Secondary Logo

Share this article on:

Third-Trimester Maternal Vaccination Against Pertussis and Pertussis Antibody Concentrations

Abraham, Cynthia, MD; Pichichero, Michael, MD; Eisenberg, Jesse, MD; Singh, Sonali, MBBS

doi: 10.1097/AOG.0000000000002438
Contents: Original Research

OBJECTIVE: To compare pertussis antibody concentrations in maternal venous serum (at the time of delivery) and umbilical cord arterial serum among women vaccinated with the tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccine from either 27–30 6/7 weeks of gestation or from 31–35 6/7 weeks of gestation.

METHODS: We conducted a prospective cohort study of pregnant women divided into two groups based on when Tdap was administered: 27–30 6/7 weeks of gestation and 31–35 6/7 weeks of gestation. Paired maternal and umbilical cord samples were obtained at the time of delivery to determine immunoglobulin G (IgG) concentrations to pertussis toxin and pertactin.

RESULTS: Eighty-eight pregnant women were enrolled. Cord serum pertussis toxin IgG concentrations were approximately twice maternal serum pertussis toxin IgG concentrations (91.6 vs 48.6 enzyme-linked immunoassay [ELISA] units/mL, P<.01) and 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. Furthermore, there was no correlation between time from vaccination to delivery and these three parameters. Cord serum pertussis toxin IgG concentrations were greater than 10 ELISA units/mL (ie, in the protective range) in 87% and 97% of those vaccinated from 27–30 6/7 weeks of gestation and from 31–35 6/7 weeks of gestation, respectively (P=.13).

CONCLUSION: Maternal vaccination against pertussis between 27 and 36 weeks of gestation was associated with a high percentage of newborns with antibody concentrations conferring protection and did not vary by gestational age at vaccination.

Maternal vaccination against pertussis in the third trimester is associated with a high percentage of newborns with protective pertussis antibody concentrations.

Hofstra University—Northwell Health System—Staten Island University Hospital, Staten Island, and Rochester General Hospital, Research Institute, Center for Infectious Diseases and Immunology, Rochester, New York.

Corresponding author: Cynthia Abraham, MD, 1176 Fifth Avenue, 9th Floor, New York, NY 10029; email: cynthia.abraham08@gmail.com.

Financial Disclosure The authors did not report any potential conflicts of interest.

The authors thank Meagan Sills, Administrative Director of Research at Hofstra University—Northwell Health System—Staten Island University Hospital, for her assistance in acquisition of funding, study approval, and processing of samples.

Each author has indicated that he or she has met the journal's requirements for authorship.

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.

Back to Top | Article Outline

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.

Back to Top | Article Outline

RESULTS

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.

Table 1

Table 1

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).

Table 2

Table 2

Fig. 1

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.

Table 3

Table 3

Back to Top | Article Outline

DISCUSSION

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.

Back to Top | Article Outline

REFERENCES

1. Tan TQ, Gerbie MV. Pertussis, a disease whose time has come: what can be done to control the problem? Obstet Gynecol 2013;122:370–3.
2. Van Rie A, Wendelboe AM, Englund JA. Role of maternal pertussis antibodies in infants. Pediatr Infect Dis J 2005;24(suppl):S62–5.
3. Mattoo S, Cherry JD. Molecular pathogenesis, epidemiology, and clinical manifestations of respiratory infections due to Bordetella pertussis and other Bordetella subspecies. Clin Microbiol Rev 2005;18:326–82.
4. Pickering LK, Baker CJ, Freed GL, Gail SA, Grogg SE, Poland GA, et al. Immunization programs for infants, children, adolescents, and adults: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis 2009;49:817–40.
5. Centers for Disease Control and Prevention. Pertussis (whooping cough): surveillance and reporting. Available at: https://www.cdc.gov/pertussis/surv-reporting.html. Retrieved October 29, 2017.
6. Centers for Disease Control and Prevention (CDC). Pertussis—United States, 2001–2003. MMWR Morb Mortal Wkly Rep 2005;54:1283–6.
7. Gonik B, Puder KS, Gonik N, Kruger M. Seroprevalence of Bordetella pertussis antibodies in mothers and their newborn infants. Infect Dis Obstet Gynecol 2005;13:59–61.
8. Campbell P, McIntyre P, Quinn H, Hueston L, Gilbert GL, McVernon J. Increased population prevalence of low pertussis toxin antibody levels in young children preceding a record pertussis epidemic in Australia. PLoS One 2012;7:e35874.
9. Li X, Chen M, Zhang T, Li J, Zeng Y, Lu L. Seroepidemiology of diphtheria and pertussis in Beijing, China: a cross-sectional study. Hum Vaccin Immunother 2015;11:2434–9.
10. Centers for Disease Control and Prevention. Advisory Committee on Immunization Practices (ACIP) recommended immunization schedule for persons aged 0 through 18 years—United States, 2013. Atlanta (GA): CDC; 2013.
11. Healy CM, Munoz FM, Rench MA, Halasa NB, Edwards KM, Baker CJ. Prevalence of pertussis antibodies in maternal delivery, cord, and infant serum. J Infect Dis 2004;190:335–40.
12. Healy CM, Rench MA, Baker CJ. Importance of timing of maternal combined tetanus, diphtheria, and acellular pertussis (Tdap) immunization and protection of young infants. Clin Infect Dis 2013;56:539–44.
13. Centers for Disease Control and Prevention (CDC). Updated recommendations for use of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine (Tdap) in pregnant women—Advisory Committee on Immunization Practices (ACIP), 2012. MMWR Morb Mortal Wkly Rep 2013;62:131–5.
14. Abu Raya B, Srugo I, Kessel A, Peterman M, Bader D, Gonen R, et al. The effect of timing of maternal tetanus, diphtheria, and acellular pertussis (Tdap) immunization during pregnancy on newborn pertussis antibody levels—a prospective study. Vaccine 2014;32:5787–93.
15. Naidu MA, Muljadi R, Davies-Tuck ML, Wallace EM, Giles ML. The optimal gestation for pertussis vaccination during pregnancy: a prospective cohort study. Am J Obstet Gynecol 2016;215:237.e1–6.
16. Gall SA, Myers J, Pichichero M. Maternal immunization with tetanus-diphtheria-pertussis vaccine: effect on maternal and neonatal serum antibody levels. Am J Obstet Gynecol 2011;204:334.e1–5.
17. Storsaeter J, Hallander HO, Gustafsson L, Olin P. Levels of anti-pertussis antibodies related to protection after household exposure to Bordetella pertussis. Vaccine 1998;16:1907–16.
18. Shakib JH, Ralston S, Raissy HH, Stoddard GJ, Edwards KM, Byington CL. Pertussis antibodies in postpartum women and their newborns. J Perinatol 2010;30:93–7.
19. Cherry JD, Gornbein J, Heininger U, Stehr K. A search for serologic correlates of immunity to Bordetella pertussis cough illnesses. Vaccine 1998;16:1901–6.
20. Hardy-Fairbanks AJ, Pan SJ, Decker MD, Johnson DR, Greenberg DP, Kirkland KB, et al. Immune responses in infants whose mothers received Tdap vaccine during pregnancy. Pediatr Infect Dis J 2013;32:1257–60.
21. Heininger U, Riffelmann M, Leineweber B, Wirsing von Koenig CH. Maternally derived antibodies against Bordetella pertussis antigens pertussis toxin and filamentous hemagglutinin in preterm and full term newborns. Pediatr Infect Dis J 2009;28:443–5.
22. Taranger J, Trollfors B, Lagergård T, Sundh V, Bryla DA, Schneerson R, et al. Correlation between pertussis toxin IgG antibodies in postvaccination sera and subsequent protection against pertussis. J Infect Dis 2000;181:1010–3.
23. Centers for Disease Control and Prevention. Pregnant women and Tdap vaccination, internet panel survey, United States, April 2016. Available at: https://www.cdc.gov/vaccines/imz-managers/coverage/adultvaxview/tdap-report-2016.html. Retrieved October 29, 2017.
24. Paddock CD, Sanden GN, Cherry JD, Gal AA, Langston C, Tatti KM, et al. Pathology and pathogenesis of fatal Bordetella pertussis infection in infants. Clin Infect Dis 2008;47:328–38.
25. Inatsuka CS, Qian X, Vujkovic-Cvijin I, Wong S, Stibitz S, Miller JF, et al. Pertactin is required for Bordetella species to resist neutrophil-mediated clearance. Infect Immun 2010;78:2901–9.
26. Trollfors B, Taranger J, Lagergård T, Lind L, Sundh V, Zackrisson G, et al. A placebo-controlled trial of a pertussis-toxoid vaccine. N Engl J Med 1995;333:1045–50.
27. Maertens K, Caboré RN, Huygen K, Hens N, Van Damme P, Leuridan E. Pertussis vaccination during pregnancy in Belgium: results of a prospective controlled cohort study. Vaccine 2016;34:142–50.
28. Villarreal Pérez JZ, Ramírez Aranda JM, de la O Cavazos M, Zamudio Osuna MJ, Perales Dávila J, Ballesteros Elizondo MR, et al. Randomized clinical trial of the safety and immunogenicity of the Tdap vaccine in pregnant Mexican women. Hum Vaccin Immunother 2017;13:128–35.
© 2018 by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.