Pertussis has made a resurgence in the past several decades1 and causes the greatest harm in infants younger than 3 months.2 Associated complications include pneumonia, apnea, and encephalopathy.3 Infants begin the pertussis vaccine series at 2 months of age, leaving a window of vulnerability to infection. Protective immunity occurs after series completion at 6 months of age.4
In 2002, approximately 2,000 cases of infant pertussis were reported, rising to 5,000 in 2012.5,6 Moreover, reports indicate that 30–90% of reproductive-aged women have low or undetectable pertussis antibodies despite childhood immunization.7–9 The Centers for Disease Control and Prevention (CDC) thus recommends tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccine administration in each pregnancy regardless of vaccination history.10
One study reported umbilical cord pertussis antibody concentrations were 1.5 times greater than maternal pertussis antibody concentrations, highlighting the efficiency of placental transfer after maternal immunization.11 However, maternal immunity wanes after vaccination early in pregnancy.12 Accordingly, the CDC recommends vaccination between 27 and 36 weeks of gestation to maximize maternal antibody response and newborn passive antibody concentrations.
The Tdap vaccines administered in pregnancy are Adacel and Boostrix. No adverse pregnancy effects with administration of these vaccines have been reported.13
This study's objective was to compare pertussis antibody concentrations in maternal venous serum (at the time of delivery) and umbilical cord arterial serum among women vaccinated with the Tdap vaccine from either 27–30 6/7 weeks of gestation or from 31–35 6/7 weeks of gestation.
MATERIALS AND METHODS
This was an institutional review board-approved prospective cohort study performed at Hofstra University—Northwell Health System–Staten Island University Hospital. Participants were recruited from July 2015 to February 2017. Informed consent was obtained before enrollment. Patients were enrolled at the time of admission to the hospital before delivery. Inclusion criteria were pregnant women between the ages of 18 and 45 years who were managed by hospitalists and who, based on a review of their prenatal records, received the Adacel Tdap vaccine between 27 and 36 weeks of gestation. Exclusion criteria were serious underlying disease (including immunosuppression), a history of febrile illness 72 hours or less before vaccine administration, a severe reaction to any vaccine, an expected delivery before 37 weeks of gestation, multiple gestation, or antenatal detection of a major birth defect. Adacel, the only Tdap vaccine administered in this institution, contains 5 flocculation units tetanus toxoid, 2 flocculation units diphtheria toxoid, 2.5 micrograms detoxified pertussis toxin, 5 micrograms filamentous hemagglutinin, 3 micrograms pertactin, and 5 micrograms fimbriae types 2 and 3, a composition designed to trigger immune responses against tetanus, diphtheria, and pertussis. Of these antigens, the ones associated with Bordetella pertussis are pertussis toxin, hemagglutinin, and pertactin. Each dose of Adacel contained 1.5 mg aluminum phosphate (0.33 mg aluminum) as the adjuvant. Adacel was offered to all patients between 27 and 36 weeks of gestation in accordance with institutional practice. The exact timing of Adacel administration within this gestational age was based on health care provider preference.
Participants were divided into two groups based on when Adacel was administered: 27–30 6/7 weeks of gestation and 31–35 6/7 weeks of gestation. The rationale for this division was to indirectly compare maternal and newborn pertussis antibody concentrations between Adacel and Boostrix. Two studies have been published investigating maternal and fetal pertussis antibody concentrations to Boostrix administered between 27 and 36 weeks of gestation.14,15 These studies also divided participants into two groups based on gestational age at the time of vaccine administration.
A sample size calculation was performed based on mean newborn antibody concentrations in response to the Tdap vaccine as reported by Gall et al.16 Based on the findings from that study, we estimated that 20 patients per group and 56 patients per group would be required to be able to demonstrate at least a 10% difference in pertussis toxin immunoglobulin G (IgG) concentrations and pertactin IgG concentrations, respectively, with a power of 0.8 and an α of 0.02. However, in that study, the actual timing of Tdap administration was not known although all patients were encouraged to receive Tdap during the second trimester, which differs from current CDC recommendations.
Blood samples for pertussis antibodies were obtained from each mother within 24 hours of delivery and from the umbilical cord artery at the time of delivery. These samples were then centrifuged to collect serum and frozen at −80°C until analyzed. The volume of each sample of serum was approximately 500 mL.
Enzyme-linked immunosorbent assays (ELISAs) were performed for antibodies to pertussis toxin and pertactin according to Good Laboratory Practices. Assays were performed in the manner reported in the study by Gall et al16 (assays for that study and this study were performed in the same laboratory). Briefly, microtiter plates were coated with diluted pertussis antigens. Serial dilutions of the study samples, controls, and reference sera were incubated and goat antihuman IgG were added. Absorbance was measured at 450 nm. The absorbance readings of the study samples were measured and quantitated against those of the reference sera. The reference sera had known quantitative antibody concentrations. Pertussis toxin IgG results are reported as ELISA units/mL. The reference sera for pertussis toxin IgG measurement that was used for calibration was from the U.S. Food and Drug Administration’s Center for Biologics Evaluation and Research. Pertactin IgG results are reported as international units/mL. The reference sera for pertactin IgG measurement that was used for calibration was from the National Institute for Biological Standards and Control/World Health Organization. The lower threshold of reporting results for each assay for antibodies was 5 ELISA units/mL for pertussis toxin and 5 international units/mL for pertactin. Based on findings from a small number of studies published regarding protective pertussis antibody concentrations, values of 10 ELISA units/mL and 10 international units/mL were used as our thresholds for predicting newborn immunity to pertussis.17–19 The following data were obtained from medical records: age, ethnicity, obstetric history, past Tdap vaccination history, and gestational age at the time of vaccination and at the time of delivery.
In general, continuous variables are presented as means along with SDs or CIs as appropriate. Categorical variables are presented as numbers with corresponding percentages and CIs (as applicable). Analysis of variance, χ2, and Fisher exact test were used to assess for differences. All continuous variables were assessed for normality. Immunoglobulin G concentrations were skewed and subsequently underwent natural log transformation. Pearson correlation coefficient was used to assess the relationship between maternal and cord serum pertussis toxin IgG concentrations and between time from vaccination to delivery and pertussis antibody concentrations. The relationship between IgG concentrations and time from vaccination to delivery was evaluated as a nonlinear one and has been presented as a set of correlation plots. Antibody concentrations less than the threshold of detection were assigned the lower threshold of reporting value. All analyses were performed with SPSS 24.0.
A total of 88 women met inclusion criteria: 52 received the vaccine from 27–30 6/7 weeks of gestation and 36 from 31–35 6/7 weeks of gestation. Demographic and clinical characteristics were similar between groups with the exception of gestational age at the time of Tdap administration and time from Tdap administration to delivery (Table 1). The times from vaccination to delivery were normally distributed.
Cord serum pertussis toxin IgG concentrations were approximately twice as high as maternal serum pertussis toxin IgG concentrations (91.6 vs 48.6 ELISA units/mL, P<.01). Maternal and cord serum pertussis toxin IgG concentrations were significantly correlated (Pearson correlation coefficient=0.85, P<.01).
There was no significant difference in maternal serum pertussis toxin IgG concentrations (48.6 vs 48.6 ELISA units/mL, P=.99), cord serum pertussis toxin IgG concentrations (92.1 vs 90.7 ELISA units/mL, P=.95), and cord serum pertactin IgG concentrations (798 vs 730 international units/mL, P=.73) between the two groups. Lack of a significant difference in antibody concentrations between the groups persisted after natural logarithmic transformation of concentrations was performed (Table 2). Furthermore, there was no correlation between time from vaccination to delivery and maternal serum pertussis toxin IgG, cord serum pertussis toxin IgG, and cord serum pertactin IgG concentrations (Fig. 1).
Overall, 91% (80/88) and 99% (87/88) of newborns had cord serum pertussis toxin IgG concentrations and pertactin IgG concentrations that were greater than 10 ELISA units/mL and 10 international units/mL, respectively (Table 3). The percentage of newborns in each group with cord serum pertussis toxin and pertactin IgG concentrations above this threshold was not significantly different between groups. In those who received the vaccine from 27–30 6/7 weeks of gestation and who had IgG concentrations below the cutoff, mean cord serum pertussis toxin and pertactin IgG concentrations were 8.9 ELISA units/mL and 5 international units/mL, respectively. In the one patient who received the vaccine from 31–35 6/7 weeks of gestation and who had an IgG level below 10 ELISA units/mL, the cord serum pertussis toxin IgG level was 5 ELISA units/mL.
This study demonstrated that Tdap vaccination, using Adacel, between 27 and 36 weeks of gestation is associated with a high percentage of newborns with protective pertussis antibody concentrations. In addition, there is no difference in antibody concentrations across this gestational age range, supporting CDC recommendations. These findings highlight the importance of maternal immunization against pertussis. Maternal and umbilical cord serum pertussis antibody concentrations were also highly correlated. Pertussis toxin IgG concentrations were twice as high in umbilical cord artery serum as in maternal serum, similar to results from other studies.20,21
Elevated pertussis antibody concentrations 1–2 months after vaccine administration are associated with protection against pertussis for 2 years after Tdap receipt.17,22 Moreover, Taranger et al22 reported in infants vaccinated against pertussis, those who developed severe pertussis, mild pertussis, or who did not develop pertussis had mean pertussis toxin IgG concentrations of 79, 156, and 246 units/mL, respectively. However, it is not possible to compare our pertussis toxin IgG concentrations with those published by Taranger et al because at the time that study was performed, no antipertussis toxin standard was available from the World Health Organization or the U.S. Food and Drug Administration. Nonetheless, pertussis toxin IgG concentrations appear to be associated with disease severity.
As stated before, we found no significant difference across the period of 27–36 weeks of gestation with respect to immunogenicity with Adacel use. These findings differ from studies of vaccination against pertussis with Boostrix during the approximate gestational age range used in our study.14,15 Abu Raya et al14 studied 51 women vaccinated with Boostrix between 27 and 36 weeks of gestation. They found that the 21 women vaccinated between 27 and 30 6/7 weeks of gestation had significantly higher cord serum pertussis toxin IgG and filamentous hemagglutinin IgG concentrations than those vaccinated between 31 and 36 weeks of gestation. Naidu et al15 studied 82 women vaccinated with Boostrix between 28 and 36 weeks of gestation. They found that the 38 women vaccinated between 28 and 32 weeks of gestation had significantly higher cord serum pertussis toxin IgG, filamentous hemagglutinin IgG, and pertactin IgG concentrations than those vaccinated between 32 and 36 weeks of gestation.
Boostrix differs from Adacel in antigen composition. Boostrix contains 8 micrograms pertussis toxin, 8 micrograms filamentous hemagglutinin, and 2.5 micrograms pertactin per dose. Adacel contains 2.5 micrograms pertussis toxin, 5 micrograms filamentous hemagglutinin, and 3 micrograms pertactin per dose. Additionally, the vaccines differ in method of pertussis toxin detoxification. Boostrix is detoxified with formaldehyde and glutaraldehyde. Adacel is detoxified only with formaldehyde. Double detoxification may cause differences in immunogenicity as antigenic epitopes are further modified, perhaps providing an explanation for the difference in results between the vaccines.
There are limitations to this study. The observational cohort design included only those who received Adacel as opposed to a prospective, randomized controlled trial including a cohort receiving Boostrix to allow direct comparisons between Tdap vaccines. We did not measure baseline maternal antibody concentrations and therefore cannot assess actual response to the Adacel vaccine. Another involves the sample size, which was constrained as a result of participant enrollment limited to those managed by hospitalists and a low institutional Tdap administration rate in pregnancy, on par with the national rate, which was 48% in 2016.23 Using the Gall et al study16 to estimate sample size was not ideal given the inability to determine exact timing of Tdap administration in that study, potentially biasing results. Our statistical power to detect a small difference in pertactin IgG concentrations was limited. Nonetheless, we had sufficient power to assess for meaningful differences in pertussis toxin IgG concentrations between groups.
Furthermore, pertussis toxin has been found be the most virulent and specific of the antigens associated with Bordetella pertussis.24 Pertactin has been associated with other Bordetella species and filamentous hemagglutinin with Haemophilus influenzae.25,26 Therefore, we did not aggressively pursue measurement of maternal pertactin IgG concentrations.
Future directions are manyfold. Measurement of pertussis antibody concentrations in infants of vaccinated mothers months after birth should be considered along with comparison of these concentrations in relation to maternal Adacel compared with Boostrix administration. In studies on pertussis antibody concentrations in infants after birth, antibody concentrations at age 2 months were significantly higher in those infants whose mothers received either Adacel or Boostrix during pregnancy than in those born to unvaccinated mothers. Adacel and Boostrix administration in pregnancy appears to close the susceptibility gap in infants.27,28
Additionally, there is a lack of consensus on the antibody concentration to be used as a marker of protective passive immunity in the newborn. Studies have suggested concentrations of either 5 or 10 ELISA units/mL or international units/mL.17–19 Moreover, cost-effectiveness studies comparing Tdap vaccines need to be performed.
In conclusion, maternal vaccination against pertussis between 27 and 36 weeks of gestation was associated with a high percentage of newborns with protective pertussis antibody concentrations. Antibody concentrations did not vary by gestational age at the time of maternal vaccination.
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