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

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

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

Maternal Mortality Rates Per 100,000 Live Births

Source: Hogan MC, et al. Lancet. 2010 May 8;375(9726):1609-23.

Neuzil et al. Am J Epi 1998

Fundamentals of Maternal Immunization

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]

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

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

IgG Subtype transfer by Gestational Age

Palmeira et al, IDOG 2012

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.

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

Impact of Malaria, HIV, and Raised on IgG Transfer

Journal of Infectious Diseases Advance

Access published July 14, 2014

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

Pertussis IgA Antibody Titers in Breast Milk

Abu Raya: Vaccine 2014

BREAST MILK IS IMMUNOLOGICALLY IMPORTANT

Brandtzaeg 2003

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

CMIAntibody

□ Pre vaccine

Post vaccine

■ After MMR

boost

Absence

of Mat

Ab

Impact of Maternal PT Titers on Infant Responses?

Van Savage et al JID 1990

Maternal Antibody Inhibits Infant Influenza Responses

Challenges to vaccine acceptance

Challenges to Vaccine Safety

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

30

a. Običan et al. AJMG. 2011b. Bednarczyk et al. AJOG. 2012 c. Weeks since fertilization

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

31

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

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”