One of the most successful interventions in reducing infectious disease worldwide, vaccination still has limited effectiveness in protecting one group of patients – newborn infants.
Now a study based at the Ragon Institute of MGH, MIT and Harvard has determined how a pregnant woman’s vaccine-induced immunity is transferred to her child, which has implications for the development of more effective maternal vaccines.
The report will be published in the June 27 issue of Cell and is receiving early online release.
“Newborns arrive into the world on the first day of life with brand-new immune systems that, like the children themselves, need to learn to cope with both helpful and harmful microbes in their environment,” says Galit Alter, Ph.D., of the Ragon Institute and the Massachusetts General Hospital (MGH) Department of Medicine, co-senior author of the Cell paper.
“To help the newborn immune system learn to discriminate between friend and foe, mothers transfer antibodies to their infants via the placenta.
The rules by which the placenta performs this absolutely essential function have been unknown but, if decoded, could hold the key to generating more powerful vaccines to protect these most precious patients.”
While maternal antibodies against some diseases such as measles can be transferred from mother to infant, providing some protection until the child is old enough for individual vaccination, antibodies to other serious diseases like polio are less efficiently transferred.
To investigate the mechanisms by which antibodies are transferred from mother to child, Alter and her team – including co-senior author Laura Riley, MD, formerly with the MGH Department of Obstetrics and Gynecology and now the chair of Obstetrics and Gynecology at Weill Cornell Medicine and NewYork-Presbyterian/Weill Cornell Medical Center – used a novel tool called system serology to compare the quantity and quality of antibodies against pertussis in blood samples from mothers and from the umbilical cords that carry blood, nutrients and immune factors from the placenta to the infant.
Their investigation revealed that the placenta preferentially sifts out and delivers to the infant antibodies that activate natural killer (NK) cells, key elements of the innate immune system.
While several important immune cells are too immature in newborns to provide effective protection, NK cells are among the most abundant and functional immune cells during the first days of life.
The team found a similar preference for placental transfer of NK-activating antibodies against influenza and respiratory syncytial virus, a common disease of childhood, and also identified antibody features that appear to regulate placental selection, features that could possibly be built into next-generation vaccines with improved mother-to-child antibody transfer.
Co-senior author Riley says, “We will now have the opportunity to create better maternal vaccines and deliver them at the ideal time during pregnancy to maximally protect newborns when they are most vulnerable.”
Riley is a paid scientific advisory board member for Sabin Vaccine Institute, a leading advocate for making vaccinations more accessible around the world.
She and Alter will be actively investigating additional aspects of maternal:infant immunity to pave the way for developing improved maternal vaccines.
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.Go to:
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.
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
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 |
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).
More information:Cell, DOI: 10.1016/j.cell.2019.05.044
Journal information: Cell
Provided by Massachusetts General Hospital
