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The Science of Maternal Vaccination
Kathryn M. Edwards, M.D.Sarah H. Sell and Cornelius Vanderbilt Professor
Department of PediatricsVanderbilt Vaccine Research Program
Vanderbilt University
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Objectives
• Why Immunize Pregnant Women?
• Fundamentals of maternal vaccination
– Mechanisms of placental antibody transport
– Breast milk antibody transfer outlined
• The impact of maternal antibody on primary immune responses in the infants
• Challenges to vaccine acceptance
• Ensuring vaccine safety and effectiveness
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Why Immunize Pregnant Women?
• Immunologic changes to decrease fetal rejection
• Potential to prevent infections in pregnant woman
• Accessible due to regular care during pregnancy
• Prevent disease in infants by reducing maternal transmission of infectious agents to the infant and by providing transplacental antibody
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Maternal Mortality Rates Per 100,000 Live Births
Source: Hogan MC, et al. Lancet. 2010 May 8;375(9726):1609-23.
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Neuzil et al. Am J Epi 1998
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Fundamentals of Maternal Immunization
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Antibody Isotypes
Isotype Types Description
IgA 2Found in mucosal areas (gut, respiratory tract, urogenital tract) and saliva, tears, breast
milk. Prevents colonization by pathogens.
IgD 1Functions mainly as an antigen receptor on B cells that unexposed to
antigens. Activate basophils and mast cells to produce antimicrobial factors.
IgE 1Binds to allergens & triggers histamine release from mast cells and basophils. Also
protects against parasitic worms.]
IgG 4Provides the majority of antibody-based immunity against invading pathogens. The only
antibody capable of crossing the placenta to give passive immunity to the fetus.
IgM 1
Expressed on the surface of B cells (monomer) and in a secreted form (pentamer) with
very high avidity. Eliminates pathogens in the early stages of B cell-mediated (humoral)
immunity before there is sufficient IgG.[3][14]
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Placental IgG transport
• Receptor-mediated binding of the Fcᵧ portion of
IgG at the maternal surface of the placenta within
the syncytiotrophoblast
• Transport of IgG in coated vesicles across the
trophoblastic layers
• Coated vesicles protect IgG against proteolysis so
that intact IgG is released into the fetal circulation
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Maternal-Fetal IgG Transport: AN ACTIVE PROCESS• Placental transfer is highly
selective for monomeric IgG,
and occurs by receptor-
mediated active transport
• Transport requires HEALTHY
placenta
• IgG1 = IgG3 > IgG4 > IgG2
• No transfer of IgM, IgA, IgE
• Begins at 17 wks; increases
with gestation
• By 33 weeks maternal = fetal
IgG levels and by 40 weeks
fetal > maternal IgG levels
Kohler and Farr. Nature 1966;21:1070
Placental transport across gestation
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IgG Subtype transfer by Gestational Age
Palmeira et al, IDOG 2012
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Impaired Placental Antibody Transport in HIV-Infected Mothers
• Lower specific antibody levels to some antigens in HIV-infected pregnant women.
• Reduced placental transfer of antibodies.
Source: Jones CE, et al. JAMA. 2011 Feb 9;305(6):576-84.
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Placental Transfer of Maternal Ab is Active But
Rate Limited: Lower Anti-Measles Ab In Babies Born to Nigerian vs German Mothers*
Total Maternal IgG
At Delivery
Mean (Range) (g/L)
Maternal
Measles
NT Ab
Cord
Measles
NT Ab
%
Trans-
mission
Nigerian 15.8
(18-26)
6.0 6.0 100%
German 8.7
(4.8- 16)
7.0 7.7 140%
*Harter et al. PIDJ 2000;19:635-41
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Impact of Malaria, HIV, and Raised on IgG Transfer
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Journal of Infectious Diseases Advance
Access published July 14, 2014
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Summary of Placental Transport
• Efficient means of providing antibody to infant
• Transfer of IgG dependent on FcRn receptor
• IgG subtypes cross placenta at different rates
• IgG transfer increases with gestation
• Impaired with HIV, malaria, elevated IgG
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Pertussis IgA Antibody Titers in Breast Milk
Abu Raya: Vaccine 2014
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BREAST MILK IS IMMUNOLOGICALLY IMPORTANT
Brandtzaeg 2003
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Inhibitory effect of maternal antibody on active
infant immunization has been well described
High maternal measles Ab markedly inhibits infant
Ab response, while lower maternal measles Ab has
more variable impact on infant Ab responses
T-cell responses to measles, as measured by
induction of Th1/TH2, levels of IFN-gamma/IL-5,
and CTL are not affected by maternal antibody
Findings replicated for tetanus toxoid vaccine
*Siegrist et al Eur J Imm 1998;28:4138
Impact of Maternal Antibody on Vaccine Responses:
Inhibition of Infant Antibody Responses
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CMIAntibody
□ Pre vaccine
Post vaccine
■ After MMR
boost
Absence
of Mat
Ab
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Impact of Maternal PT Titers on Infant Responses?
Van Savage et al JID 1990
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Maternal Antibody Inhibits Infant Influenza Responses
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Challenges to vaccine acceptance
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Challenges to Vaccine Safety
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Teratogenic Exposure in Pregnant Woman Teratogenic Exposure: increases the risk for
Birth defects
Functional impairment
Growth restriction
Impaired viability
Critical time periods
Period Age weeks Teratogenic Potential
BeforeImplantation
0-2Kills the embryo or no effect
“All or None”
Embryonic 2-9May affect organogenesis and cause major defects in organs
Fetal 9-term May affect growth, differentiation, maturation
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a. Običan et al. AJMG. 2011b. Bednarczyk et al. AJOG. 2012 c. Weeks since fertilization
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Background Rates for Selected Pregnancy Outcomes in US
Conditions Background rate
Spontaneous abortion 10.4% - 22.4%a
Fetal death (≥20 weeks) 0.61 per 100 live births plus fetal deaths b
Preterm birth (<37 weeks) 11.9%c
Small for gestational age 8-16%d
Major birth defects 3%e
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a Black et al. Importance of background rates of disease in assessment of vaccine safety during mass
immunization with pandemic H1N1 influenza vaccines. Lancet 2009;374:2115-22.b MacDorman MF, et al. Fetal and perinatal mortality, United States, 2006. Natl Vital Stat Rep 2012;60(8):1-23. c. Martin, JA, et al. Births: final data for 2010. National Vital Statistics Report. 2012;61(1):1-100d CDC. QuickStats: Percentage of Small-for-Gestational-Age Births, by Race and Hispanic Ethnicity --- United States,
2005. MMWR Weekly Report. December 19, 2008;57(50):1359 available at: e Correa et al., Reporting birth defects
surveillance data 1968-2003. Birth Defects Res A Clin Mol Teratol. 2007 Feb;79(2):65-186.
Rates established prior to onset of maternal vaccination studies
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Conclusions
• Pregnancy is a time of immunologic changes with increased susceptibility to some infections
• Transplacental antibody transfer is an active process but reduced in some conditions
• Maternal antibody inhibits infant responses, but antibody inhibition can generally be overcome
• Uptake of vaccines in pregnancy is challenging• Adverse outcomes of pregnancy not uncommon• Maternal immunization protects both mother
and infant or a “Two-fer”