothers and
their infants following maternal immunization
with TIV or TT (control)
18000
16000
14000
12000
10000
8000
6000
4000
2000
0
Control Control Control H1N1
H1N1 H3N2
B
H3N2
B
Mother delivery Infant delivery Infant 2 mo
Englund et al: J Infect Dis 1993;168:647-56
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
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
Summary of Benefits
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
Summary of Benefits
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
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
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)
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.
Pertussis trends
0-11 months of age
Tanaka M. JAMA. 2003 Dec 10;290(22):2968-75.
Pertussis Deaths
Pertussis Deaths in Infants Younger Than 1 Years of Age in 1938 – 1940 and 1990 –
1999 in the United States
1990 – 199925*
1938 - 194024
Age (mo)
n
%
n
%
0
1
2
3
4
5
6
7
8
9
10
11
396
1166
1061
791
646
515
502
458
447
417
361
363
5.6
16.4
14.9
11.1
9.1
7.2
7.0
6.4
6.3
5.9
5.1
5.1
35
33
12
4
3
2
1
3
0
0
0
0
38.0
34.8
13.0
4.4
3.3
2.2
1.1
3.3
0.0
0.0
0.0
0.0
*Also
personal communications with Dr. Tanaka.
Van Rie A. Pediatr Infect Dis J 2005;24
Which Family Members?
Grandparent
8%
Other
25%
Sibling
20%
Father
15%
Mother
32%
Bisgard KM, et al. Pediatr Infect Dis J. 2004;23:985-989.
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
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
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
Maternal Tdap vaccination
leads to higher Ab levels in
infants
Geometric mean concentrations
(GMCs) and % of placental
transfer of Ab (n=196)
Antigen
Maternal serum
GMC (95%CI)
Cord Serum
GMC (95% CI)
Placental transfer
%
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
PT
deVoer RM. Clin Infect Dis 2009 Jul 1;49(1):58-64
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
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
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
Current ACIP Reccs:
Moniz & Beigi Hum Vaccin Immunother 2014;10
www.cdc.gov
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
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’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
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)
Complexity of Intervention
Acceptance
Moniz & Beigi Hum Vaccin Immunother 2014;10
Promoting Maternal Acceptance
Moniz & Beigi Hum Vaccin Immunother 2014;10
NATIONAL VACCINE ADVISORY COMMITTEE (NVAC)
MATERNAL IMMUNIZATION WORKING GROUP (MIWG)
Federal Advisory Committee Recommendations
for Overcoming Barriers to Maternal
Immunization
50
New Developments - Research
PhRMA
– New candidate vaccines
GBS, RSV, etc.
NIH/NIAID/DMID:
– 2011 – Current:
“Research on vaccines and antimicrobials in
pregnancy”
Multidisciplinary: FDA, NIH, Industry, Academia
Delineated paradigm & recommendations for
vaccine/antimicrobial trials in pregnancy
Summary
Influenza Vaccine
– High risk group, Safe, Neonatal protection
– Fetal Protection, CE (Cost-Saving)
– Ob-Gyn’s: 13% in pregnancy 2008
Improvement seen nationally (40-50%) 2013
Much room for growth (80% - HP 2020)
– Direct OB provider recommendation KEY
Tdap
– Recommended in pregnancy 27-36 wks
– Neonatal protection (10 < 2-4 mos)
Summary
Paradigm shift in OB immunization
– Exciting time for Maternal Immunization
Demonstrated Success - past & present
Ongoing changes occurring
– Recommendations & Expectations
– PhRMA involvement
– HHS policy/agenda
Foundation for robust advancement