The Impact of IgG transplacental transfer on early life immunity

Abstract

Pediatric vaccines have significantly reduced infectious disease-related infant mortality, but as protective immunity often require several infant vaccine doses; maternally-acquired antibodies are critical to protect infants during the first months of life. Consequently, immunization of pregnant women is an important strategy not only to protect mothers from infection, but also to provide immunity to young infants. Nevertheless, maternal immunization can also negatively impact early life immunity. In fact, maternal antibodies can interfere with the development of infant immune responses, though it is unclear if such interference is clinically significant. Moreover, the transplacental transfer of maternal immunoglobulin therapeutics can be harmful to the fetus. Thus, the risk/benefit of maternal immunization for both the mother and the fetus should be carefully weighed. In addition, it is critical to fully understand the mechanisms by which IgG is transferred across the placenta in order to develop optimal maternal and infant immunization strategies.

Introduction

The WHO estimates that 5.9 million children under 5 years of age died in 2015, with more than 40% of these deaths due to infectious diseases (1). Children are particularly vulnerable during the neonatal period as 45% of less than 5-year-old children deaths occur during the first month of life. Maternal antibodies transferred to the baby in utero across the placenta and through breastfeeding are critical to protect infants from infections during the first months of life. Vaccination during pregnancy to boost maternal antibody levels and enhance infant passive immunization has been effective to fight against some neonatal infections such as tetanus (2, 3). Nevertheless, the incidence of other neonatal pathogens such as pertussis has increased over the last 3 decades (4). Importantly, even when infants passively acquire protective levels of pertussis-specific IgG, these antibodies rapidly wane during the first two months of life leaving the infant vulnerable to infection (5, 6). On the other hand, licensed maternal vaccines are not yet available against some life-threatening neonatal pathogens such as group B streptococcus or respiratory syncytial virus. Novel approaches to extend the period during which infants are protected by maternal antibodies as well as novel maternal vaccines would be critical to reduce infectious disease-related neonatal and infant mortality.

The Fc neonatal receptor (FcRn) has been demonstrated to play a critical role in mediating IgG transplacental transfer (7, 8), but recent studies demonstrating distinct transfer efficiencies of different epitope specific-IgG suggest that other mechanisms could also contribute to the regulation of IgG transfer. This review summarizes current knowledge on the mechanism of IgG transplacental transfer and on factors associated with impaired IgG transfer. In addition, the potential benefits and harms of IgG transplacental transfer on the fetus and the timing of maternal immunization for optimal transplacental transfer are discussed.

1. Mechanisms of IgG transplacental transfer

In order to be transferred from the maternal to the fetal circulation, IgG must cross several anatomical barriers. In fact, the fetal and maternal circulatory systems are separated by placental tree-like floating villous structures made up of syncytiotrophoblasts in the outermost cell layer, with a cytotrophoblast cell layer directly beneath (9). The villous trees contain fetal blood vessels, which feed into the umbilical cord and ultimately into the fetal circulatory system (9). To reach the fetal circulation, maternal IgG must cross the syncytiotrophoblast and cytotrophoblast cell barriers, and then be transferred across the villous stroma to ultimately reach the lumen of fetal endothelial vessels.

1.1 Role of Fc neonatal receptor (FcRn) in IgG transplacental transfer

FcRn is a major histocompatibility complex (MHC) class I related molecule (10) that plays a central role in the regulation of IgG homeostasis and in IgG transport across polarized epithelial barriers (11, 12). It is expressed by a variety of cells including epithelial cells, endothelial cells and myeloid derived antigen presenting cells. Expression of FcRn on antigen-presenting cells appears to be crucial for efficient IgG mediated phagocytosis (13) whereas expression on endothelial cells is important to prolong IgG half-life by recycling internalized IgG back to the surface (14). Early studies have demonstrated that the Fc receptor neonatal (FcRn) expressed on syncytiotrophoblast cells is a key contributor to IgG transplacental transfer (15, 16). FcRn is mostly present in the cytosol and it binds the Fc portion of IgG at acidic pH (17, 18). It is thought that maternal IgG in the intervillous space undergoes fluid-phase endocytosis into syncytiotrophoblast cells into endosomes that undergo slight acidification (12, 19–21). FcRn then binds to maternal IgG in these mildly acidic endosomes and is carried to the basal plasma membrane where IgG is released from FcRn upon exposure to normal pH in inside the villous tree (12). Yet, several steps in the IgG transport across the placenta remain incompletely understood. For example, the mechanism by which maternal IgG enters syncytiotrophoblast cells from the intervillous space is not completely elucidated (12, 16) nor is the mechanism by which maternal IgG is transported through the villous stroma. Importantly, aside from FcRn, several other Fcγ receptors (FcγRs) are expressed in the placenta (Table 1), but their physiologic relevance is not understood. Notably, Hofbauer cells contained in the villous stroma express FcγRI, FcγRII, and FcγRIII (22) and fetal endothelial cells express the low affinity monomeric IgG receptor FcγRIIb (15, 23, 24). Future studies should therefore focus on elucidating the mechanism of IgG transplacental transfer across the distinct placental anatomical barriers and explore the role of placental FcγRs in modulating IgG transfer.

Table 1.

Fc receptor expression in distinct placental cell populations crossed by IgG

Placental Fc receptor	FcγRI (CD64)	FcγRII (CD32)	FcγRIII (CD16)	FcRn
Trophoblasts	−(139, 140)	−(139, 140)	+(139–144)	+(15, 16, 18, 145)
Stromal cells	+(140, 143)	+(140)	+(140)	NR
Hofbauer cells	+(139–141, 143)	+(139–141, 143, 146)	+(139, 142, 143)	NR
Fetal endothelial cells	−(139, 140)	+(24, 139–141, 143, 147)	+(140)/−(139)	−(15, 16)

+ Detected, − Not detected, NR not reported

1.2 Timing of IgG transfer during gestation

The transplacental transfer of maternal IgG to the fetus begins during the first trimester of pregnancy. In fact, maternal IgG can be detected in cord blood as early as 8–10 weeks of gestation (7). However, only small amounts of maternal IgG are transferred in the first trimester, with an estimated transplacental transfer of approximately 10% of maternal IgG concentrations by 17–22 weeks gestation (25). The concentration of maternal IgG in infant cord blood reach approximately 50% of the maternal IgG levels by 30 weeks gestation (25) and by 37–40 weeks of gestation, infant cord blood concentrations of maternal IgG often exceed that of maternal serum by the delivery time point in full term, healthy pregnancies (25–28). Thus, while maternal IgG is transferred across the placenta throughout pregnancy, the majority of the transfer occurs in the last trimester of gestation; possibly due to an increase in the surface area of IgG uptake from maternal blood with higher gestational age. Yet, certain pathologic conditions of the placenta and maternal immunity can impair the efficiency of placental IgG transfer, including maternal HIV-1 and malaria infections. The timing and efficiency of the IgG transplacental transfer has important implications for the development of maternal immunization strategies to protect infants.

Passively acquired maternal antibodies with different antigen-specificity have been reported to have distinct half-lives in infants. For example, although in normal pregnancy pertussis-specific IgG levels in cord blood achieve >100% of maternal levels, maternal pertussis-specific IgG has a half-life of 6 weeks in infants and wane to undetectable levels as early as 4 months of life (29). In contrast, maternal passively acquired measles-specific IgG remains near or above protective levels in 6-month-old infants and are still detectable by 1 year of life (30, 31). This suggests that maternally acquired measles-specific IgG compared to pertussis-specific IgG may have slower decay rates in infants. It remains unclear why different maternally acquired IgG responses have distinct decay rates in infants. However, the distinct half-lives of pertussis and measles-specific IgG in infants could, in part, be due to: A) distinct Fc region characteristics such as IgG subclass or Fc region glycans, or B) distinct interactions with the IgG recycling receptor in humans: FcRn. A deeper understanding the mechanism(s) of the distinct kinetics of maternally-acquired antigen-specific IgG in infants is critical to guide the development of strategies to increase the durability of maternal passively acquired IgGs and ultimately extend the window of antibody-mediated protection in the first year of life.

1.3 IgG characteristics that modulate IgG transplacental transfer

The efficiency of IgG transfer can vary from one antigen-specificity to another. For example, in normal pregnancy the transfer efficiency of IgG against pertussis can be up to 200% whereas for group B streptococcus it is only 70% (32, 33). Distinct characteristics of antigen-specific antibodies may contribute to explain these differences. Several reports have indicated that IgG subclass is an important determinant of transplacental transfer efficiency. IgG1 is the most efficiently transferred subclass, whereas IgG2 is transferred with the least efficiency (34, 35). Importantly, IgG subclass responses are distinctly modulated against different antigens (36). For example, the IgG response against polysaccharide antigens such bacterial capsule of Group B streptococcus or Haemophilus influenzae Type B (HiB) is primarily IgG2 subclass whereas the response against tetanus toxoid is predominantly IgG1 (28, 36). In addition to IgG subclass, antibody avidity (37, 38) and Fc region glycosylation profile may influence transplacental transfer (39, 40). The affinity of IgG binding to the canonical FcRn may also contribute to modulate the transplacental transfer efficiency. In fact the highly transfered IgG1 and IgG4 subclasses have comparably high affinity to FcRn whereas both IgG3 and IgG2 had lower affinities for FcRn (41). The differential transfer of antibodies of distinct subclasses has important implications for the development of monoclonal antibody therapeutics used during pregnancy.

1.4 Factors that impair IgG transplacental transfer

Transplacental transfer of maternal IgG is a highly efficient process in healthy pregnancies. In fact, infant cord blood concentrations of maternal IgG can well exceed maternal IgG serum concentrations by delivery in full term pregnancies (25–27). However, several factors can impair IgG transplacental transfer including: maternal infections during pregnancy (i.e., HIV and malaria), placental pathologies, and maternal hypergammaglobulinemia.

Placental malaria has been associated with reduced IgG transplacental transfer of malaria and vaccine-antigen-specific IgG (42–45). While the mechanism of this impaired IgG transfer remains unclear, studies have demonstrated that placental malaria leads to placental pathologies through an increased influx of monocytes, macrophages, and cytotoxic T cells into the placental intervillous space (46). Several studies have also indicated that HIV exposed uninfected (HEU) infants have lower levels of maternal antibodies than their unexposed counterparts (42, 45, 47–50). In fact, maternal HIV infection has been associated with poor transfer of antibodies against some pathogens including Streptococcus pneumonia, Haemophilus influenzae, Group B Streptoccoccus, Pertussis, poliomyelitis and measles (reviewed in (51)). In contrast, reports on the impact of maternal HIV on the transfer of other antibody specificities, such as anti-tetanus toxoid antibodies, have been variable between studies and populations (reviewed in (51)). It was recently reported that women on long-term antiretroviral therapy (ART) have improved IgG transplacental transfer than women who receive a short course of ART (52). Importantly, some studies have suggested that maternal HIV infection may also impact the quality of the transferred antibodies (53, 54). This observation needs to be confirmed in large cohorts of HIV infected mothers and HEU infants.

Maternal hypergammaglobulinemia, which is characterized by abnormally high levels of serum immunoglobulin, has also been associated with poor IgG transfer (44, 55). Notably, HIV and malaria induced maternal hypergammaglobulinemia was independently associated with poor transfer of IgG against tetanus toxoid, measles, and respiratory syncytial virus (42, 56). While it remains unclear how high maternal IgG serum levels interfere with IgG transplacental transfer, a potential mechanism could be the saturation of placental shuttle Fc receptors such as FcRn. Understanding the mechanism by which maternal pathologies lead to poor IgG transplacental transfer is crucial to devise optimal maternal immunization strategies to extend the window of infant protection against common neonatal pathogens during the first year of life.

2. Maternal immunization to protect infants from neonatal pathogens

Pregnancy is associated with a specific immunologic milieu, as the maternal immune system needs to tolerate the fetus allograft. As a result, some infections are more severe in pregnant women than in their non-pregnant counterparts. For example, influenza-related hospitalization and mortality are higher in pregnant women (57–60). The most effective way to protect pregnant women from the morbidity associated with infections is to vaccinate them against vaccine-preventable diseases (3). Maternal vaccination has the added benefit of protecting infants because antibodies are transferred to the fetus across the placenta. Protection of infants from maternal immunity was first observed in the 1800s during a measles outbreak as infants born to women who survived the disease were protected (61). More recent studies have demonstrated that similar to disease-induced IgG, vaccine-elicited IgG antibodies are efficiently transferred across the placenta (62, 63). Currently, vaccines routinely administered during pregnancy include influenza and Tdap. In addition, some vaccines such as those against pneumonia, meningococcus, hepatitis A and hepatitis B are recommended during pregnancy under specific circumstances (Table 2).

Table 2.

Maternal vaccine recommendations in the United States (adapted from 2016 CDC ACIP guidelines (148))

	Vaccine	Type	Indications
Routinely administered vaccines	Tdap	Toxoid/ inactivated	All pregnant women
	Influenza	Inactivated	All women pregnant during the influenza season
	Influenza	Live attenuated (LAIV)	Contraindicated during pregnancy
	Hepatitis A	Inactivated	Prior to travel, history of injection of illicit drug, professional exposure, chronic liver disease
	Hepatitis B	Protein	Prior to travel, sexual exposure, drug usage
	Meningoccal	Inactivated	Risk benefit assessment
	MMR	Live attenuated	Contraindicated during pregnancy. Postpartum if rubella non-immune
	Pneumococcal PCV 13	Conjugate	No recommendation
	Pneumococcal PPSV23	Polysaccharide	Inadequate data
	Poliomyelitis (IPV)	Inactivated	Use if needed
	Varicella	Live attenuated	Contraindicated during pregnancy. Postpartum if varicella non-immune
	Zoster	Live attenuated	Contraindicated during pregnancy
Other vaccines	Anthrax	Sub-unit	Vaccination not recommended in pre-event setting. May be used if high risk of exposure in post event setting.
	BCG	Live	Contraindicated
	Japanese encephalitis virus	Inactivated	Inadequate data for specific recommendation
	Typhoid	Live and inactivated	Inadequate data. Use Vi polysaccharide vaccine if needed
	Rabies	Inactivated	May be used if needed
	Yellow fever	Live attenuated	Risk benefit assessment

2.1 Vaccines routinely administered during pregnancy

Influenza vaccine

Influenza viruses represent one of the most significant causes of acute upper respiratory tract infections worldwide. While the virus causes morbidity in all age groups, influenza-associated complications and hospitalization rates are higher among pregnant women (60, 64, 65), and young infants (66, 67). Maternal immunization is critical to protect young infants because there is currently no licensed influenza vaccine capable of eliciting an immunogenic response in infants younger than 6 months. Thus, young infants are left unprotected during a period when they are susceptible to develop severe complications. The safety, immunogenicity, and efficacy of a trivalent influenza vaccine were recently evaluated in HIV infected and uninfected women from South Africa (clinicaltrials.gov numbers NCT013066669 and NCT01306682). The vaccine was found to be immunogenic and partially protective in both populations of pregnant women (68). Moreover, maternal vaccination was associated with protection of infants from PCR-confirmed influenza illness. But, the protection was short-lived (first 8 weeks of life) and correlated with a decrease in maternally acquired antibodies (6). A longer period of infant protection (4 months) was observed following immunization of pregnant women from Mali during the third trimester of gestation (69). Maternal vaccination was also associated with reduced rates of laboratory-confirmed influenza in a phase 4 randomized trial conducted in Nepal (clinicaltrials.gov number NCT01034254, (70)) and with reduced influenza related infant hospitalization in the United States (71).

Tetanus, Diphtheria, and Pertussis vaccines

A different setting in which maternal vaccination is critical for infant protection is when several doses of vaccine are required to achieve protective immunity in infants. This is the case for tetanus, diphtheria and pertussis for which booster doses are require to achieve protective antibody levels (72), which is achieved sometimes after 4–6 months of life. The causal agent of tetanus is Clostridium tetani, an anaerobic bacterium. C. tetani releases a neurotoxin that causes prolonged muscular contractions. Maternal and neonatal tetanus was a common life threating infection as a result of unclean delivery and umbilical care practices. The implementation of maternal immunization to protect against neonatal tetanus in the 1960’s has resulted in a 92% decrease in neonatal tetanus mortality rates worldwide (2). Routine vaccination has also led to the near eradication of diphtheria an upper respiratory infection caused by Corynebacterium diphtheria in the United States (73).

In contrast to tetanus and diphtheria, pertussis, a respiratory infection caused by Bordetella pertussis continues to be an important risk concern despite the availability of a vaccine (74, 75). Pertussis-related morbidity and mortality disproportionately affects young infants (74, 76, 77) and a significant decrease in pertussis related hospitalization only occurs after the administration of two vaccine doses (78). As the current vaccine schedule recommends Tdap vaccination at 2 months of age with booster doses as 4, 6, 15, 18 months, then between 4 and 6 years of age; infants less than 4 months of age are particularly vulnerable to infection. In a randomized trial, the addition of a vaccine dose at 14 days of life was associated with lower antibody responses, raising concerns about vaccine efficacy (79). Thus, protection of infants in the first months of life heavily depends on maternally acquired antibodies. Consequently, the World Health Organization (WHO) recommends that national programs consider vaccination of pregnant women with a dose of Tdap in addition to infant pertussis immunization in countries with high pertussis-related infant morbidity/mortality (80). In the United States, the Advisory Committee on Immunization Practices recommended Tdap immunization of unvaccinated pregnant women to protect young infants from pertussis in 2011 (81). This recommendation was updated in 2012 to extend Tdap immunization to all pregnant women in every pregnancy (82). Recent reports have demonstrated that maternal vaccination is effective to prevent infant pertussis, especially during the first two months of life (83).

2.2 Vaccines currently under research for the prevent of neonatal infections

While vaccines such as influenza and Tdap significantly contribute to reduce neonatal infections, these vaccines were not specifically developed to target pregnant women. Nevertheless, some maternal vaccines specifically aimed at fetal-infant immunization are at different stages of research and development.

Streptococcus agalactiae (group B streptococcus (GBS))

Infant GBS infection can result in early-onset (during the first week of life) or late onset disease (8 to 90 days of life). Intrapartum antibiotic prophylaxis to colonized mothers has reduced the incidence of early onset neonatal GBS but had little impact on late onset disease in the United States (84). Importantly, screening and treatment of all colonized pregnant women is not feasible in the developing world where GBS is a significant contributor to neonatal mortality. A maternal vaccine could therefore help reduce the burden of neonatal disease as well as potentially impact adverse pregnancy outcomes associated with GBS such as miscarriage, preterm birth and premature rupture of membranes. In fact, a recent study has indicated that a maternal GBS vaccine could be a cost effective intervention in low-income countries, especially in areas with high case fatality rates (85). A trivalent conjugate vaccine containing serotype Ia, Ib and III was found to be safe and immunogenic in phase I and II clinical trials (86, 87). While, the serotypes included in this vaccine are representative of the predominant serotypes in Europe and America, other serotypes also contribute the neonatal infections in other areas of the world (88). Thus, the impact of this vaccine in parts of the world where GBS serotypes not included in the vaccine are prevalent may be limited. A multivalent GBS vaccine is currently tested for safety and immunogenicity in a Phase 1/2 trial in healthy non-pregnant adults (clinicaltrials.gov number NCT03170609) and is planned for testing in pregnant women.

Respiratory syncytial virus (RSV)

RSV is the leading cause of viral acute lower respiratory tract infections and it is estimated that in the United States, 60% of infants will be infected during their first RSV season. RSV infection is particularly severe in preterm infants (89). A monoclonal antibody (palivizumab) is administered to infants at high risk of severe disease in many developed countries, but this approach can be cost prohibitive. A formalin-inactivated vaccine developed in the 1960s was associated with enhanced disease among vaccinated children, slowing vaccine development for several years. Vaccine studies in infants < 6 months with novel vaccine candidates have generally demonstrated poor immunogenicity (90). A maternal vaccine would therefore be ideal to protect neonates and infants. The development of a maternal vaccine is notably supported by the association between high levels of maternal antibodies with less severe disease (91) as well by the protection conferred by passive immunization with palivizumab. In addition, maternal immunization would allow to bypass the safety concern associated with RSV vaccination in infants (92). To this end, an F protein nanoparticle maternal vaccine is currently evaluated in phase III clinical trials (clinicaltrails.gov number NCT02624947).

2.3 Unmet needs for maternal vaccines

Maternal vaccination could also be important for the prevention of other vertically transmitted infections, such as HIV and cytomegalovirus (CMV).

Maternal HIV vaccines

Despite the wide availability and high efficacy of maternal antiretroviral medication, over 150,000 infants worldwide continue to acquire HIV in the pre- and postnatal period and the risk of an HIV-exposed infant becoming infected can be as high as 14% in some regions (93). One of the highest risk settings is a new diagnosis or acquisition of HIV during pregnancy, where initiation of antiretroviral medications during pregnancy is associated with high risk of vertical virus transmission (94). Thus, strategies that can synergize with maternal antiretroviral medication are needed to eliminate the pediatric HIV epidemic. One possible strategy is the development of a maternal vaccine that can elicit maternal immunity that can block HIV transmission to the infant. As the infant acquires maternal IgG via the placenta throughout pregnancy, infant transmission has the unique characteristic of occurring in the setting of antibodies that were induced by the autologous virus strain present in the HIV-exposed host. The role of maternal antibodies in defining the risk of virus transmission from mother to child transmission has been extensively studied, and variable conclusions have been reached on the protective nature of maternal antibodies, depending on the population studied (95). Yet, all modes of infant transmission are consistently associated with a strict viral genetic bottleneck, similar to that of heterosexual transmission, in which a single or small number of transmitted/founder maternal viruses initiate infection in the infant (96–100). Moreover, evidence exists that the resistance to autologous virus neutralizing antibodies may be responsible for the selection of infant transmitted variants (101–105). Thus, there is the potential that enhancement of the mother’s ability to neutralize her own autologous virus variants could contribute to reducing the risk of infant transmission. Interestingly, common HIV envelope-specific antibodies that are readily induced by current generation HIV vaccines, such as variable loop 3 and CD4 binding site-specific antibodies that demonstrate neutralization potency against only tier 1 “easy to neutralize” heterologous virus variants, have recently been established to have autologous neutralizing activity (106, 107). The ability of these easy-to-induce antibodies to neutralize autologous virus suggests that current HIV vaccines administered to HIV-infected pregnant women could play a role in further reducing vertical virus transmission. Work to model this strategy of employing HIV envelope vaccines to enhance autologous virus neutralizing activity that could block vertical virus transmission is ongoing in nonhuman primate models.

Maternal CMV vaccines

Congenital cytomegalovirus (CMV) is the leading infectious cause of infant brain damage and permanent disabilities worldwide. Nearly 1% of all infants are born with congenital CMV, and at least 20% of those infected infants will go onto have life-long disabilities, most commonly, hearing loss (108). Moreover, up to a quarter of infant hearing loss is attributable to congenital CMV infection. The annual impact of congenital CMV in the U.S. alone has been estimated to be 4 billion dollars. Thus, a vaccine to eliminate congenital CMV transmission is of highest public health priority, and was named a top tier priority vaccine by the National Academy of Medicine over 15 year ago (109). Yet, few CMV vaccines have moved into late phase clinical trials. One complicating factor is that while primary CMV infection of the mother is the highest risk for congenital transmission, CMV can be placentally-transmitted in the setting of natural maternal immunity. Yet, the risk of CMV transmission to the fetus after maternal reinfection in the setting of pre-existing maternal immunity is considerably lower than that of primary maternal infection (110, 111). Thus, a vaccine that is fully protective against congenital transmission must elicit immunity that is distinct from or improves on natural CMV immunity. While a CMV vaccine would be most effective against congenital CMV infection if administered universally prior to child bearing years, one possible strategy is to provide temporary passive or active immunity to women who remain without potentially-protective CMV immunity during pregnancy to ameliorate the high risk of transmission in the setting of primary maternal infection. In fact, a recent study in the non-human primate model of congenital CMV transmission demonstrated that passive infusion of polyclonal anti-CMV antibodies prior to maternal virus challenge was protective against placental virus transmission (112). While clear immune correlates of protection against HCMV acquisition in humans are not yet known, in a recent Phase I clinical trial, a replication incompetent CMV virus vaccine (V160) was demonstrated to be safe and induced neutralizing antibodies and cell-mediated responses in healthy seronegative adults (clinicaltrials.gov number NCT01986010). More studies in both healthy adults and pregnant populations are needed to evaluate the role of CMV vaccine-elicited neutralizing antibodies and cell-mediated responses. Furthermore, a better understanding of maternal immune correlates of transmission risk in the setting of pre-existing immunity could direct maternal vaccine development to enhance the identified protective response during pregnancy. Thus, maternal vaccination for CMV may be an effective strategy to temporarily improve the mother’s ability to block congenital CMV transmission upon CMV exposure.

Maternal ZIKV vaccine

ZIKV is a mosquito-borne flavivirus that was first discovered in Africa in the 1940’s and was previously associated with mild disease, with no known pregnancy-related complications.

As of March 2017, more than 80 countries have reported evidence of ZIKV transmission (113) and in recent years, ZIKV infection has been associated with several complications, including neurological defects in infants born to ZIKV infected-women (114). Several ZIKV vaccine candidates using different platforms have shown promising results in preclinical studies. A purified inactivated virus vaccine derived from a Puerto Rican strain was shown to induce ZIKV specific neutralizing antibodies and protect from virus challenge in mice and NHP models (115) and DNA vaccines encoding the prM/E genes of ZIKV elicited strong binding and neutralizing antibodies in rhesus monkeys (116, 117). In addition, an mRNA vaccine encoding the prM and E genes of a French Polynesian strain induced strong CD4+ T cell and neutralizing antibody responses in non-pregnant mice and protected mice and NHP from virus challenge (118). Importantly, it was recently reported that an inactivated virus vaccine was safe in humans and elicited neutralizing antibody responses that were higher than the protective threshold observed in animal studies (119). Several additional clinical trials testing different vaccine platforms including inactivated virus, DNA, mRNA, virus-vector and synthetic peptide vaccines are ongoing. It is worth noting that although congenital ZIKV infection is a major public health concern, none of these vaccine platforms specifically target pregnant women. Designing ethical clinical trials that include pregnant women may be warranted for the eradication of mother to child transmission of ZIKV.

2.4 Importance of timing of maternal vaccination

Multiple factors need to be considered when determining the timing of maternal immunization. These include: whether the goal is to protect mothers, infants or both; the kinetics of maternal response to vaccination; the efficiency and timing of IgG transfer; and the half-life of antibodies. Thus, the timing of maternal vaccination for optimal antibody levels in infants at birth may vary between vaccines. For example transfer of HiB specific antibodies is greater when women are immunized at least one month prior to delivery (62). Moreover, the concentration and the avidity of pertussis toxin-specific antibodies in the cord blood are higher when mothers are immunized during the second trimester (120) or early in the third trimester of gestation (121) as compared to mothers immunized later in the third trimester. Similarly, the proportion of preterm and full term babies with protective levels of anti-pertussis antibodies at birth is higher when mothers are immunized during the second trimester of gestation (120, 122). It was also previously demonstrated that the transplacental transfer of maternal pertussis-specific IgG is higher in women immunized during pregnancy (123) than in those immunized before pregnancy. Nevertheless, these maternal antibodies rapidly wane and thus, it is estimated that by 2 months of age only 41% of infants have detectable levels of pertussis-specific IgG (123). Matching the peak immune response post maternal vaccination and the peak IgG transplacental transport may results in high IgG transfer efficiency in full term babies, but protection of premature babies may require maternal immunization early in pregnancy. Thus, the infant target population (full term babies versus all viable babies) should be carefully considered when developing maternal immunization strategies.

3. Impact of IgG transplacental transfer on infant immunity

3.1 Early life vaccination

Because of the high vulnerability of infants to infections, the first months of life constitute a critical window for the generation of protection immunity via vaccination. Vaccination in early life is unique in that occurs 1) in the setting of an immune system transitioning from an environment in which the fetus is exposed to a limited set of antigens including the placental microbiome to exposure to a wide variety of antigens from the external world and 2) in the presence of maternally-acquired antibodies. Only a few vaccines are administered to neonates at birth and the majority of vaccines administered during the first months of life are initiated at 6–8 weeks of life (124). These vaccines usually require booster doses to induce high magnitude, durable responses (72). Importantly, recent studies have highlighted the importance of adjuvants for inducing robust durable immune responses in early life (125). Moreover, some studies have indicated that immunization in early life can induce more durable antibody responses than in adults (126, 127).

3.2 Interference of maternal antibodies with infant vaccine responses

While maternal antibodies transferred across the placenta are important to protect infants during the first months of life, several reports have indicated that maternal antibodies interfere with the development of infant immune responses. One of the best-studied examples of maternal antibody impact on infant immune response is the measles vaccine. In fact, several studies have demonstrated that infant immunization in the presence of maternal antibodies leads to poor antibody responses (reviewed in (128)). Nevertheless, maternal antibodies do not interfere with the induction of measles-specific T cell responses (129). Moreover, infant immunization in the presence of maternal antibodies leads to B cell priming as enhanced immune responses are observed after a booster dose of vaccine (130). To assess the impact of maternal antibodies on vaccine commonly administered in infancy, Jones et al examined the relationship between the concentration of antibodies against pertussis, Hib, tetanus toxoid and pneumococcal antigens at birth and after primary immunization (131). High concentrations of antibody at birth were associated with lower post immunization titers for tetanus and pneumococcus, but this association was not observed with HiB or pertussis. Importantly, despite maternal interference, most infants achieved protective levels of antibodies following vaccination. Previous studies have also indicated that maternal antibodies did not suppress infant antibody responses to HiB vaccines (132). Similarly, it was recently reported that maternal levels of HIV-specific antibodies do not prevent the development of HIV vaccine elicited antibodies in HIV exposed infants (126). Importantly, animal studies have indicated that the effects of maternal antibodies can last even after waning as maternal antibodies can shape the B cell repertoire of the offspring (133). Several mechanisms have been hypothesized to explain how maternal antibodies inhibit infant responses. These include 1) live viral vaccines neutralization by maternal antibodies; 2) antibody feedback mechanisms; 3) elimination of vaccine-antigen/maternal antibody immune complexes by phagocytosis; 4) inhibition of B cell responses through epitope masking, and 5) inhibition of B cell responses by binding of IgG to the FcγRIIB (134, 135). A better understanding of how maternal antibodies interfere with the infant immune system is key to develop combined maternal and infant immunization strategies that will ensure the continuous protection of infants.

3.3 Impact of monoclonal antibody biologics administered during pregnancy on the fetus

As the number of effective monoclonal antibody biologics for treatment of immune-mediated diseases and cancer is on the rise and while typically contraindicated in pregnancy, these highly effective therapies are often needed to treat maternal disease during pregnancy. Thus, the safety of these products for fetal development has become an important question. The majorities of antibody therapeutics are IgG isotype and contain Fc regions that can interact with FcRn, thus can be transferred across the placenta to the fetal circulation. Therefore, there is a risk of fetal effects from the maternal treatments. In fact, fetal effects of maternal monoclonal antibody biologic treatment have been reported: infants exposed to maternal rituximab, an anti-CD20 monoclonal antibody, have been reported to have low B cell numbers, circulating IgG levels, (136, 137), and potential infection complications (136, 138). Moreover, the impact of modifications of the Fc receptor binding site that have successfully prolonged the half-life of monoclonal antibody biologics on placental transfer risk is unknown. Therefore, a better understanding of the mechanisms of IgG transfers across all cell layers of the placenta are highly needed to inform the design of biologics that can effectively treat maternal disease, but avoid transfer across the placenta.

Conclusion

The transfer of IgG from mother to fetus across the placenta is critical to protect infants during the first few months of life. This transfer can be improved through maternal vaccination during pregnancy and the timing of vaccination is critical to provide adequate protection to both mother and infant. Importantly, maternal immunization could also have deleterious effects on the neonate or young infant. A better understanding of the mechanisms of IgG transfers across all cell layers of the placenta are highly needed to 1) inform the design of biologics that can safety be administered to pregnant women with limited impact on the fetus/infant; and 2) optimize maternal immunization regimens to protect infants during the first months of life.