Infants experience the highest rates of serious complications, hospitalization and death from pertussis1–3 because they have not yet received or mounted an adequate immune response to the primary diphtheria, tetanus and acellular pertussis (DTaP) immunization series.4 Maternal vaccination during pregnancy has been suggested as early as 1995 for transplacentally transferring maternal antibodies that may help protect infants against pertussis during their first months of life.5–8 The current Adolescent9 and Adult10 Immunization Schedules recommend pregnant women receive 1 dose of Tdap vaccine during each pregnancy. We studied pregnant women who chose to receive Tdap to determine whether prenatal Tdap vaccination reduces infant immune response to routine DTaP immunization.
MATERIALS AND METHODS
A cohort study was designed to evaluate woman–infant pairs, with a control group-to-Tdap group ratio of 3.5:1, in anticipation of control group attrition. The Tdap group consisted of a convenience sample of pregnant women who received Adacel (Sanofi Pasteur, Swiftwater, PA; see Table, Supplemental Digital Content 1, https://links.lww.com/INF/B624) in any trimester, during a 2006 respiratory outbreak for which retrospective investigations subsequently demonstrated pertussis was unlikely to have been the primary etiology.11 The Tdap group of women was contacted via e-mail solicitation for participation before delivery; none exhibited symptoms of pertussis during the suspected outbreak.
Cord blood is routinely collected at delivery. If the woman opted to participate, maternal blood was collected within 24 hours of delivery. Exclusion criteria included multiple gestations, serious underlying health issues in either mother or infant, preterm infants, and infants needing transfusions or advised not to have blood draws for health reasons. Mothers provided written informed consent. All participants received $25 per study visit.
Data Collection
Cord blood and maternal serum were collected at birth. Infant serum samples were then sought before and 1 month following the DTaP primary series and before and 1 month after the booster DTaP (see Fig., Supplemental Digital Content 2, https://links.lww.com/INF/B625).
Baseline demographic and medical data were collected on all patients including age, date of Tdap vaccination (if any), any history of pertussis-like illness, and infant anomalies, if any.
Vaccination of Infants
Most infants in the maternal Tdap group received the same vaccine products, but control group infants received various vaccine products, a consequence of the licensure of new vaccines during the study. The infant’s primary care provider determined which DTaP product was given. Figure, Supplemental Digital Content 3, https://links.lww.com/INF/B626, shows the vaccine products given during the primary series and for the toddler booster. Table, Supplemental Digital Content 1, https://links.lww.com/INF/B624, shows their antigenic compositions.
Laboratory Methods
All serum samples were refrigerated for <24 hours, frozen at −20°C, then sent to the serology laboratory at Sanofi Pasteur for blinded analysis. Enzyme-linked immunosorbent assays were performed according to standard methods for antibodies to the following: pertussis toxin (PT), filamentous hemagglutinin (FHA), pertactin (PRN) and fimbriae types 2 and 3 (FIM).12 Antibodies to diphtheria, tetanus, Haemophilus influenzae type b, hepatitis B and polio types 1, 2, and 3 were also measured in infant serum samples using standard methods.
Statistical Analysis
Geometric mean antibody concentrations (GMCs) or titers (GMTs) were calculated for each antigen. Mean maternal-to-cord blood antibody ratios were calculated to assess the degree of placental antibody transfer. Fold differences between the Tdap group and control group were calculated by dividing the GMC or GMT of the Tdap group by the GMC or GMT of the control group. Analyses were descriptive.
Antibody concentrations in infants of mothers vaccinated during pregnancy were compared with the control group at 4 time points (see Fig., Supplemental Digital Content 2, https://links.lww.com/INF/B625). Pertussis antibody concentrations were classified based on protective benchmarks defined as >5 EU/mL for PT and FHA and >10 EU/mL for PRN and FIM. There are no acceptable levels of protection concentrations approved by the Food and Drug Administration; however, the use of these values is supported by previous analyses performed by Storsaeter et al13 and Cherry et al.14 Because the cut points for PRN and FIM had greater variability in these previous studies, the protective range for PRN and FIM was defined more conservatively at >10 EU/mL, as in Shakib et al.15 These benchmark levels were determined based on vaccinated pediatric subjects and may or may not be applicable to passive immunity levels. The protective concentrations for the nonpertussis antigens are defined by the Food and Drug Administration.16
RESULTS
Enrollment
The control group included 54 women (mean age 28.5 years) who delivered between March 2008 and February 2009. The Tdap group consisted of all 16 pregnant women (mean age 31 years) vaccinated prenatally with Tdap during the 2006 pseudo-outbreak11: 4 during the first trimester, 8 in the second and 4 in the third.
Because of delayed institutional review board approval relative to the delivery dates, maternal and cord blood were collected at delivery from only 5 of the Tdap group women, but all 16 infants were followed. Of these 5 women, 3 were vaccinated during their first trimester and 2 during their second. Serum samples were available for 11, 15, 9 and 14 of the 16 Tdap group infants at 2, 7, 15 and 19 months of age, respectively.
Maternal and cord serum samples were collected from 53 control group women and their infants. All control group women denied exposure to pertussis or a cough consistent with pertussis during pregnancy. Twenty-eight infants discontinued participation due to travel distance from rural study site. Serum samples were available from 38, 32, 24 and 26 control infants at 2, 7, 15 and 19 months of age, respectively. All infants received their vaccines according to recommended immunization schedules.
Mother and Infant Antibody Concentrations at Delivery
At delivery, maternal and cord antibody concentrations were higher against PT, FHA, PRN and FIM in the Tdap group compared with the control group (maternal: 1.9- to 20.4-fold greater; cord: 2.7- to 35.5-fold greater) (Table 1). A greater percentage of women who received the Tdap vaccine during pregnancy (75–100%) had antibody concentrations against each of the 4 pertussis antigens that were at or above the defined benchmark protective concentrations as compared with the control group (36–66%) (Table 1 and Table, Supplemental Digital Content 4, https://links.lww.com/INF/B627).
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TABLE 1: Antibody Concentrations and Percent of Subjects at Protective Levels* of the 4 Different Pertussis Antigens for Control and Tdap Mothers and Infants
Tdap group infants had higher antibody concentrations to pertussis antigens than those of their mothers (2.0- to 2.5-fold greater) at delivery. Compared with controls, more newborns in the Tdap group demonstrated pertussis antibody concentrations at or above the defined benchmark levels: a greater percentage of infants born to Tdap-immunized mothers (80–100%) had antibody concentrations against each of the 4 pertussis antigens that were at or above the defined benchmark protective concentrations as compared with infants in the control group (40–81%). Similarly, among mother–infant pairs in the control group, infants at delivery had higher antibody concentrations to pertussis antigens than those of their mothers (1.4- to 1.7-fold greater).
Maternal antibody concentrations to diphtheria, tetanus, hepatitis B, H. influenzae type b and polio (types 1, 2 and 3) were higher among the Tdap group (see Table, Supplemental Digital Content 4, https://links.lww.com/INF/B627). Likewise, antibody concentrations to all nonpertussis antigens tested in the Tdap group infants were higher, except polio 1 (see Table, Supplemental Digital Content 4, https://links.lww.com/INF/B627).
Maternal and cord blood antibody concentrations within the Tdap group were similar for women immunized in each trimester.
Infant Antibody Concentrations Before and in Response to Vaccinations
At 2 months of age (before the first infant vaccination), pertussis antibody GMCs in infants of mothers vaccinated with Tdap during pregnancy remained higher than those of control infants (3.2- to 22.8-fold greater). Following the primary series, antibody concentrations to pertussis antigens were modestly lower in the Tdap group (0.7- to 0.8-fold lower), except for FIM (1.5-fold greater). Antibody concentrations before and after the booster dose of DTaP at 12–18 months of life showed no notable differences between groups. The differences in FIM values before and after the booster dose are difficult to interpret, due to the differences in FIM content of the different DTaP vaccine preparations (Table 1 and Table, Supplemental Digital Content 4, https://links.lww.com/INF/B627).
At every time point, the percentages of infants who achieved benchmark concentrations of antibody were higher in the Tdap group until 7 months of life. At this point, the concentration of FIM antibody decreased, likely due to the absence of FIM in most of the DTaP vaccine products (ie, Pediarix and Infanrix) administered to the Tdap group (see Table, Supplemental Digital Content 1, https://links.lww.com/INF/B624).
During the period between birth and the first dose of DTaP, the antibody concentrations to pertussis antigens of infants in the Tdap group remained in the presumed protective range and were higher than those of control infants. In response to the booster dose given at 12 to 18 months of age, both control and Tdap children showed increases in antibody concentration.
Both infant groups had protective antibody concentrations to tetanus, diphtheria, hepatitis B, H. influenzae type b and polio antigens at the time cord blood was drawn. Mean antibody concentrations in the 2 groups during the course of routine vaccination are provided in Table, Supplemental Digital Content 4, https://links.lww.com/INF/B627.
DISCUSSION
Our study is the first to investigate the impact of maternal prenatal Tdap vaccination on infant immune response at birth and at intervals during the first 18 months of life. Our study shows that vaccinating mothers during pregnancy appears to result in higher concentrations of pertussis antibodies in their infants compared with infants of unvaccinated mothers and a greater percentage of infants with protective levels of pertussis antigens. This effect persists until after the third DTaP dose, although the levels present between Tdap primary series doses are unknown. Although encouraging, it should be noted that these protective benchmark levels were established based on vaccinated subjects in whom active immunity is induced, not infants in whom immunity was transferred passively.
Despite having maternal and cord blood samples collected from only 5 mother–infant pairs in the Tdap group, we found mothers who received Tdap vaccine during pregnancy and their infants had higher concentrations of pertussis antibodies compared with controls. Maternal Tdap vaccination had no material or consistent effect on infant responses to antigens not included in Tdap. The lower pertussis antibody levels in the Tdap group after the primary vaccination series are unlikely to be clinically relevant, and these differences largely disappeared before and after the booster doses in this small sample.
The “cocooning” strategy is difficult to implement, and vaccination rates among infant caregivers are insufficient to be effective.17–19 The strategy of vaccinating mothers postpartum may not be effective because antibody response to Tdap in healthy, nonpregnant women occurs by day 14, which may not be sufficiently rapid to protect infants during their first weeks of life.20 Moreover, such a strategy misses the opportunity for protection of the infant through transplacental antibody transfer. It may be that the best way to ensure that infants are adequately protected during their most vulnerable period for pertussis would be through maternal vaccination during pregnancy.
Maternal vaccination during pregnancy provided higher antibody titers against pertussis antigens in infants during the period between birth and their first DTaP dose, the time of greatest susceptibility to morbidity from pertussis. The presence of these antibodies can potentially provide pertussis protection before DTaP can be given to the infant. Exact correlations between antibody concentrations and protection are not known, but the increased antibody concentrations seen in the Tdap group would be expected to confer greater protection from pertussis. This concept is consistent with Heininger et al21 who found that maternally derived antibodies may provide protection from pertussis among young infants. They documented that median anti-PT, anti-FHA and anti-PRN IgG antibody values in the cord blood of 20 infants with confirmed Bordetella pertussis infection <6 months of age were lower than their 80 birth date–matched controls, although these differences were not statistically significant.
The finding of higher pertussis antibody concentrations in both maternal and cord blood after pertussis immunization of pregnant women is similar to previous studies investigating passive immunity to pertussis of infants.22–25 Our observation that maternal vaccination with Tdap interfered only minimally with the infant’s response to routine DTaP immunization is novel and extends the findings of Englund et al,5 who documented that the PT antibody response to diphtheria, tetanus, and whole cell pertussis, unlike DTP, was not adversely affected by preexisting maternally derived antibody to PT among women not vaccinated during pregnancy. Although inhibitory effects with respect to FHA, PRN and FIM were seen with both diphtheria, tetanus, and whole cell pertussis, and DTaP in that study, they were relatively modest.
Our study had several important limitations. Sample size was dependent on access to a small group of already vaccinated pregnant women, many of whom did not have cord blood collected at delivery due to delayed institutional review board approval (pending resolution of the institutional review board’s ethical concerns about the collection of cord blood). The study may also not be representative of other geographical areas, particularly with respect to ethnicity, race and age. Not all participants provided complete sets of specimens, with a moderate loss to follow-up within our sample due to travel distance from this rural study site. Thus, confidence intervals for maternal antibody concentrations were large in the Tdap group, especially for PT and PRN. Control group infants received different formulations of DTaP vaccine, containing different antigen concentrations. Additionally, the Tdap and control groups were not followed over the same time period. New Hampshire reported 226 cases of pertussis in 2006, compared with 49 cases in 2008 and 76 cases in 2009. The differences in the prevalence of pertussis in the community during these time periods may have introduced bias to the results. Even so, our findings suggest that Tdap vaccination during pregnancy enhances infant antibody concentrations against pertussis in the first months of life. Because the first 2 months of life, the time between birth and the first dose of DTaP vaccine, are the period of highest risk for pertussis morbidity or death, improving protection during this period likely would outweigh any potential increase in pertussis infection during the period between the first dose of DTaP vaccine and the booster, when there is lower morbidity and mortality.
Our study supports the recent recommendation for Tdap vaccination of all women during each pregnancy.9,10 A larger controlled trial of prenatally vaccinated women is needed to confirm these findings. Maternal vaccination to provide passive immunity has been used with great success to reduce rates of other diseases.26–28 The use of maternal Tdap vaccination in pregnancy may increase protection of infants <6 months of age and decrease pertussis morbidity and mortality in this vulnerable population.
ACKNOWLEDGMENTS
We thank Dr. Robert Lersch for his editorial expertise and advice; Dr. Amitabha Bhaumik for his statistical assistance; Kathryn E. Fay for her assistance with data collection; Jenna Katz for her editorial assistance; the newborn and obstetric nurses, the pediatric residents and the general pediatric attendings at Dartmouth-Hitchcock Medical Center for their support; and the families who participated in the project.
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