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Published in final edited form as: Vaccine. 2020 May 29;38(31):4869–4876. doi: 10.1016/j.vaccine.2020.05.036

Efficiency of Placental Transfer of Vaccine-elicited Antibodies Relative to Prenatal Tdap Vaccination Status

Annalisa L Post a,*, Shuk Hang Li b,*, Madison Berry b, Hannah Itell b, David R Martinez b, Guanhua Xie b, Sallie R Permar b,c, Geeta K Swamy a,†, Genevieve G Fouda b,c,†,‡
PMCID: PMC7388058  NIHMSID: NIHMS1599438  PMID: 32482459

Abstract

Administration of vaccines during pregnancy provides maternal protection against infectious diseases. This protection is extended to their infants during the first months of life, as pathogen-specific antibodies formed in response to maternal vaccination are transferred across the placenta to the fetus. Notably, Tdap (tetanus-diphtheria-acellular pertussis) vaccination booster is routinely administered to pregnant women both to prevent neonatal tetanus and to ensure that infants have protective levels of pertussis antibodies until they are able to establish their own vaccine-induced levels. Whether infant protection through maternal immunization is merely due to an increase in maternal antibody levels or whether maternal immunization enhances the transfer of vaccine-specific antibodies is unclear. Moreover, the potential impact of prenatal vaccinations on the transplacental transfer of other antibodies, such as antibodies raised as a result of infections or other vaccines administered prior to pregnancy, has not been studied.

The goal of this study was to define the impact of maternal vaccination on IgG transplacental transfer efficiency. We analyzed antigen-specific antibody populations and IgG subclass distribution in maternal and cord blood samples from 58 mother-infant pairs. All women received the seasonal inactivated influenza vaccine during pregnancy and 25 women received the Tdap vaccine during the second or third trimester of gestation. Prenatal Tdap vaccination did not impact the efficiency of IgG transplacental transfer; however, it was associated with higher maternal and infant vaccine-elicited Tdap-specific antibody levels, and with a higher proportion of infants with protective levels of antibodies, especially against diphtheria. There was also no difference in the IgG transplacental transfer rate of antibodies against non-Tdap vaccines between the two groups of women. Our results confirm previous reports demonstrating the benefits of prenatal Tdap immunization and indicate that this strategy does not impede the transplacental transfer of other antibodies that are also important for infant protection.

Keywords: Tdap, maternal immunization, infant protection, IgG transplacental transfer, antibodies

INTRODUCTION

At birth, infants have a population of circulating protective antibodies that originate from their mothers through transplacental transfer. Maternal antibodies, which develop following either maternal infection or vaccination, are critical for infant protection until the maturation of the neonatal adaptive immune system, which occurs over the first year of life [1–4]. Transplacental transfer of IgG from maternal to fetal circulatory system begins in the first trimester of gestation and continues to increase with advancing gestation [5]. Most antibodies are transferred during the third trimester and by 37–40 weeks fetal antibody levels reach or even surpass maternal levels [5–10]. The transplacental transfer of IgG occurs by a receptor-mediated mechanism in which interactions between IgG and Fc receptors allow IgG to move from maternal to fetal circulation [7]. This transport is complex and yet incompletely understood [11]. However, increasing knowledge of this process is leading to clinical innovations and changes in standard pregnancy care.

Several factors can influence the efficiency of IgG transplacental transfer, including maternal health and total IgG levels, as well as antibody properties such as Fc receptors affinity, Fc glycosylation and IgG subclass [9,12,13]. In fact, several studies have reported preferential transplacental transfer of IgG1 subclass, with lesser amounts of IgG3 and IgG4, and little IgG2 being transferred. IgG1 is the most abundant IgG subclass in maternal blood, but cord blood levels of IgG1 are even consistently higher than maternal levels, whereas cord blood levels of IgG2 are generally lower than maternal levels [8,14–16]. The differential transfer of antibodies of distinct IgG subclass may be related to the affinity of their binding to Fc receptors expressed in the placenta [17]. Thus, the IgG subclass composition of antigen-specific antibodies in maternal plasma could impact the efficiency of IgG transplacental transfer and the levels of protective antibodies that infants have at birth.

Maternal vaccination during pregnancy can boost the levels of vaccine-specific antibodies and therefore enhance transplacental transfer of protective IgG. In fact, maternal immunization is an important strategy for the protection of both the mothers and the infants [18]. An example of therapeutic exploitation of this strategy is maternal immunization against pertussis during pregnancy. This results in passively acquired IgG in the fetal circulation of sufficient amount and longevity to provide infant protection against pertussis for a few months after birth [1,19,20]. Therefore, Tdap vaccination during pregnancy is now recommended as standard practice by the Centers for Disease Control and Prevention (CDC) and the American College of Obstetricians and Gynecologists (ACOG) [21,22]. Another example of boosting neonatal levels of protective antibodies with maternal vaccination is the routine influenza vaccination for pregnant women [23]. This is recommended for maternal benefit as pregnant women have altered cell-mediated immunity and physiologic changes including decreased lung capacity and increased cardiac output that make them more susceptible to influenza-related complications [23]. In addition, the inactivated influenza vaccine is not licensed for infants until they are at least 6 months of age, and infants are particularly vulnerable to influenza-related complications. Thus, antepartum vaccination and transplacental transfer of influenza-specific antibodies are vital for protecting the infants in the first few months of life [24–27].

It is well established that maternal vaccination during pregnancy leads to increased infant protection and to high antibody levels in both mothers and infants [2]. However, whether maternal vaccination impacts IgG transplacental transfer is unclear. In a study conducted in Brazil, maternal Tdap was associated with higher maternal and infant antibody levels but also to a lower transplacental transfer ratio of pertussis-specific antibodies [28]. Assessing transfer efficiency of Tdap-specific antibodies in other populations is important to confirm these results. In addition, it is unclear whether boosting of specific antibody populations by maternal immunization is associated with lower transfer of antibody specificities that were not boosted during pregnancy. The goal of this study was therefore to measure vaccine-elicited antibody levels in mothers who received Tdap either during or before pregnancy and in their infants; and to assess if Tdap vaccination during pregnancy impacts the efficiency of IgG transplacental transfer of Tdap-specific antibodies and of antibody specificities not boosted during pregnancy.

MATERIALS AND METHODS

Study population

This study relied on available samples, utilizing 58 maternal and cord blood pairs which were collected from 2011–2017 through three study arms (see below). All three arms were clinical studies of administration of the seasonal inactivated influenza vaccine (IIV) in pregnancy; therefore, all women received IIV during pregnancy. 25 (43.1%) of the women also received Tdap vaccine during pregnancy.

Arm 1:

From 2011–2012, pregnant women were given seasonal IIV which included A/California/7/2009, A/Perth/16/2009, and B/Brisbane/60/2008 antigenic components. A total of 25 mother-infant pairs were available from this study arm including 2 (8%) women who received Tdap vaccine during the third trimester (31.1 and 32.3 weeks).

Arm 2:

From 2013–2014, pregnant women were given seasonal IIV which included A/California/7/2009, A/Victoria/361/2011, B/Massachusetts/2/2012, and B/Brisbane/60/2008 antigenic components. A total of 19 mother-infant pairs were available from this study arm including 9 (47.4%) who received the Tdap vaccine during the third trimester between 28.1 and 33.1 weeks.

Arm 3:

From 2016–2017, pregnant women were given IIV and Tdap vaccine, randomized to either simultaneous or sequential administration. Seasonal IIV included A/California/7/2009, A/Hong Kong/4801/2014, B/Phuket/3073/2013 and B/Brisbane/60/2008 antigenic components. A total of 14 mother-infant pairs were available from this study arm. 2 of the 14 women received the Tdap vaccine during the second trimester (26.6 and 26.9 weeks) while the rest of them received Tdap during the third trimester between 28.7 and 33.6 weeks.

Antigens and reference standards

Antigens and reference standards used to quantify antibody concentrations are listed in Table S1. Hep B surface antigen (adw) protein and rubella virus capsid full-length protein were purchased from AbCam (Cambridge, UK). Bordetella pertussis toxin, pertussis filamentous hemagglutinin (FHA), and Corynebacterium diphtheria toxin were purchased from Sigma-Aldrich (St. Louis, MO). Tetanus toxoid was purchased from Reagent Proteins (San Diego, CA). Influenza recombinant hemagglutinin (rHA) antigens were purchased from Protein Sciences (Meriden, CT). Pertussis fimbriae 2/3 and pertussis pertactin (69 kDa protein) were purchased from List Biological Labs (Campbell, CA).

The following World Health Organization (WHO) international reference standards were obtained from the National Institute of Biological Standards and Control (NIBSC, Potters Bar, UK) for calculating antigen-specific IgG concentrations: anti-hepatitis B surface antigen immunoglobulin, anti-rubella immunoglobulin, pertussis antiserum, tetanus immunoglobulin, and diphtheria antitoxin IgG (NIBSC code numbers: 07/164, RUBI-1–94, 06/140, TE-3, 10/262, respectively). A commercially available polyclonal IVIG preparation, Privigen, was purchased from CSL Behring (King of Prussia, PA) and used as positive control for influenza-specific antibody measurement.

Measurement of antigen-specific IgG levels

An adaptation of the recently published pediatric vaccine multiplex assay (PVMA) was used to measure maternal and infant antigen-specific IgG levels [29]. Briefly, 25 μg of antigens were coupled to a total of 5 × 106 carboxylated microspheres (Bio-Rad Laboratories, Hercules, CA), and 5,000 antigen-coupled microspheres of each of the antigens were then added to each well. Standard curves and plasma samples were prepared in duplicate in a background-reducing assay diluent (PBS, 1% evaporated milk, 5% goat serum, 0.05% polyvinyl alcohol, and 0.08% polyvinylpyrrolidone) and incubated on a microplate shaker at room temperature for 1 hour before added to the wells (Table S1). Antigen-specific IgG was detected with mouse anti-human IgG-PE at 2 μg/mL (SouthernBiotech, Birmingham, AL). The plates were read on a Bio-Plex 200 system (Bio-Rad Laboratories, Hercules, CA). All mean fluorescent intensity (MFI) values were blank well subtracted. Bio-Plex Manager (Bio-Rad Laboratories, Hercules, CA) was used to interpolate unknown concentrations from standard curves using the background-subtracted MFIs.

Intra-assay coefficients of variance (CVs), which are the average CVs of duplicate wells within one assay, were determined for each sample and samples with CVs greater than 25% were repeated. Samples with blank bead MFIs greater than 1,000 were excluded from analysis.

Measurement of antigen-specific IgG subclass

To measure antigen-specific IgG subclass responses, maternal serum and infant cord blood samples were tested against the same antigen panel (Table S1) at 1:25. All steps are the same as quantification of antigen-specific IgG responses as described previously, but biotinylated secondary for each IgG subclass was used instead of mouse anti-human IgG PE secondary. 100 μL of 4 μg/mL mouse anti-human IgG1-biotin (BD Biosciences, San Jose, CA), 5 μg/mL mouse anti-human IgG2 Fc-biotin (SouthernBiotech, Birmingham, AL), 2 μg/mL mouse anti-human IgG3 hinge-biotin (MilliporeSigma, Burlington, MA), and 2 μg/mL mouse anti-human IgG4 biotin (BD Biosciences, San Jose, CA) were used respectively for each subclass. Subsequently, streptavidin-conjugated phycoerythrin antibody (BD Biosciences, San Jose, CA) was diluted at 1:100 and added to the wells. The plates were read on a Bio-Plex 200 system (Bio-Rad Laboratories, Hercules, CA). All MFI values were blank subtracted.

Statistical Analysis

Maternal characteristics were compared between women who received Tdap before pregnancy and during pregnancy and between the three arms of the study (Table 1 and Table S2). These characteristics included age, race, gravidity, smoking status, insurance status (private, public, or no insurance), body mass index (BMI), and gestational age at delivery. Continuous variables were compared using t-tests (Table 1) and ANOVA tests (Table S2), and categorical variables were compared using Chi- Square Test of Independence.

Table 1.

Maternal characteristics by timing of Tdap vaccination.

Tdap before pregnancy (n = 33) Tdap during pregnancy (n = 25) P value
Mean age (years) 30.0 ± 5.5 28.3 ± 6.4 0.271
Race
White 18 (54.5%) 15 (60%) 0.878
Black 14 (42.4%) 9 (36%)
Multiracial 1 (3.0%) 1 (4%)
Mean gravidity 3.0 ± 1.6 3.2 ± 2.7 0.639
Smoker 4 (12.1%) 5 (20%) 0.412
Insurance
Private 21 (63.6%) 8 (32%) 0.052
Medicaid 9 (27.3%) 14 (56%)
None 3 (9.1%) 3 (12%)
Mean BMI 30.4 ± 10.4 32 ± 6.8 0.498
Gestational age at delivery (weeks) 38.3 ± 1.93 39.06 ± 2.56 0.213
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P values for continuous variables were determined by t-tests and P values for categorical variables were determined by Chi-Square Test.

Maternal and fetal concentrations of each antibody were then compared for all samples with Tdap administration during pregnancy vs those who had Tdap before pregnancy using the Wilcoxon Rank Sum Test; Log 10 transformations of the data were performed when necessary to calculate P values for non-normal distributions. Raw P values were corrected to yield the FDR P value [30].

Maternal to cord transfer ratios were calculated as infant antigen-specific IgG (Log10 MFI) / maternal antigen-specific IgG (Log10 MFI) x 100. Transfer ratios are only calculated when both the mother and the infant MFI were within the assay linear range (MFI between 100 and 24000). Transfer ratios were compared between the two groups with Wilcoxon Rank Sum Test (FDR corrected). Frequency of infants with protective titers was determined and compared between infants born to mothers who received Tdap vaccination during pregnancy vs those who received Tdap before pregnancy using Chi-Square Test of Independence. Spearman correlation between maternal levels of antigen-specific IgG and transfer ratio was performed.

The detection frequency of all four IgG subclasses for each vaccine-elicited antibody was calculated for both maternal and fetal samples. Maternal and fetal detection frequency was compared between the two groups with Chi-Square Test of Independence and raw P values were corrected to get the FDR P values. The IgG subclass antibody levels were compared between the two Tdap administration groups using the Wilcoxon Rank Sum Tests (FDR corrected). Finally, Spearman correlation was used for correlation analysis between maternal subclass MFI and transfer ratio of each mother-infant pair. All statistical tests were completed using SAS v9.4 (SAS Institute Inc., Cary, NC). A P value less than 0.05 (2-tailed) was considered significant for all analyses.

RESULTS

Clinical characteristics of study participants

We analyzed antibody populations and IgG subclass distribution in 58 mother-infant serum sample pairs. A total of 33 of the included women received Tdap vaccination prior to pregnancy and 25 women were vaccinated with Tdap during pregnancy (Table 1). The majority of the women from the Tdap prior to pregnancy group had private insurance (63.6%) whereas the majority of the women from the Tdap during pregnancy group had Medicaid (56%). Maternal age, race, gravidity, smoking status, BMI, and gestational age at delivery were comparable between the groups.

Concentrations of vaccine-elicited IgG in mothers and infants

We first assessed whether the Tdap vaccination status of the mothers during pregnancy affects vaccine-elicited antibody levels in mother-infant pairs at birth. In general, the concentrations of Tdap-elicited antibodies were higher in mothers who received Tdap during pregnancy and in their infants (Fig. 1). Notably, the concentrations of IgG against the three pertussis antigens (pertussis toxin, pertactin, and pertussis FHA) were on average 0.5 to 1 log higher in women and infants from the Tdap during pregnancy group as compared to the Tdap before pregnancy group. Similarly, the concentrations of diphtheria toxin-specific IgG were significantly higher in mothers and infants from the Tdap during pregnancy group as compared to mother-infant pairs who received Tdap before pregnancy (P < 0.001, Wilcoxon Rank Sum Test). The levels of anti-tetanus IgG were marginally higher in women immunized with Tdap during pregnancy, but this difference did not reach statistical significance. However, infants born to mothers who received Tdap during pregnancy had significantly more tetanus-specific IgG when compared to infants from the Tdap before pregnancy group (P = 0.00586, Wilcoxon Rank Sum Test).

Figure 1. Higher concentrations of vaccine-elicited IgG in serum and cord blood of mother-infant pairs that received Tdap vaccination during pregnancy vs prior to pregnancy.

Figure 1.

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IgG levels were assessed in maternal serum (circle) and infant cord blood (square) from the Tdap before pregnancy and Tdap during pregnancy groups using a pediatric vaccine multiplex assay (PVMA). Horizontal lines indicate the median IgG concentrations. **P < 0.01, *** P < 0.001, Wilcoxon Rank Sum Test.

To determine whether Tdap vaccination during pregnancy impacts the transfer of other vaccine-elicited antibodies, we compared the antibody levels against non-Tdap vaccines (HBV and rubella) between the two groups of mother-infant pairs. Comparable concentrations of HBV-specific and rubella-specific IgG were found in maternal plasma and infant cord blood between the groups (Fig.1). In addition, maternal and infant antibody levels against the influenza strains common to vaccines administered to the diverse mother-infant cohorts (Influenza A/California and Influenza B/Brisbane) were comparable between the Tdap during pregnancy and Tdap prior to pregnancy groups (Fig. S1). Our results indicate that Tdap vaccination during pregnancy does not negatively impact the transplacental transfer of antibodies against other vaccines administered either before or during pregnancy.

IgG transplacental transfer efficiency in mothers and infants

We next examined the impact of Tdap vaccination during pregnancy on IgG transfer efficiency. IgG transplacental transfer ratios were calculated as the percentage of infant antibody levels in cord blood over maternal antibody levels at the time of delivery. Even though the levels of almost all Tdap antibodies were higher in women who received Tdap vaccine during pregnancy and in their infants, there was no significant difference in Tdap-specific antibody transfer ratios between the two mother-infant groups (Fig. 2A). There were also no differences in transfer ratios of antibodies against non-Tdap vaccines between the two groups (Fig. 2B).

Figure 2. The timing of Tdap administration did not impact the transplacental transfer efficiency of vaccine-elicited IgG.

Figure 2.

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IgG transplacental transfer ratios were calculated using the Log10 mean fluorescent intensity (MFI) of maternal plasma and infant cord blood IgG levels for Tdap-elicited antibodies (A) and other vaccine-elicited antibodies (B). No significant difference was observed between transfer ratios of mother-infant pairs who received Tdap during and before pregnancy (Wilcoxon Rank Sum Test). Horizontal lines indicate the median IgG placental transfer efficiency.

As previous studies have suggested that abnormally high levels of maternal serum antibodies can lead to lower IgG transplacental transfer [12], we next examined the association between the maternal concentrations of antigen-specific IgG and the efficiency of their transplacental transfer. There was no correlation between maternal IgG concentrations and placental transfer efficiency of the vaccine-elicited antibodies tested (Table S3). This suggests that the higher levels of antibodies observed in infants in the context of maternal Tdap vaccination were a result of higher maternal antibody levels and not an increase in the rate of IgG transplacental transfer. Thus, our results suggest that the rate of IgG transplacental transfer is not impacted by Tdap vaccination during pregnancy.

Frequency of infants with protective antibody concentrations

The WHO has defined antibody titers associated with clinical protection for some vaccine-elicited antibodies including tetanus (0.1 IU/mL), diphtheria (0.1 IU/mL), HBV (0.01 IU/mL), and rubella (10 IU/mL) [31]. We determined the proportion of infants with protective levels of antibodies of these specificities in the two immunization groups. All infants in both groups had concentrations of tetanus-specific and HBV-specific IgG above the protective cutoff in cord blood (Table 2). On the other hand, only a minority of infants had protective levels of anti-rubella IgG: 9 out of the 25 infants (36%) born to mothers who had Tdap during pregnancy had protective levels of rubella-specific IgG, and 14 out of 33 infants (42%) born to mothers who received Tdap before pregnancy had protective levels. Notably, 100% of the infants born to mothers who received Tdap during pregnancy had protective concentrations of anti-diphtheria IgG while only 62.5% of infants from the Tdap before pregnancy group had protective concentrations of this antibody (P = 0.00057, Chi-Square Test of Independence).

Table 2.

Percentage of infants with antibody levels above the protective threshold determined by WHO.

Tdap during pregnancy (%) Tdap before pregnancy (%) P value
Tetanus 100 100 NA
Diphtheria 100 62.5 0.00057
HBV 100 100 NA
Rubella 36 37.5 0.907
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Antibody protective cutoffs as defined by the World Health Organization are: 0.1 IU/mL anti-tetanus IgG, 0.1 IU/mL anti-diphtheria IgG, 0.01 IU/mL anti-HBV IgG, and 10 IU/mL anti-rubella IgG. The frequency of protective levels of antibodies was compared between the groups. P values were determined by Chi-Square Test of Independence.

The frequency of infants with protective levels of pertussis-specific IgG was not determined because the protective threshold of anti-pertussis antibodies is not well-defined as several proteins, pertussis toxin, pertactin, and pertussis FHA, are included in the pertussis vaccine and may contribute to its efficacy [31]. Nonetheless, concentrations of IgG against all pertussis antigens tested were significantly higher in both mothers and infants in the Tdap during pregnancy group (P < 0.001) (Fig. 1).

Frequency of IgG subclass antibody responders in mothers and infants

To assess whether IgG subclass composition plays a role in the efficiency of transplacental transfer, we measured IgG subclass antibody levels against the same antigen panel in the 58 mother-infant pairs. Most of the mothers and infants had detectable IgG1 levels against the vaccines tested with the exception of rubella, and the frequency of antigen-specific IgG1 subclass detection was higher than that of other IgG subclasses (Fig. 3A). The majority of mothers and infants also had detectable IgG4 against Tdap antigens (Fig. 3D).

Figure 3. Higher frequency of detectable IgG1 and IgG4 Tdap-specific antibodies in mother-infant pairs that received Tdap during pregnancy.

Figure 3.

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Frequency of vaccine-elicited IgG1 (A), IgG2 (B), IgG3 (C), and IgG4 (D) was determined in both maternal and cord blood plasma. The majority of mothers and infants had detectable levels of IgG1 against the vaccines tested. A high proportion of mothers and infants also had vaccine-specific IgG4 antibodies whereas the frequency of vaccine-elicited IgG2 and IgG3 responses was generally lower. * P < 0.05, ** P < 0.01, *** P < 0.001, Chi-Square Test of Independence.

Mother-infant pairs in the Tdap during pregnancy group had higher frequency of detectable IgG1 against pertussis toxin, pertactin, and pertussis fimbriae and higher frequency of IgG4 against pertussis toxin, pertactin, and diphtheria compared to those who did not receive Tdap during pregnancy. On the other hand, the frequency of vaccine-elicited IgG2 and IgG3 subclass detection was generally low (Fig. 3B and 3C), and there was no difference in frequency of antigen-specific IgG2 subclass responses between the Tdap during pregnancy and Tdap before pregnancy group. However, the frequency of pertussis toxin-specific and pertussis FHA-specific IgG3 was significantly higher in infants born to mothers who received Tdap during pregnancy than those who did not.

IgG subclass antibody levels in mothers and infants

IgG subclass antibody levels in maternal and neonatal samples were also evaluated to determine whether Tdap vaccination during pregnancy affects the transplacental transfer of IgG subclass antibodies. Levels of IgG1 against most Tdap antigens were significantly higher in both mothers and infants in the Tdap during pregnancy group (Fig. 4A). Similarly, women who received Tdap during pregnancy had higher IgG2 against pertussis toxin, pertussis FHA, and diphtheria and their infants had higher levels of IgG2 against the same antigens (Fig. 4B). The levels of both tetanus-specific and diphtheria-specific IgG3 were significantly higher in mother-infant pairs that received Tdap boosting during pregnancy, and some anti-pertussis IgG3 antibodies were also significantly higher in maternal samples (pertussis toxin and pertussis FHA) and infant samples (pertussis toxin, pertactin, and pertussis FHA) (Fig. 4C). Finally, mothers and infants from the Tdap during pregnancy group had higher levels of IgG4 against pertussis toxin, pertactin, pertussis FHA, and diphtheria when compared to the Tdap before pregnancy group; infants in the Tdap during pregnancy group also had higher IgG4 against tetanus (Fig. 4D).

Figure 4. Higher levels of Tdap-specific IgG subclass antibodies in mother-infant pairs that received Tdap during pregnancy.

Figure 4.

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Vaccine-specific IgG1 (A), IgG2 (B), IgG3 (C), and IgG4 (D) were measured in all 58 mother-infant pairs by PVMA. Horizontal lines indicate the median antigen-specific IgG subclass MFI. * P < 0.05, ** P < 0.01, *** P < 0.001, Wilcoxon Rank Sum Test.

Importantly, there was no association between maternal IgG subclass antibody levels and transfer efficiency for most antigens; some values were weakly correlated but none reached statistical significance (Table S4). There were also no differences in transfer ratios of subclass antibodies against Tdap or non-Tdap vaccines between the Tdap during pregnancy group and Tdap before pregnancy group (Table S5). Thus, Tdap vaccination during pregnancy increases the overall levels of all IgG subclasses in immunized mothers and their infants, yet does not impact the transfer efficiency of IgG subclass antibodies.

DISCUSSION

Infectious diseases remain a threat to neonates around the globe and a comprehensive understanding of transplacental transfer of vaccine-elicited IgG is crucial for improving maternal immunization strategies that protect both mothers and their infants. In this study, we examined the impact Tdap vaccination during pregnancy has on the transplacental transfer of maternal antibodies. Importantly, these maternal antibodies include antibodies raised against vaccine administered during or prior to pregnancy and/or antibodies against natural infections. Our results indicate that Tdap vaccination during pregnancy enhances the concentrations of Tdap-elicited antibodies in both mothers and infants, but does not affect the transplacental transfer of antigen-specific antibodies whether they are boosted or not during pregnancy.

Several factors influence the rate of IgG transplacental transfer, including the maternal total IgG concentration and IgG subclass distribution [12,13,32]. The efficiency of IgG placental transfer has been reported to differ for distinct IgG subclasses with IgG1 and IgG4 being the most efficiently transferred while IgG2 is the least efficiently transferred [4,12,16,33]. We noted that mothers who received Tdap during pregnancy and their infants generally had higher levels of IgG1, IgG2, IgG3, and IgG4 against most Tdap antigens (Fig. 4). The transfer ratio for all IgG subclasses was between 0.9 to 1.1 in both the Tdap during pregnancy and Tdap prior to pregnancy groups (Table S5), suggesting no preferential transfer of a particular IgG subclass. Importantly, even though both total and subclass IgG concentrations were higher in mothers who were immunized with Tdap during pregnancy, the transfer efficiency of vaccine-elicited antibodies in these mothers was similar to that of mothers who received Tdap prior to pregnancy (Fig. 2 and Table S5). There was also no correlation between transfer efficiency and maternal plasma total IgG or subclass IgG levels (Table S3 and Table S4). As other studies have shown that a threshold concentration of maternal IgG must be reached to saturate binding to the neonatal Fc receptor (FcRn) before a significant reduction of transplacental IgG transfer is observed [34–38], it is possible that antibody levels of mothers in our cohort who were immunized during pregnancy were lower than this saturation threshold.

An ultimate goal of maternal immunization is to ensure that infants achieve, through passive transfer, protective levels of antibodies. Interestingly, we observed that 100% of infants whose mothers received Tdap during pregnancy had protective titers of anti-diphtheria IgG as compared to only 62.5% of the infants from the Tdap before pregnancy group (Table 2). While antenatal Tdap has previously been demonstrated to increase protective titers against pertussis and is administered primarily for this indication, our findings are notable as the effect of antenatal Tdap vaccination on protective titers against diphtheria has not been reported previously.

Another important observation from our study is that Tdap vaccination during pregnancy does not alter maternal or infant concentrations of antigen-specific IgG elicited by vaccination and/or natural infection prior to pregnancy (HBV and rubella, Fig. 1). Transfer efficiency of HBV and rubella antibodies was also independent of the timing of Tdap administration (prior to or during pregnancy; Fig. 2B). Similarly, levels of anti-influenza IgG were comparable between women who received Tdap during pregnancy and those who were immunized before pregnancy (Fig. S1), and transfer ratios of IgG against influenza were not reduced in women who received Tdap during pregnancy. Overall, these results indicate that Tdap administration during pregnancy is not detrimental to the transfer of antibodies of other specificities whether they were elicited prior to pregnancy (HBV, Rubella) or boosted during pregnancy (influenza).

In this study, the majority of the women received Tdap during the third trimester of gestation between 28.1 and 33.6 weeks, with only two women receiving Tdap during the second trimester (26.6 and 26.9 weeks). The optimal timing of Tdap immunization during pregnancy to maximize IgG transplacental transfer remains uncertain. Both CDC and ACOG recommend that pregnant women receive Tdap during the third trimester of pregnancy, between 27 and 36 weeks of gestation [21,22], but some studies have indicated that Tdap vaccine might be more effective when administered during the second trimester of pregnancy [39]. The majority of the IgG transplacental transfer occurs during the third trimester of gestation, suggesting it would be ideal to boost maternal antibody concentrations when the transfer process is the most efficient [1,40–42]. Moreover, passively acquired maternal IgG has different half-lives in infants, suggesting that some antigen-specific IgG decay faster than others [32,43,44]. On the other hand, immunizing women earlier in pregnancy may have other potential benefits, including providing protection to preterm infants since IgG transplacental transfer correlates with gestational age in normal pregnancies [12,40]. Investigating the potential impact of the timing of Tdap administration during pregnancy on IgG transfer in large cohorts of mother-infant pairs is therefore critical to inform maternal immunization strategies aiming at improving the durability of passively acquired antibodies.

Recent studies have suggested that the Fc region of antibodies plays a role in mediating selective IgG placental transfer [13,45]. Notably, certain Fc region glycan profiles have been associated with more efficient IgG transplacental transfer in HIV-infected women. Our finding that Tdap immunization during pregnancy does not affect the rate of IgG transplacental transfer suggests that Fc characteristics important for IgG transfer are comparable in women who received Tdap before and during pregnancy. Nonetheless, in future studies, it will be important to formally investigate if immunization during pregnancy affects the glycan profile of vaccine-elicited antibodies and if potential changes in glycan profiles through vaccination affect the interaction between vaccine-elicited IgG and Fc receptors expressed in the placenta.

In conclusion, our findings provide further evidence that antenatal Tdap vaccination is associated with increased infant levels of protective antibodies including IgG against diphtheria, and provides new evidence that antenatal Tdap does not impact the transfer of other antibodies elicited by vaccination and/or natural infection prior to pregnancy. Future studies that examine the mechanism of transplacental transfer of vaccine-elicited antibodies, the optimal timing of vaccine immunization during pregnancy, and the impact of prenatal immunization on Fc glycosylation will further our understanding of maternal vaccination during pregnancy and help guide vaccine development for optimal protection of infants from infectious diseases.

Supplementary Material

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HIGHLIGHTS.

  • High maternal/infant levels of Tdap-specific IgG associated with prenatal Tdap

  • Tdap-specific IgG transfer efficiency independent from the timing of immunization

  • Transfer efficiency of IgG against other vaccines not affected by prenatal Tdap

ACKNOWLEDGMENTS

We would like to thank the participants and staff who supplied the samples for this study. We would like to specifically thank Brian Antczak for specimen collection, organization and transport; and Kristin Weaver for help with regulatory oversight and recruitment. This study was supported by the Charles B. Hammond Research Fund to ALP and an R03 from NICHD to GGF (HD085871).

Footnotes

Declaration of interests

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

CONFLICT OF INTEREST

SRP is serving as a consultant for vaccine programs at Merck, Pfizer, Sanofi, and Moderna. GKS is on the scientific advisory board for investigational vaccine products with GlaxoSmithKline, the Chair of Data Safety and Monitoring Board with GlaxoSmithKline and with Pfizer, and the site PI at Duke for testing investigational vaccines and products with Novavax, Regeneron, and GlaxoSmithKline/Novartis. All other authors declare no conflicts of interest.

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NIHMS1599438-supplement-1.pdf (35.7KB, pdf)
2
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