Congenital Human Cytomegalovirus Infection Is Associated With Decreased Transplacental IgG Transfer Efficiency Due to Maternal Hypergammaglobulinemia

Eleanor C Semmes; Shuk Hang Li; Jillian H Hurst; Zidanyue Yang; Donna Niedzwiecki; Genevieve G Fouda; Joanne Kurtzberg; Kyle M Walsh; Sallie R Permar

doi:10.1093/cid/ciab627

. 2021 Jul 14;74(7):1131–1140. doi: 10.1093/cid/ciab627

Congenital Human Cytomegalovirus Infection Is Associated With Decreased Transplacental IgG Transfer Efficiency Due to Maternal Hypergammaglobulinemia

Eleanor C Semmes ^1,^2,⁴, Shuk Hang Li ², Jillian H Hurst ^3,⁴, Zidanyue Yang ⁵, Donna Niedzwiecki ⁵, Genevieve G Fouda ^2,^3,⁴, Joanne Kurtzberg ⁶, Kyle M Walsh ^4,⁷, Sallie R Permar ^2,^4,^8,^✉

PMCID: PMC8994583 PMID: 34260701

Abstract

Background

Placentally transferred maternal immunoglobulin G (IgG) protects against pathogens in early life, yet vertically transmitted infections can interfere with transplacental IgG transfer. Although human cytomegalovirus (HCMV) is the most common placentally-transmitted viral infection worldwide, the impact of congenital HCMV (cCMV) infection on transplacental IgG transfer has been underexplored.

Methods

We evaluated total and antigen-specific maternal and cord blood IgG levels and transplacental IgG transfer efficiency in a US-based cohort of 93 mother-infant pairs including 27 cCMV-infected and 66 cCMV-uninfected pairs, of which 29 infants were born to HCMV-seropositive nontransmitting mothers and 37 to HCMV-seronegative mothers. Controls were matched on sex, race/ethnicity, maternal age, and delivery year.

Results

Transplacental IgG transfer efficiency was decreased by 23% (95% confidence interval [CI] 10–36%, P = .0079) in cCMV-infected pairs and 75% of this effect (95% CI 28–174%, P = .0085) was mediated by elevated maternal IgG levels (ie, hypergammaglobulinemia) in HCMV-transmitting women. Despite reduced transfer efficiency, IgG levels were similar in cord blood from infants with and without cCMV infection.

Conclusions

Our results indicate that cCMV infection moderately reduces transplacental IgG transfer efficiency due to maternal hypergammaglobulinemia; however, infants with and without cCMV infection had similar antigen-specific IgG levels, suggesting comparable protection from maternal IgG acquired via transplacental transfer.

Keywords: congenital CMV infection, human cytomegalovirus, maternal hypergammaglobulinemia, maternal-fetal vaccination, transplacental IgG transfer

We evaluated transplacental IgG transfer in a case-control cohort of mother-infant pairs with and without congenital human cytomegalovirus (cCMV) infection. Transplacental immunoglobulin G (IgG) transfer efficiency was reduced in pairs with cCMV infection, primarily attributable to maternal hypergammaglobulinemia in HCMV-transmitting mothers.

Human cytomegalovirus (HCMV) is the most common placentally transmitted viral infection worldwide, affecting 1 out of 150 births or nearly 1 million newborns annually [1, 2]. Over 80% of reproductive-aged women are latently infected with HCMV and placental transmission occurs during primary and nonprimary maternal infection [2]. Although most congenital HCMV (cCMV) infections are asymptomatic, serious disease consequences including fetal demise, hearing loss, neurodevelopmental delay, and increased risk of hematologic malignancy can occur following infection [3, 4]. Screening for cCMV infection is not routine because treatment options remain limited, leaving most cases undiagnosed and the true burden of disease underestimated [5].

Antibody production is limited in early life, so the fetus and neonate rely on transplacental transfer of naturally acquired or vaccine-induced maternal immunoglobulin G (IgG) for protection against infectious diseases [6–8]. Transplacental IgG transfer from mother-to-fetus is primarily mediated by the neonatal Fc receptor (FcRn), and transfer efficiency can be modulated by IgG subclass, Fc receptor (FcR) binding affinity, glycosylation, and antigen specificity [9, 10]. Maternal human immunodeficiency virus (HIV) and placental malaria infection have been associated with compromised transplacental IgG transfer and lower cord blood IgG levels, yet whether cCMV infection impacts transplacental IgG transfer remains unknown [11–13]. Because HCMV can cause degradation of FcRn in vitro [14], we hypothesized that HCMV infection might disrupt transplacental IgG transfer, thereby jeopardizing the immunity of neonates with cCMV infection.

We leveraged cord blood and maternal sera from mother-infant donors to a US-based public cord blood bank to evaluate transplacental IgG transfer in mother-infant pairs with and without cCMV infection. We quantified total and pathogen-specific IgG levels in mother-infant pairs and utilized a multivariable mediation regression model to estimate the effect of maternal hypergammaglobulinemia on placental IgG transfer efficiency. Our study represents the largest U.S.-based birth cohort of cCMV-infected and uninfected mother-infant pairs studied to-date and reveals novel insight about transplacental IgG transfer in cCMV infection that will inform future active and passive maternal immunization strategies to protect neonates against HCMV and other pathogens.

METHODS

Study Population

We analyzed sera from 93 mother-infant pairs recruited from 2006 to 2018 by the Carolinas Cord Blood Bank (CCBB), which were identified from over 29,000 CCBB donor records (see Supplementary Figure 1 outlining pair selection). The CCBB collects clinical data and maternal/cord blood biospecimens at delivery. Maternal donors undergo infectious diseases screening for HCMV; hepatitis B virus; syphilis; hepatitis C virus; HIV-1/2, HTLV I and II; Chagas Disease; and West Nile virus via serologic and/or nucleic acid amplification testing, and cord blood is screened for HCMV infection with a real-time PCR (RT-PCR) COBAS AmpliPrep/TaqMan nucleic acid test.

Cases of congenital HCMV infection (ie, cCMV+) were defined as mother-infant donors for which cord blood was positive for HCMV viremia at birth. Control pairs without cCMV infection (cCMV-) were identified as cord blood HCMV RT-PCR negative at birth. Mother-infant pairs with cCMV infection (n = 27 pairs) were matched to at least 2 control pairs without cCMV infection (n = 66 pairs) on infant race/ethnicity, sex, maternal age, and delivery year (Supplementary Figure 1). Our control group included 29 cCMV-uninfected infants born to HCMV-seropositive mothers and 37 cCMV-uninfected infants born to HCMV-seronegative mothers. Maternal HCMV IgG seropositivity and avidity was confirmed by an in-house HCMV enzyme-linked immunosorbent assay (ELISA) [15, 16] and HCMV immunoglobulin M (IgM) seropositivity was determined using a clinical diagnostic ELISA (Bio-Rad). Maternal donors provided informed consent to the CCBB for the use of biospecimens, and data for research and approval was obtained from Duke’s Institutional Review Board (Pro00089256) to use de-identified clinical data and biospecimens.

HCMV IgG Binding and Avidity

HCMV strain TB40/E was propagated as previously described [15, 16]. ELISA plates were coated with 33 plaque-forming units of TB40/E per well, incubated, and then blocked with diluent [15]. Sera serial dilutions were tested starting at 1:30, plated in duplicate, and then incubated before adding horseradish peroxidase (HRP)-conjugated goat anti-human IgG (Jackson ImmunoResearch). Plates were developed with tetramethylbenzidine (TMB) and peroxidase substrate (KPL), and then optical density (OD) was measured. HCMV hyperimmunoglobulin (HCMV-HIG), seropositive, and seronegative sera were included as controls. HCMV-specific IgG concentrations were interpolated from the linear range of a 5-parameter HCMV-HIG standard curve. HCMV-specific IgG transfer efficiency was calculated as (cord blood IgG)/(maternal IgG)×100%. For avidity, duplicate wells were treated with 7M urea or 1X phosphate-buffered saline (PBS), and relative avidity index was calculated as (OD with urea)/(OD with PBS)×100% [15].

Total IgG Levels

ELISA plates were coated with goat anti-human polyvalent Ig (Life Technologies), incubated, and then blocked with diluent. Normal human serum IgG (Sigma-Aldrich) was used as a standard. Sera serial dilutions were tested starting at 1:1000, plated in duplicate, and then incubated before adding HRP-conjugated goat anti-human IgG and TMB/KPL as above. IgG concentrations were interpolated from the linear range of the normal human serum IgG 5-parameter standard curve. Total IgG transfer efficiency was calculated as (cord blood IgG)/(maternal IgG)×100%.

Binding Antibody Multiplex Assay (BAMA) of Antigen-specific IgG Levels

BAMA was run as previously described [7, 11, 17, 18] to quantify hepatitis B virus (HBV), Haemophilus influenzae type b (Hib), Bordetella pertussis (pertussis), respiratory syncytial virus (RSV), and Clostridium tetani (tetanus)-specific IgG levels. Pathogen-specific antigens were coupled to fluorescent beads (Bio-Rad), and World Health Organization (WHO) reference sera were used as standard controls (Supplementary Table 1). Sera was diluted (1:25 and 1:200) in diluent, plated in duplicate, and then coincubated with antigen-coupled beads. IgG binding was detected with mouse anti-human IgG-PE (SouthernBiotech) and mean fluorescent intensity was measured (Bio-Plex 200). Antigen-specific IgG concentrations were interpolated from standard curves and transfer efficiency was calculated as (cord blood IgG)/(maternal IgG)×100%. An antigen-specific IgG transfer efficiency score was calculated as the mean of all antigen-specific IgG transfer efficiencies for each pair.

Statistical Analysis

Duplicates with coefficients of variance > 20% (ELISA) and > 25% (BAMA) were repeated. Continuous variables were summarized by medians/interquartile range (IQR) and compared using Wilcoxon rank-sum, signed rank test, or Kruskal-Wallis tests. Categorical variables were summarized by frequencies/percentages and compared using χ ² or Fisher exact tests. A Bonferroni correction was used to adjust for multiple comparisons. Pearson’s correlation coefficient was calculated for normally distributed data, and Spearman’s correlation coefficient was used for non-normal variables. Box cox transformation was used to assess the relationship between total IgG levels. Antigen-specific IgG transfer efficiency was modeled as a function of cCMV status using generalized linear regression with a log link function, adjusting for gestational age. The SAS procedure PROC CAUSALMED was used to estimate the direct, indirect, and total effect of cCMV infection on antigen-specific IgG transfer with maternal IgG levels as the mediator. A Gamma distribution and log link function was specified for the antigen-specific IgG transfer efficiency score to be modeled as the outcome. Effect estimates were exponentiated and reported with 95% confidence intervals (CI) obtained based on 1000 bootstrap samples and adjusted for gestational age. Statistical analyses were performed in SAS v9.4 and R v4.0.4.

RESULTS

Case-control Cohort

Demographic and clinical characteristics were comparable between cCMV-infected (cCMV+) and cCMV-uninfected (cCMV-) mother-infant pairs (Supplementary Figure 1), although mothers of cCMV-infected infants had a higher rate of Cesarean section (Table 1). We measured HCMV-specific IgG avidity and HCMV-specific IgM to determine whether HCMV-seropositive mothers had primary or non-primary infection during pregnancy [2, 19]. HCMV-specific IgG avidity was similar in HCMV-transmitting (83.9%) and HCMV-seropositive non-transmitting mothers (88.9%; P = .11), and all HCMV-seropositive mothers had high-avidity HCMV-specific IgG (>60%), suggesting, but not confirming, non-primary infection [19]. HCMV-specific IgM was detectable in 8/27 (29.6%) HCMV-transmitting and 2/29 (6.9%) HCMV-seropositive non-transmitting mothers, indicating recent re-infection or primary infection (Table 1). Although more mothers in the cCMV+ group had detectable HCMV-specific IgM compared to HCMV-seropositive mothers in the cCMV- group, this difference was not statistically significant. Moreover, the avidity results suggest that most seropositive mothers were chronically HCMV-infected.

Table 1.

Baseline Characteristics of Mother-Infant Pairs With and Without Congenital Human Cytomegalovirus (cCMV) Infection

Mother-Infant Pair Characteristics	cCMV-infected (n = 27)^a	cCMV-uninfected (n = 66)^b
Infant sex, n (%)
Male	17 (63.0%)	42 (63.6%)
Female	10 (37.0%)	24 (36.4%)
Infant race, n (%)
White	17 (63.0%)	42 (63.6%)
Black	5 (18.5%)	12 (18.2%)
Hispanic	1 (3.7%)	2 (3.0%)
Other	4 (14.8%)	10 (15.2%)
Maternal age (years), median (range)	29 (20–40)	30 (18–43)
Gestational age (months), median (range)	39 (36–41)	39 (37–41)
Delivery year, median (range)	2015 (2008–2018)	2016 (2006–2018)
Delivery type, n (%)
Vaginal	11 (40.7%)	39 (59.1%)
Cesarean section	16 (59.3%)	27 (40.9%)
Maternal HCMV IgG, n (%)
Seropositive	27 (100%)	29 (43.9%)
Seronegative	0 (0%)	37 (56.1%)
Maternal HCMV IgG avidity index, median (Q1, Q3)	83.9 (76.6, 89.3)	88.9 (84.7, 91.9)
Maternal HCMV IgM, n (%)
Seropositive	8 (29.6%)	2 (3.0%)
Seronegative	19 (70.4%)	64 (97.0%)
HCMV viral load, median [range] ^c	856 (137–18,100)	ND

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cCMV+ and cCMV− pairs were matched on maternal age (±3 years), infant race, sex, and delivery year (±3 years).

Abbreviations: HCMV, human cytomegalovirus; IgG, immunoglobulin G; IgM, immunoglobulin M; ND, not detected.

^acCMV-infected (cCMV+) indicates mother-infant pair with cCMV infection.

^bcCMV-uninfected (cCMV-) indicates mother-infant pair without cCMV infection and includes HCMV-seropositive non-transmitting (n = 29) and HCMV-seronegative (n = 37) mothers.

^cHCMV viral copies detected in cord blood and listed in IU/mL.

In utero HCMV Infection Is Associated With Reduced Transplacental IgG Transfer Efficiency

We observed a 20% decrease in total IgG transfer efficiency in cCMV-infected (71%) versus uninfected (91%) pairs (Figure 1A; P = .014). Within the cCMV- control group, total IgG transfer efficiency was similar in pairs with HCMV-seropositive (90.0%) and seronegative mothers (90.9%). Transplacental transfer efficiency of IgG against HBV (P = .0096), pertussis (P = .037), RSV (P = .0092), and tetanus (P = .035) was also decreased in cCMV-infected versus uninfected pairs (Figure 1B and 1D). Hib-specific IgG transfer was low in both infected and uninfected pairs and poorly correlated with other transfer efficiencies (Figure 1B and 1D; Supplementary Figure 2A–B). An antigen-specific IgG transfer score summarizing antigen-specific IgG transfer within each mother-infant pair [11] was highly correlated with total IgG transfer efficiency (Supplementary Figure 2C; ρ = 0.71, P < .0001) and lower in cCMV-infected pairs (Figure 1C; P = .016). Using generalized linear regression modeling, cCMV infection was significantly associated with a 24% reduction in antigen-specific IgG transfer after adjusting for gestational age (0.76, 95% CI .62–0.92, P = .0062).

Maternal Hypergammaglobulinemia Mediates Decreased Transplacental IgG Transfer Efficiency in cCMV Infection

Maternal hypergammaglobulinemia (total IgG levels > 15 mg/dL) has been associated with compromised transplacental IgG transfer in maternal HIV and placental malaria infection [12, 13, 20], so we next examined maternal IgG levels. HCMV-transmitting mothers had higher total IgG levels compared to mothers of uninfected infants (Figure 2A; P = .014) and 10/27 (37%) HCMV-transmitting mothers had hypergammaglobulinemia compared to 16/62 (26%) mothers of uninfected infants (Figure 2A). Maternal total IgG levels were significantly negatively correlated with total and antigen-specific IgG transfer efficiencies (Figure 2B; ρ = -0.46, P < .0001) as well as HBV, pertussis, RSV, and tetanus-specific IgG transfer efficiencies in cCMV-infected and uninfected pairs (Supplementary Figure 3). Total IgG levels in paired maternal and cord blood sera were highly correlated (Figure 2C; ρ = 0.76, P < .0001); however, this correlation was lower in infected (ρ = 0.61) versus uninfected pairs (ρ = 0.89; Supplementary Figure 4). We performed a box cox analysis to assess the relationship between maternal and cord blood total IgG levels and determined that the relationship was logarithmic (λ = 0.10 95% CI −.10, .34), as demonstrated by decreasing rates of transplacental IgG transfer at higher maternal IgG levels (Figure 2C). Specifically, we observed a saturation of transplacental IgG transfer at higher maternal IgG levels in cCMV-infected pairs (Figure 2C, Supplementary Figure 4A), which was not observed in uninfected pairs and was obscured by log-transformation of IgG concentration (Figure 2C, Supplementary Figure 4A–B).

Figure 2. — Elevated maternal total IgG levels in HCMV-transmitting mothers correlate with decreased transplacental IgG transfer efficiency. A, Log-transformed maternal total IgG levels in mothers of cCMV + and cCMV- pairs. Dashed line indicates cutoff for hypergammaglobulinemia (total IgG levels > 15 mg/dL). Black bars denote median. B, Correlation between IgG transfer efficiency and log-transformed maternal total IgG levels for total IgG (*left*) and antigen-specific IgG (*right*) transfer efficiency. C, Scatterplot showing relationship between non-transformed maternal and cord blood total IgG levels. Box cox analysis was performed to assess the nature of the relationship between maternal and cord total IgG levels, which are modeled by the black trend line. D, Mediation regression model showing relationship between HCMV transmission, ie, cCMV infection, maternal total IgG levels, and antigen-specific IgG transfer efficiency. Differences between cCMV+ (n = 27) and cCMV− (n = 66) pairs were compared by Wilcoxon rank-sum tests. Raw uncorrected P-values reported. * P < .05. Correlations were computed using Spearman’s rank correlation. Abbreviations: cCMV, congenital HCMV; HCMV, human cytomegalovirus; IgG, immunoglobulin G.

To make causal inference about the relationship between maternal total IgG levels and transplacental IgG transfer, we used a multivariable mediation regression analysis. Our analysis demonstrated that congenital HCMV transmission, directly and indirectly through maternal total IgG levels, causes a 23% reduction (0.77, 95% CI.64–.90, P = .0079) in antigen-specific IgG transfer efficiency and that 74.5% of this effect is mediated by elevated maternal total IgG levels (ie, hypergammaglobulinemia) in HCMV-transmitting women (Figure 2D; Table 2).

Table 2.

Mediation Model Examining the Association Between Congenital Human Cytomegalovirus (cCMV) infection, Maternal Total IgG Levels, and Transplacental IgG Transfer Efficiency^a

	Estimated Ratio of IgG Transfer Efficiency (95% CI)	P value
Total effect^b	0.77 (0.64, 0.90)	.0079
NDE^c	0.93 (0.78, 1.10)	.4691
NIE^d	0.82 (0.69, 0.94)	.0022
Percentage mediated^e	74.5 (27.9, 174.0)	.0085

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Abbreviations: CI, confidence interval; IgG, immunoglobulin G; NDE, natural direct effect; NIE, natural indirect effect.

^aThe antigen-specific transplacental IgG transfer efficiency score was modeled as a function of infant cCMV status with maternal total IgG levels specified as the mediator. The regression model was adjusted for gestational age. Bold indicates statistical significance.

^bThe effect of HCMV transmission on IgG transfer efficiency (directly and indirectly though the mediator).

^cNDE refers to the effect of HCMV transmission on IgG transfer efficiency directly.

^dNIE refers to the effect of HCMV transmission on IgG transfer efficiency indirectly (through the mediator).

^ePercentage of the effect of HCMV transmission on IgG transfer efficiency mediated by maternal total IgG levels.

Cord Blood Antigen-specific IgG Levels Are Comparable in cCMV-infected and Uninfected Infants

Despite lower IgG transfer efficiency, antigen-specific IgG levels were similar in the cord blood of cCMV-infected and uninfected infants (Figure 3), and maternal and cord blood antigen-specific IgG levels were highly correlated in cCMV-infected and uninfected pairs (Figure 4; correlation coefficients > 0.86, P < .0001). Moreover, a similar proportion of cCMV-infected and uninfected infants had HBV, Hib, and tetanus-specific IgG levels protective against disease acquisition based on established WHO immune correlates of protection (Figure 4; Supplementary Figure 5) [21]. Although no immune correlates of protection are established for RSV and pertussis, infected and uninfected infants also had comparable IgG levels against these pathogens (Figure 3).

Figure 3. — Antigen-specific IgG levels are similar in mother-infant pairs with and without congenital HCMV infection. Cord blood (infant) and maternal antigen-specific IgG levels were measured with a binding antibody multiplex assay. Concentrations of antigen-specific IgG against HBV surface antigen (HBsAg), *Haemophilus influenzae* type b (Hib), pertussis toxin (PT), respiratory syncytial virus (RSV) F protein, and tetanus toxoid (TT) were determined using WHO reference sera in international units (IU) or μg/mL and were log-transformed. Dashed lines indicate lower limit of quantification. Black bars denote median. Concentrations were compared between cCMV + (n = 27) and cCMV− (n = 51) pairs by non-parametric Wilcoxon rank-sum test. * P < .05. Abbreviations: cCMV, congenital HCMV; HBV, hepatitis B virus; HCMV, human cytomegalovirus; IgG, immunoglobulin G; WHO, World Health Organization.

Figure 4. — Correlations between maternal and cord blood antigen-specific IgG levels in mother-infant pairs with and without congenital HCMV infection. Cord blood (infant) and maternal antigen-specific IgG levels against HBV surface antigen, Hib, pertussis toxin, RSV F protein, and tetanus toxoid were measured with a binding antibody multiplex assay. Concentrations of antigen-specific IgG were determined using WHO reference sera in international units (IU) or μg/mL and were log-transformed. Dashed lines indicate the threshold of protection against disease acquisition based on established immune correlates of protection. Pearson’s correlation for RSV and Spearman’s correlations for HBV, Hib, pertussis, and tetanus for cCMV+ (n = 27) and cCMV− (n = 51) pairs. All correlations were considered statistically significant (P < .0001). Abbreviations: cCMV, congenital HCMV; HBV, hepatitis B virus; HCMV, human cytomegalovirus; Hib, *Haemophilus influenzae* type b; IgG, immunoglobulin G; RSV, respiratory syncytial virus; WHO, World Health Organization.

Transplacental Transfer of HCMV-specific IgG Is Altered in cCMV Infection

In a subgroup analysis excluding pairs with HCMV-seronegative mothers, we compared HCMV-specific IgG transfer in HCMV-transmitting (ie, cCMV-infected) and nontransmitting (ie, cCMV-uninfected) mother-infant pairs. HCMV-specific IgG transfer efficiency was reduced in transmitting versus non-transmitting pairs (Figure 5A; P = .032). Cord blood levels of HCMV-specific IgG were significantly lower than maternal levels in HCMV-transmitting (−338 µg/mL; P = .0089) but not in non-transmitting (−35 µg/mL; P = .1135) pairs (Figure 5A), although HCMV-specific IgG levels were similar in mothers and infants from both groups (Figure 5A). HCMV-specific IgG avidity was comparable in the mothers and infants from transmitting and non-transmitting pairs (Figure 5B); however, avidity was lower in the cord blood of cCMV-infected infants compared to their mothers (P = .049; Figure 5B).

Figure 5. — HCMV-specific IgG transfer and avidity in HCMV-transmitting versus nontransmitting mother-infant pairs. HCMV-specific IgG levels and avidity were determined with a whole virion ELISA against HCMV strain TB40/E. HCMV-specific IgG relative avidity index was determined as a ratio of (OD binding with urea)/(OD binding with PBS)×100%. A, HCMV-specific IgG transfer efficiency was calculated as (cord blood HCMV-specific IgG)/(maternal HCMV-specific IgG)×100% and log-transformed HCMV-specific IgG levels were compared between groups. B, HCMV-specific IgG relative avidity was compared in paired maternal and cord samples. Thin black lines connect individual mother-infant pairs and thick black bars denote median. Differences were compared between HCMV-transmitting/cCMV-infected (n = 27) and nontransmitting/cCMV-uninfected (n = 29) pairs by nonparametric Wilcoxon rank-sum test or signed-rank test. Raw uncorrected P-values reported. * P < .05, *** P < .0001. Abbreviations: cCMV, congenital HCMV; ELISA, enzyme-linked immunsorbent assay; HCMV, human cytomegalovirus; IgG, immunoglobulin G; OD, optical density; PBS, phosphate-buffered saline.

DISCUSSION

Our study is the first to comprehensively investigate transplacental IgG transfer in cCMV infection. We found that total, HBV, pertussis, RSV, tetanus, and HCMV-specific IgG placental transfer efficiencies are reduced in cCMV infection due to elevated maternal total IgG levels (ie, hypergammaglobulinemia). Despite this decrease in IgG transfer efficiency, we observed that infants with and without cCMV infection had similar levels of transplacentally transferred maternal IgG against heterologous pathogens. These results support the further development of maternal immunization strategies leveraging transplacental IgG transfer and provide insight into the mechanisms governing efficient transplacental IgG transfer.

Our results are consistent with prior literature associating elevated maternal total IgG levels due to maternal infections with decreased transplacental IgG transfer, which has been described extensively in maternal HIV infection [12, 13, 20, 22]. Our study is the first to observe this phenomenon in an HIV-uninfected US-based cohort and to identify lower rates of placental IgG transfer in cCMV infection. The mechanisms underlying reduced transplacental IgG transfer due to maternal hypergammaglobulinemia are poorly understood, yet it has been hypothesized that FcRn becomes saturated in the setting of elevated maternal IgG levels, leading to decreased transplacental IgG transfer rates [9, 22]. Our findings further support this FcRn saturation hypothesis, as we observed decreasing rates of antigen-specific IgG transfer at higher maternal total IgG levels in cCMV infection (Figure 2).

Unlike other antigen specificities, Hib-specific IgG transfer was comparable in cCMV-infected and uninfected pairs. Hib-specific IgG transfer ratios were low overall, consistent with prior studies demonstrating that Hib-specific IgG (primarily IgG subclass 2) is inefficiently transferred across the placenta [6, 12]. Why Hib-specific IgG is poorly transferred and minimally impacted by maternal hypergammaglobulinemia should be explored.

Our mediation analysis implicated maternal hypergammaglobulinemia as the main driver of reduced transplacental IgG transfer efficiency in cCMV infection; however, it is possible that placental HCMV infection may also modify IgG transfer directly through additional mechanisms. HCMV can induce FcRn degradation in vitro [14] and downregulate the expression of other placental FcRs [23, 24]. Thus, altered placental FcR expression as well as elevated maternal IgG levels may act synergistically to cause saturation of FcR-IgG binding and lower rates of IgG transfer. Moreover, HCMV-induced placental inflammation and syncytiotrophoblast damage may also disrupt efficient IgG shuttling across the placenta.

Despite decreased transplacental IgG transfer, cord blood from cCMV-infected and uninfected infants had similar HBV, pertussis, RSV, and tetanus-specific IgG levels, suggesting equivalent protection from maternal IgG for these pathogens. In some studies, decreased transplacental IgG transfer rates have been associated with lower cord blood IgG levels [20, 25], whereas others indicate that lower IgG transfer ratios are not always associated with lower cord blood IgG levels [22, 26]. These divergent findings and our results highlight the importance of reporting cord blood IgG levels as well as transfer ratios as many studies define “impaired placental IgG transfer” as transfer ratios < 1.0 or < 100% [8, 10, 11, 27], yet lower transfer ratios do not always correlate with lower IgG levels in the neonatal circulation, as our findings reveal. The clinical significance of establishing consistent definitions of effective transplacental IgG transfer has been recently highlighted by several conflicting studies on placental IgG transfer in maternal severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and vaccination. Although some studies describe efficient transplacental transfer of anti-SARS-CoV-2 IgG [27, 28], others suggest that transfer may be compromised and that neutralizing antibodies are poorly transferred [28, 29], which has important implications for neonatal passive immunity, as infants are currently ineligible for SARS-CoV-2 vaccines.

Our study is the first to identify hypergammaglobulinemia in maternal HCMV infection, although hypergammaglobulinemia has been observed in HCMV/HIV coinfection and HCMV mononucleosis [30, 31]. This finding aligns with a recent study showing that HCMV glycoprotein-specific IgG levels are elevated in HCMV-transmitting women [32]. Taken together, these results suggest that hypergammaglobulinemia may be common in HCMV-transmitting mothers, an important finding because maternal HCMV hyperimmunoglobulin (HCMV-HIG) is being actively explored as a preventative treatment for cCMV infection. Numerous studies suggest that maternal passive immunization with CMV-specific IgG protects against placental HCMV transmission [33–37]; however, HCMV-HIG has shown variable efficacy in preventing transmission in clinical trials and caused adverse side effects in some women [38, 39]. Our findings suggests that maternal hypergammaglobulinemia should be considered in future HCMV-HIG clinical trials because preexisting hypergammaglobulinemia may render HCMV-HIG less efficacious in this population, which may have confounded the effectiveness of HCMV-HIG in clinical trials to date. As there are no licensed therapies to prevent cCMV, an improved understanding of potential modifiers of the efficacy of antibody-based cCMV prophylaxis or treatment is needed to guide future interventions.

Our study also provides insight into HCMV-specific IgG transfer across the placenta. Although HCMV-specific IgG is efficiently transferred in non-transmitting pregnancies [26, 40], our study is the first to our knowledge to report on HCMV-specific IgG transfer in cCMV infection. Low avidity HCMV-specific IgG has been posited to enhance transmission risk by forming HCMV-IgG immune complexes that bind FcRn and allow HCMV to cross placenta, yet this has not been confirmed in vivo. Whether placentally-transferred HCMV-specific IgG enhances risk or mediates protection against transmission remains underexplored, but our study suggests that transplacental transfer of high avidity, HCMV-specific IgG may be compromised in HCMV-transmitting pregnancies.

Although statistical power in our study was limited by small sample size, this matched case-control cohort represents the largest US-based birth cohort of mother-infant pairs with and without cCMV infection studied to date. Additional limitations to our study include the lack of longitudinal biospecimens and placenta samples as well as limited information on maternal symptoms during pregnancy or infant sequalae due to the retrospective study design. Moreover, we measured pathogen-specific IgG binding rather than function (eg, neutralizing antibody titers), so we cannot conclude whether cCMV infection alters the transfer of IgG most capable of mediating anti-pathogenic functions [10, 11, 22].

Overall, our results suggest that transplacental IgG transfer efficiency is reduced in cCMV infection due to FcRn saturation in the setting of maternal hypergammaglobulinemia, but that, despite this phenomenon, cCMV-infected and uninfected infants have equivalent protection from placentally transferred maternal IgG. These findings imply that maternal immunization to boost neonatal immunity through transplacental IgG transfer will be effective in the setting of cCMV infection.

Supplementary Data

Supplementary materials are available at Clinical Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.

ciab627_suppl_Supplementary_Materials

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Notes

Author Contributions. E. C. S. and S. H. L. conducted the experiments, acquired the data, and completed the primary data analysis. E. C. S., J. H. H., G. G. F., K. M. W., and S. R. P. designed the research study. K. M. W. and S. R. P. acquired funding for the study. Z. Y. and D. N. completed the statistical analyses apart from the box cox analysis, which was supervised by K. M. W. J. K. provided the biospecimens for the study. E. C. S., S. H. L., J. H. H., Z. Y., D. N., G. G. F., J. K., K. M. W., and S. R. P. all contributed to writing and editing the manuscript.

Acknowledgments. The authors thank the CCBB donors and staff including Jose Hernandez, Ann Kaestner, and Korrynn Vincent who were instrumental in acquiring the biospecimens and donor clinical information relevant to this study. They also thank Dr Tina Davenport from the Duke Department of Biostatistics and Bioinformatics for helpful input on the mediation analysis.

Financial support. This work was supported by the National Institutes of Health National Cancer Institute (grant number 1R21CA242439-01) “Immune Correlates and Mechanisms of Perinatal Cytomegalovirus Infection and Later Life ALL Development” to K. M. W. and S. R. P. and National Institutes of Health National Institute of Allery and Infectious Diseases (grant number 1R21-AI147992) “Humoral immune correlates of protection against congenital CMV and HSV transmission in HIV-infected women” to S. R. P. Additional support was provided by Duke University School of Medicine through Translating Duke Health’s Children’s Health and Discovery Initiative and the Medearis CMV Scholars Program to S. R. P. Statistical analyses reported in this publication was supported by the National Center For Advancing Translational Sciences of the National Institutes of Health (grant number UL1TR002553). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. D. N. and L. Z. Y. report that the Duke CTSA provides funding to support the infrastructure of their work unit, the BERD Methods Core (grant number UL1TR002553 Boulware (PI) 05/02/18–4/30/23). They do not receive any payments from it to support this research project and manuscript.

Potential conflict of interest. S. R. P. provides consulting services to Moderna, Merck/Merck and Co Vaccines, Pfizer Inc., Dynavax and Sanofi for their HCMV vaccine programs, outside submitted work. S. R. P. reports support from Merck Vaccines and Moderna (institutional sponsored program), outside the submitted work. S. R. P. and E. S. report receiving support for manuscript from the National Institutes of Health (NIH), Children’s Health and Discovery Initiative, Duke University School of Medicine and Medearis CMV Scholars, Duke University School of Medicine, during scope of the project. E. S. reports receiving support for manuscript from NIH and Children’s Health and Discovery Initiative, Duke University School of Medicine, during the conduct of the study.

J. H. reports the institution receiving grants not related to the present work from Merck Investigator Studies Program, Burroughs Wellcome Fund, National Center for Advancing Translation Sciences, Centers for Medicare and Medicaid Services, National Cancer Institute, Food and Drug Administration, and the Duke Endowment, outside the submitted work. All other authors report no potential conflicts.

All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

References

1. Coppola T, Mangold JF, Cantrell S, Permar SR. Impact of maternal immunity on congenital cytomegalovirus birth prevalence and infant outcomes: a systematic review. Vaccines (Basel) 2019; 7: 129. doi: 10.3390/vaccines7040129. [DOI] [PMC free article] [PubMed] [Google Scholar]
2. Permar SR, Schleiss MR, Plotkin SA. Advancing our understanding of protective maternal immunity as a guide for development of vaccines to reduce congenital cytomegalovirus infections. J Virol 2018; 92: e00030– 18. doi: 10.1128/JVI.00030-18. [DOI] [PMC free article] [PubMed] [Google Scholar]
3. Boppana SB, Ross SA, Fowler KB. Congenital cytomegalovirus infection: clinical outcome. Clin Infect Dis 2013; 57 Suppl 4:S178–81. [DOI] [PMC free article] [PubMed] [Google Scholar]
4. Francis SS, Wallace AD, Wendt GA, et al. In utero cytomegalovirus infection and development of childhood acute lymphoblastic leukemia. Blood 2017; 129:1680–4. [DOI] [PMC free article] [PubMed] [Google Scholar]
5. Manicklal S, Emery VC, Lazzarotto T, Boppana SB, Gupta RK. The “silent” global burden of congenital cytomegalovirus. Clin Microbiol Rev 2013; 26:86–102. [DOI] [PMC free article] [PubMed] [Google Scholar]
6. Fouda GG, Martinez DR, Swamy GK, Permar SR. The impact of IgG transplacental transfer on early life immunity. Immunohorizons 2018; 2:14–25. [DOI] [PMC free article] [PubMed] [Google Scholar]
7. Post AL, Li SH, Berry M, et al. Efficiency of placental transfer of vaccine-elicited antibodies relative to prenatal Tdap vaccination status. Vaccine 2020; 38:4869–76. [DOI] [PMC free article] [PubMed] [Google Scholar]
8. Munoz FM, Patel SM, Jackson LA, et al. Safety and immunogenicity of three seasonal inactivated influenza vaccines among pregnant women and antibody persistence in their infants. Vaccine 2020; 38:5355–63. [DOI] [PMC free article] [PubMed] [Google Scholar]
9. Wilcox CR, Holder B, Jones CE. Factors affecting the FcRn-mediated transplacental transfer of antibodies and implications for vaccination in pregnancy. Front Immunol 2017; 8:1294. [DOI] [PMC free article] [PubMed] [Google Scholar]
10. Jennewein MF, Goldfarb I, Dolatshahi S, et al. Fc Glycan-mediated regulation of placental antibody transfer. Cell 2019; 178:202–15.e14. [DOI] [PMC free article] [PubMed] [Google Scholar]
11. Martinez DR, Fong Y, Li SH, et al. Fc characteristics mediate selective placental transfer of IgG in HIV-infected women. Cell 2019; 178:190–201.e11. [DOI] [PMC free article] [PubMed] [Google Scholar]
12. Okoko BJ, Wesumperuma LH, Ota MO, et al. The influence of placental malaria infection and maternal hypergammaglobulinemia on transplacental transfer of antibodies and IgG subclasses in a rural West African population. J Infect Dis 2001; 184:627–32. [DOI] [PubMed] [Google Scholar]
13. de Moraes-Pinto MI, Verhoeff F, Chimsuku L, et al. Placental antibody transfer: influence of maternal HIV infection and placental malaria. Arch Dis Child Fetal Neonatal Ed 1998; 79:F202–5. [DOI] [PMC free article] [PubMed] [Google Scholar]
14. Liu X, Palaniyandi S, Zhu I, et al. Human cytomegalovirus evades antibody-mediated immunity through endoplasmic reticulum-associated degradation of the FcRn receptor. Nat Commun 2019; 10:3020. [DOI] [PMC free article] [PubMed] [Google Scholar]
15. Nelson CS, Huffman T, Jenks JA, et al. HCMV glycoprotein B subunit vaccine efficacy mediated by nonneutralizing antibody effector functions. Proc Natl Acad Sci U S A 2018; 115:6267–72. [DOI] [PMC free article] [PubMed] [Google Scholar]
16. Bialas KM, Westreich D, Cisneros de la Rosa E, et al. Maternal antibody responses and nonprimary congenital cytomegalovirus infection of HIV-1-exposed infants. J Infect Dis 2016; 214:1916–23. [DOI] [PMC free article] [PubMed] [Google Scholar]
17. Itell HL, McGuire EP, Muresan P, et al. Development and application of a multiplex assay for the simultaneous measurement of antibody responses elicited by common childhood vaccines. Vaccine 2018; 36:5600–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
18. Singh T, Lopez CA, Giuberti C, et al. Efficient transplacental IgG transfer in women infected with Zika virus during pregnancy. PLoS Negl Trop Dis 2019; 13:e0007648. [DOI] [PMC free article] [PubMed] [Google Scholar]
19. Prince HE, Lapé-Nixon M. Role of cytomegalovirus (CMV) IgG avidity testing in diagnosing primary CMV infection during pregnancy. Clin Vaccine Immunol 2014; 21:1377–84. [DOI] [PMC free article] [PubMed] [Google Scholar]
20. Jallow S, Agosti Y, Kgagudi P, et al. Impaired Transplacental transfer of respiratory syncytial virus-neutralizing antibodies in human immunodeficiency virus-infected versus -uninfected pregnant women. Clin Infect Dis 2019; 69:151–4. [DOI] [PubMed] [Google Scholar]
21. Plotkin SA. Correlates of protection induced by vaccination. Clin Vaccine Immunol 2010; 17:1055–65. [DOI] [PMC free article] [PubMed] [Google Scholar]
22. Atwell JE, Thumar B, Robinson LJ, et al. Impact of placental malaria and hypergammaglobulinemia on transplacental transfer of respiratory syncytial virus antibody in Papua New Guinea. J Infect Dis 2016; 213:423–31. [DOI] [PMC free article] [PubMed] [Google Scholar]
23. Johnson EL, Boggavarapu S, Johnson ES, et al. Human cytomegalovirus enhances placental susceptibility and replication of human immunodeficiency virus type 1 (HIV-1), which may facilitate in utero HIV-1 transmission. J Infect Dis 2018; 218:1464–73. [DOI] [PMC free article] [PubMed] [Google Scholar]
24. Martinez DR, Fouda GG, Peng X, Ackerman ME, Permar SR. Noncanonical placental Fc receptors: what is their role in modulating transplacental transfer of maternal IgG? PLoS Pathog 2018; 14:e1007161. [DOI] [PMC free article] [PubMed] [Google Scholar]
25. Jones CE, Naidoo S, De Beer C, Esser M, Kampmann B, Hesseling AC. Maternal HIV infection and antibody responses against vaccine-preventable diseases in uninfected infants. JAMA 2011; 305:576–84. [DOI] [PubMed] [Google Scholar]
26. Pou C, Nkulikiyimfura D, Henckel E, et al. The repertoire of maternal anti-viral antibodies in human newborns. Nat Med 2019; 25:591–6. [DOI] [PubMed] [Google Scholar]
27. Flannery DD, Gouma S, Dhudasia MB, et al. Assessment of maternal and neonatal cord blood SARS-CoV-2 antibodies and placental transfer ratios. JAMA Pediatr 2021; 175:594–600. [DOI] [PMC free article] [PubMed] [Google Scholar]
28. Sherer ML, Lei J, Creisher P, et al. Pregnancy alters IL-1β expression and anti-viral antibody responses during SARS-CoV-2 infection. Am J Obstet Gynecol 2021. [DOI] [PMC free article] [PubMed] [Google Scholar]
29. Atyeo C, Pullen KM, Bordt EA, et al. Compromised SARS-CoV-2-specific placental antibody transfer. Cell 2021; 184:628–42.e10. [DOI] [PMC free article] [PubMed] [Google Scholar]
30. Lane HC, Masur H, Edgar LC, Whalen G, Rook AH, Fauci AS. Abnormalities of B-cell activation and immunoregulation in patients with the acquired immunodeficiency syndrome. N Engl J Med 1983; 309:453–8. [DOI] [PubMed] [Google Scholar]
31. Hutt-Fletcher LM, Balachandran N, Elkins MH. B cell activation by cytomegalovirus. J Exp Med 1983; 158:2171–6. [DOI] [PMC free article] [PubMed] [Google Scholar]
32. Dorfman JR, Balla SR, Pathirana J, Groome MJ, Madhi SA, Moore PL. In utero human cytomegalovirus infection is associated with increased levels of putatively protective maternal antibodies in nonprimary infection: evidence for boosting but not protection. Clin Infect Dis 2021; 73:e981–7. [DOI] [PubMed] [Google Scholar]
33. Chatterjee A, Harrison CJ, Britt WJ, Bewtra C. Modification of maternal and congenital cytomegalovirus infection by anti-glycoprotein b antibody transfer in guinea pigs. J Infect Dis 2001; 183:1547–53. [DOI] [PubMed] [Google Scholar]
34. Nigro G, Adler SP. Hyperimmunoglobulin for prevention of congenital cytomegalovirus disease. Clin Infect Dis 2013; 57 Suppl 4:S193–5. [DOI] [PubMed] [Google Scholar]
35. Nigro G, Adler SP, Parruti G, et al. Immunoglobulin therapy of fetal cytomegalovirus infection occurring in the first half of pregnancy–a case-control study of the outcome in children. J Infect Dis 2012; 205:215–27. [DOI] [PubMed] [Google Scholar]
36. Nigro G, Adler SP, La Torre R, Best AM; Congenital Cytomegalovirus Collaborating Group. . Passive immunization during pregnancy for congenital cytomegalovirus infection. N Engl J Med 2005; 353:1350–62. [DOI] [PubMed] [Google Scholar]
37. Nelson CS, Cruz DV, Tran D, et al. Preexisting antibodies can protect against congenital cytomegalovirus infection in monkeys. JCI Insight 2017; 2: e94002. doi: 10.1172/jci.insight.94002. [DOI] [PMC free article] [PubMed] [Google Scholar]
38. Revello MG, Lazzarotto T, Guerra B, et al. ; CHIP Study Group. . A randomized trial of hyperimmune globulin to prevent congenital cytomegalovirus. N Engl J Med 2014; 370:1316–26. [DOI] [PubMed] [Google Scholar]
39. Hughes B, Clifton RG, Rouse DJ, et al. Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal–Fetal Medicine Units Network. A trial of hyperimmune globulin to prevent congenital cytomegalovirus infection. N Engl J Med 2021; 385:436–444. doi: 10.1056/NEJMoa1913569 [DOI] [PMC free article] [PubMed] [Google Scholar]
40. Mussi-Pinhata MM, Pinto PC, Yamamoto AY, et al. Placental transfer of naturally acquired, maternal cytomegalovirus antibodies in term and preterm neonates. J Med Virol 2003; 69:232–9. [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

ciab627_suppl_Supplementary_Materials

Click here for additional data file.^{(967.5KB, pdf)}

[CIT0001] 1. Coppola T, Mangold JF, Cantrell S, Permar SR. Impact of maternal immunity on congenital cytomegalovirus birth prevalence and infant outcomes: a systematic review. Vaccines (Basel) 2019; 7: 129. doi: 10.3390/vaccines7040129. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0002] 2. Permar SR, Schleiss MR, Plotkin SA. Advancing our understanding of protective maternal immunity as a guide for development of vaccines to reduce congenital cytomegalovirus infections. J Virol 2018; 92: e00030– 18. doi: 10.1128/JVI.00030-18. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0003] 3. Boppana SB, Ross SA, Fowler KB. Congenital cytomegalovirus infection: clinical outcome. Clin Infect Dis 2013; 57 Suppl 4:S178–81. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0004] 4. Francis SS, Wallace AD, Wendt GA, et al. In utero cytomegalovirus infection and development of childhood acute lymphoblastic leukemia. Blood 2017; 129:1680–4. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0005] 5. Manicklal S, Emery VC, Lazzarotto T, Boppana SB, Gupta RK. The “silent” global burden of congenital cytomegalovirus. Clin Microbiol Rev 2013; 26:86–102. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0006] 6. Fouda GG, Martinez DR, Swamy GK, Permar SR. The impact of IgG transplacental transfer on early life immunity. Immunohorizons 2018; 2:14–25. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0007] 7. Post AL, Li SH, Berry M, et al. Efficiency of placental transfer of vaccine-elicited antibodies relative to prenatal Tdap vaccination status. Vaccine 2020; 38:4869–76. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0008] 8. Munoz FM, Patel SM, Jackson LA, et al. Safety and immunogenicity of three seasonal inactivated influenza vaccines among pregnant women and antibody persistence in their infants. Vaccine 2020; 38:5355–63. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0009] 9. Wilcox CR, Holder B, Jones CE. Factors affecting the FcRn-mediated transplacental transfer of antibodies and implications for vaccination in pregnancy. Front Immunol 2017; 8:1294. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0010] 10. Jennewein MF, Goldfarb I, Dolatshahi S, et al. Fc Glycan-mediated regulation of placental antibody transfer. Cell 2019; 178:202–15.e14. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0011] 11. Martinez DR, Fong Y, Li SH, et al. Fc characteristics mediate selective placental transfer of IgG in HIV-infected women. Cell 2019; 178:190–201.e11. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0012] 12. Okoko BJ, Wesumperuma LH, Ota MO, et al. The influence of placental malaria infection and maternal hypergammaglobulinemia on transplacental transfer of antibodies and IgG subclasses in a rural West African population. J Infect Dis 2001; 184:627–32. [DOI] [PubMed] [Google Scholar]

[CIT0013] 13. de Moraes-Pinto MI, Verhoeff F, Chimsuku L, et al. Placental antibody transfer: influence of maternal HIV infection and placental malaria. Arch Dis Child Fetal Neonatal Ed 1998; 79:F202–5. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0014] 14. Liu X, Palaniyandi S, Zhu I, et al. Human cytomegalovirus evades antibody-mediated immunity through endoplasmic reticulum-associated degradation of the FcRn receptor. Nat Commun 2019; 10:3020. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0015] 15. Nelson CS, Huffman T, Jenks JA, et al. HCMV glycoprotein B subunit vaccine efficacy mediated by nonneutralizing antibody effector functions. Proc Natl Acad Sci U S A 2018; 115:6267–72. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0016] 16. Bialas KM, Westreich D, Cisneros de la Rosa E, et al. Maternal antibody responses and nonprimary congenital cytomegalovirus infection of HIV-1-exposed infants. J Infect Dis 2016; 214:1916–23. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0017] 17. Itell HL, McGuire EP, Muresan P, et al. Development and application of a multiplex assay for the simultaneous measurement of antibody responses elicited by common childhood vaccines. Vaccine 2018; 36:5600–8. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0018] 18. Singh T, Lopez CA, Giuberti C, et al. Efficient transplacental IgG transfer in women infected with Zika virus during pregnancy. PLoS Negl Trop Dis 2019; 13:e0007648. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0019] 19. Prince HE, Lapé-Nixon M. Role of cytomegalovirus (CMV) IgG avidity testing in diagnosing primary CMV infection during pregnancy. Clin Vaccine Immunol 2014; 21:1377–84. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0020] 20. Jallow S, Agosti Y, Kgagudi P, et al. Impaired Transplacental transfer of respiratory syncytial virus-neutralizing antibodies in human immunodeficiency virus-infected versus -uninfected pregnant women. Clin Infect Dis 2019; 69:151–4. [DOI] [PubMed] [Google Scholar]

[CIT0021] 21. Plotkin SA. Correlates of protection induced by vaccination. Clin Vaccine Immunol 2010; 17:1055–65. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0022] 22. Atwell JE, Thumar B, Robinson LJ, et al. Impact of placental malaria and hypergammaglobulinemia on transplacental transfer of respiratory syncytial virus antibody in Papua New Guinea. J Infect Dis 2016; 213:423–31. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0023] 23. Johnson EL, Boggavarapu S, Johnson ES, et al. Human cytomegalovirus enhances placental susceptibility and replication of human immunodeficiency virus type 1 (HIV-1), which may facilitate in utero HIV-1 transmission. J Infect Dis 2018; 218:1464–73. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0024] 24. Martinez DR, Fouda GG, Peng X, Ackerman ME, Permar SR. Noncanonical placental Fc receptors: what is their role in modulating transplacental transfer of maternal IgG? PLoS Pathog 2018; 14:e1007161. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0025] 25. Jones CE, Naidoo S, De Beer C, Esser M, Kampmann B, Hesseling AC. Maternal HIV infection and antibody responses against vaccine-preventable diseases in uninfected infants. JAMA 2011; 305:576–84. [DOI] [PubMed] [Google Scholar]

[CIT0026] 26. Pou C, Nkulikiyimfura D, Henckel E, et al. The repertoire of maternal anti-viral antibodies in human newborns. Nat Med 2019; 25:591–6. [DOI] [PubMed] [Google Scholar]

[CIT0027] 27. Flannery DD, Gouma S, Dhudasia MB, et al. Assessment of maternal and neonatal cord blood SARS-CoV-2 antibodies and placental transfer ratios. JAMA Pediatr 2021; 175:594–600. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0028] 28. Sherer ML, Lei J, Creisher P, et al. Pregnancy alters IL-1β expression and anti-viral antibody responses during SARS-CoV-2 infection. Am J Obstet Gynecol 2021. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0029] 29. Atyeo C, Pullen KM, Bordt EA, et al. Compromised SARS-CoV-2-specific placental antibody transfer. Cell 2021; 184:628–42.e10. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0030] 30. Lane HC, Masur H, Edgar LC, Whalen G, Rook AH, Fauci AS. Abnormalities of B-cell activation and immunoregulation in patients with the acquired immunodeficiency syndrome. N Engl J Med 1983; 309:453–8. [DOI] [PubMed] [Google Scholar]

[CIT0031] 31. Hutt-Fletcher LM, Balachandran N, Elkins MH. B cell activation by cytomegalovirus. J Exp Med 1983; 158:2171–6. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0032] 32. Dorfman JR, Balla SR, Pathirana J, Groome MJ, Madhi SA, Moore PL. In utero human cytomegalovirus infection is associated with increased levels of putatively protective maternal antibodies in nonprimary infection: evidence for boosting but not protection. Clin Infect Dis 2021; 73:e981–7. [DOI] [PubMed] [Google Scholar]

[CIT0033] 33. Chatterjee A, Harrison CJ, Britt WJ, Bewtra C. Modification of maternal and congenital cytomegalovirus infection by anti-glycoprotein b antibody transfer in guinea pigs. J Infect Dis 2001; 183:1547–53. [DOI] [PubMed] [Google Scholar]

[CIT0034] 34. Nigro G, Adler SP. Hyperimmunoglobulin for prevention of congenital cytomegalovirus disease. Clin Infect Dis 2013; 57 Suppl 4:S193–5. [DOI] [PubMed] [Google Scholar]

[CIT0035] 35. Nigro G, Adler SP, Parruti G, et al. Immunoglobulin therapy of fetal cytomegalovirus infection occurring in the first half of pregnancy–a case-control study of the outcome in children. J Infect Dis 2012; 205:215–27. [DOI] [PubMed] [Google Scholar]

[CIT0036] 36. Nigro G, Adler SP, La Torre R, Best AM; Congenital Cytomegalovirus Collaborating Group. . Passive immunization during pregnancy for congenital cytomegalovirus infection. N Engl J Med 2005; 353:1350–62. [DOI] [PubMed] [Google Scholar]

[CIT0037] 37. Nelson CS, Cruz DV, Tran D, et al. Preexisting antibodies can protect against congenital cytomegalovirus infection in monkeys. JCI Insight 2017; 2: e94002. doi: 10.1172/jci.insight.94002. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0038] 38. Revello MG, Lazzarotto T, Guerra B, et al. ; CHIP Study Group. . A randomized trial of hyperimmune globulin to prevent congenital cytomegalovirus. N Engl J Med 2014; 370:1316–26. [DOI] [PubMed] [Google Scholar]

[CIT0039] 39. Hughes B, Clifton RG, Rouse DJ, et al. Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal–Fetal Medicine Units Network. A trial of hyperimmune globulin to prevent congenital cytomegalovirus infection. N Engl J Med 2021; 385:436–444. doi: 10.1056/NEJMoa1913569 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0040] 40. Mussi-Pinhata MM, Pinto PC, Yamamoto AY, et al. Placental transfer of naturally acquired, maternal cytomegalovirus antibodies in term and preterm neonates. J Med Virol 2003; 69:232–9. [DOI] [PubMed] [Google Scholar]

PERMALINK

Congenital Human Cytomegalovirus Infection Is Associated With Decreased Transplacental IgG Transfer Efficiency Due to Maternal Hypergammaglobulinemia

Eleanor C Semmes

Shuk Hang Li

Jillian H Hurst

Zidanyue Yang

Donna Niedzwiecki

Genevieve G Fouda

Joanne Kurtzberg

Kyle M Walsh

Sallie R Permar

Abstract

Background

Methods

Results

Conclusions

METHODS

Study Population

HCMV IgG Binding and Avidity

Total IgG Levels

Binding Antibody Multiplex Assay (BAMA) of Antigen-specific IgG Levels

Statistical Analysis

RESULTS

Case-control Cohort

Table 1.

In utero HCMV Infection Is Associated With Reduced Transplacental IgG Transfer Efficiency

Figure 1.

Maternal Hypergammaglobulinemia Mediates Decreased Transplacental IgG Transfer Efficiency in cCMV Infection

Figure 2.

Table 2.

Cord Blood Antigen-specific IgG Levels Are Comparable in cCMV-infected and Uninfected Infants

Figure 3.

Figure 4.

Transplacental Transfer of HCMV-specific IgG Is Altered in cCMV Infection

Figure 5.

DISCUSSION

Supplementary Data

Notes

References

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

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