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Preliminary Communication |

Safety and Immunogenicity of Tetanus Diphtheria and Acellular Pertussis (Tdap) Immunization During Pregnancy in Mothers and Infants:  A Randomized Clinical Trial FREE

Flor M. Munoz, MD1,2; Nanette H. Bond, PAC2; Maurizio Maccato, MD1,3; Phillip Pinell, MD1,3; Hunter A. Hammill, MD4; Geeta K. Swamy, MD5; Emmanuel B. Walter, MD6; Lisa A. Jackson, MD7; Janet A. Englund, MD8; Morven S. Edwards, MD1; C. Mary Healy, MD1; Carey R. Petrie, PhD9; Jennifer Ferreira, ScM9; Johannes B. Goll, MS9; Carol J. Baker, MD1,2
[+] Author Affiliations
1Department of Pediatrics, Baylor College of Medicine, Houston, Texas
2Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas
3Woman’s OB/GYN Specialists, Houston, Texas
4Private obstetric practice, Houston, Texas
5Department of Obstetrics and Gynecology, Duke University School of Medicine, Durham, North Carolina
6Department of Pediatrics, Duke University School of Medicine, Durham, North Carolina
7Group Health Research Institute, Seattle, Washington
8Seattle Children’s Research Institute, Department of Pediatrics, University of Washington, Seattle
9EMMES Corporation, Rockville, Maryland
JAMA. 2014;311(17):1760-1769. doi:10.1001/jama.2014.3633.
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Published online

Importance  Maternal immunization with tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccine could prevent infant pertussis.

Objective  To evaluate the safety and immunogenicity of Tdap immunization during pregnancy and its effect on infant responses to diphtheria and tetanus toxoids and acellular pertussis (DTaP) vaccine.

Design, Setting, and Participants  Phase 1-2, randomized, double-blind, placebo-controlled, clinical trial conducted from 2008 to 2012. Forty-eight pregnant women aged 18 to 45 years received Tdap (n = 33) or placebo (n = 15) at 30 to 32 weeks’ gestation, with crossover immunization postpartum.

Interventions  Tdap vaccination at 30 to 32 weeks’ gestation or postpartum.

Main Outcomes and Measures  Primary outcomes were maternal and infant adverse events, pertussis illness, and infant growth and development until age 13 months. Secondary outcomes were antibody concentrations in pregnant women before and 4 weeks after Tdap immunization or placebo, at delivery and 2 months’ postpartum, and in infants at birth, at 2 months, and after the third and fourth doses of DTaP.

Results  No Tdap-associated serious adverse events occurred in women or infants. Injection site reactions after Tdap immunization were reported in 26 (78.8% [95% CI, 61.1%-91.0%]) and 12 (80% [95% CI, 51.9%-95.7%]) pregnant and postpartum women, respectively (P > .99). Systemic symptoms were reported in 12 (36.4% [ 95% CI, 20.4%-54.9%]) and 11 (73.3% [95% CI, 44.9%-92.2%]) pregnant and postpartum women, respectively (P = .03). Growth and development were similar in both infant groups. No cases of pertussis occurred. Significantly higher concentrations of pertussis antibodies were measured at delivery in women who received Tdap during pregnancy vs postpartum (eg, pertussis toxin antibodies: 51.0 EU/mL [95% CI, 37.1-70.1] and 9.1 EU/mL [95% CI, 4.6-17.8], respectively; P < .001) and in their infants at birth (68.8 EU/mL [95% CI, 52.1-90.8] and 14.0 EU/mL [95% CI, 7.3-26.9], respectively; P < .001) and at age 2 months (20.6 EU/mL [95% CI, 14.4-29.6] and 5.3 EU/mL [95% CI, 3.0-9.4], respectively; P < .001). Antibody responses in infants born to women receiving Tdap during pregnancy were not different following the fourth dose of DTaP.

Conclusions and Relevance  This preliminary assessment did not find an increased risk of adverse events among women who received Tdap vaccine during pregnancy or their infants. For secondary outcomes, maternal immunization with Tdap resulted in high concentrations of pertussis antibodies in infants during the first 2 months of life and did not substantially alter infant responses to DTaP. Further research is needed to provide definitive evidence of the safety and efficacy of Tdap immunization during pregnancy.

Trial Registration  clinicaltrials.gov Identifier: NCT00707148

Figures in this Article

Pertussis is a highly contagious and potentially fatal vaccine-preventable disease that has reemerged in the United States despite high childhood immunization rates. Infants younger than 6 months are at greatest risk of disease, hospitalization, and death and account for more than 90% of all pertussis-associated deaths in the United States.1 Infants too young to receive the primary diphtheria and tetanus toxoids and acellular pertussis (DTaP) immunization series as recommended at 2, 4, and 6 months of age depend on passive maternal antibodies for protection against pertussis. However, pregnant women have very low concentrations of pertussis antibodies to transfer to their newborn at the time of delivery.24

To protect young infants, tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccine was first recommended by the Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control and Prevention in 2008 for postpartum women and close contacts of infants,57 then in 2011 for previously Tdap unimmunized pregnant women,8 and in 2012 for all pregnant women during every pregnancy, regardless of prior Tdap immunization history.9

In this phase 1-2 study initiated prior to the ACIP recommendation to immunize pregnant women with Tdap, we evaluated the safety and immunogenicity of Tdap vaccine administered to women in the third trimester of pregnancy and measured placental transfer of maternal pertussis antibodies to the neonate, their persistence during the first 2 months of life, and their potential effect on infant immune responses to DTaP immunizations.

Study Design

This was a phase 1-2, randomized, double-blind, placebo-controlled clinical trial conducted in 3 National Institutes of Health Vaccine Treatment Evaluation Unit sites in the United States (Houston, Durham, Seattle) from October 2008 to May 2012. Healthy pregnant women aged 18 to 45 years and at low risk for obstetrical complications were recruited from academic and private obstetric office practices. Women with no underlying chronic medical conditions, a singleton pregnancy, and prenatal evaluation that predicted an uncomplicated pregnancy with normal first or second trimester screening test results and detailed anatomic fetal ultrasound at 18 to 22 weeks’ gestation were invited to participate. Women who had previously received Tdap or any tetanus-containing vaccine within the prior 2 years were excluded (complete inclusion/exclusion criteria are reported in the eAppendix in Supplement). Race and ethnicity as defined by the participant were reported as required by the sponsor. After written informed consent was obtained, eligible pregnant women were randomized 2:1 to receive Tdap vaccine or a saline placebo injection at 30 through 32 weeks’ gestation. Women who received saline during pregnancy were given Tdap vaccine postpartum prior to hospital discharge, and women who received Tdap during pregnancy were given saline postpartum (crossover vaccine administration to ensure blinding of investigators and participants).

Randomization was stratified by site with random block sizes. Each participant was assigned a unique treatment number that corresponded to her treatment allocation. Only the unblinded vaccine administrator had access to the treatment allocation. An age-matched comparison group of healthy nonpregnant women also received Tdap (open label). These nonpregnant women volunteers recruited from the community at each study site provided written informed consent prior to enrollment. Study visits for pregnant women occurred at the day of antepartum vaccination, 4 weeks after vaccination, at delivery, and at 2 and 4 months postpartum; for nonpregnant women, at enrollment, 4 weeks, and 6 months after Tdap immunization; and for infants, at birth and at ages 2 months, 7 months, and 13 months. The study protocol was approved by the institutional review board and ethics committee at each study site.

Study Vaccines

Licensed Tdap vaccine (Adacel, Sanofi Pasteur) was administered as a 0.5-mL intramuscular injection containing 5 Lf tetanus toxoid, 2 Lf diphtheria toxoid, 2.5 µg detoxified pertussis toxin, 5 µg filamentous hemagglutinin, 3 µg pertactin, and 5 µg fimbriae types 2 and 3 in a sterile liquid suspension adsorbed onto aluminum phosphate in single-dose vials. The saline control (Hospira Inc) contained 2 mL of 0.9% sodium chloride for injection. Each vial was used for a single intramuscular dose of 0.5 mL. Infants received DTaP vaccine (Pentacel, Sanofi Pasteur) containing the same antigens as in Adacel (but in different quantities), plus inactivated poliovirus and Haemophilus influenzae type b conjugate (tetanus toxoid conjugate), administered by their pediatricians at 2, 4, 6, and 12 months of age.

Safety Assessments

Safety assessments were the primary outcomes. Injection site and systemic reactions were assessed in all women by 30-minute observation and completion of a 7-day symptom diary after each injection. Adverse events and serious adverse events were recorded at each study visit for pregnant women from the day of antepartum vaccination to 4 months postpartum, for nonpregnant women for 6 months after Tdap immunization, and for infants from birth to approximately 13 months of age. Whether an adverse event was attributable to vaccination was judged by the investigators considering temporality, biologic plausibility, and identification of alternative etiologies for each event. The outcomes of pregnancy were documented for mothers and infants at the time of delivery through review of delivery records. Infant growth (weight, length, and fronto-occipital circumference) was assessed at each study visit at ages 2, 7, and 13 months, and development was assessed with the Bayley-III Scales of Infant and Toddler Development Third Edition Screening Test (PsychCorp) at the last study visit. Pertussis illness was evaluated in mothers and infants by documenting at each study visit any reported cough lasting more than 2 weeks.

Immunogenicity Assessments

Immunogenicity assessments were secondary outcomes. Blood samples were obtained from pregnant women prior to and 4 weeks after Tdap or placebo antepartum immunization, at delivery, and 2 months after the postpartum Tdap or placebo immunization; in infants at birth (cord blood), approximately age 2 months (prior to the first dose of DTaP), 7 months (4 weeks after the third dose of DTaP), and 13 months (4 weeks after the fourth dose of DTaP). Nonpregnant women had samples collected prior to and 4 weeks after Tdap immunization.

Antibody Assays

Serum antibody assays were performed by Sanofi Pasteur, Swiftwater, Pennsylvania, in a blinded manner. Pertussis IgG enzyme-linked immunosorbent assays (ELISAs) were used to quantify the concentration of antibodies to pertussis toxin, filamentous hemagglutinin, pertactin, and fimbriae types 2 and 3, expressed in ELISA Units per milliliter (EU/mL).10 The lower limit of quantitation (LLOQ) was 3 EU/mL for filamentous hemagglutinin and 4 EU/mL for pertussis toxin, pertactin, and fimbriae types 2 and 3. Antitetanus toxoid antibodies were measured by IgG ELISA using the World Health Organization International Standard for Tetanus Immunoglobulin, Human, Lot TE3. The LLOQ of the assay was 0.01 International Units per milliliter (IU/mL). Antidiphtheria antibody responses were measured by the ability of the test sera to protect Vero cells from a diphtheria toxin challenge using World Health Organization reference serum. The lower limit of detection was 0.005 IU/mL.

Statistical Analysis

This phase 1-2 exploratory study was not powered to test any specific hypotheses. The primary outcome (safety) measures were the incidence of injection site and systemic reactions recorded 0 to 7 days after each injection, the frequency of vaccine-associated adverse events and serious adverse events, the incidence of pertussis illness captured by surveillance of reported cough lasting more than 2 weeks, infant growth measurements, and Bayley III developmental screening of infants. The secondary outcome (immunogenicity) measures were the concentration of IgG antibodies to the vaccine antigens (pertussis toxin, pertactin, filamentous hemagglutinin, fimbriae types 2 and 3, tetanus toxoid, and diphtheria toxoid).

Safety outcome measures were described using frequency, proportion, and 2-sided exact 95% CIs. All participants receiving at least 1 injection were included in the safety summaries. Pertussis antibody geometric mean concentration (GMC) and 95% CI were calculated for each time point and study group. Placental transfer of antibodies at delivery (ratio of cord blood GMC to maternal GMC) and antibody decay in infants (ratio of GMC at 2 months to cord blood GMC) were estimated. Spearman rank correlation was used to detect monotonically increasing or decreasing associations between concentrations and avoid influence of outlying observations. The GMC of pertussis antibodies after 3 doses of DTaP were correlated with cord blood levels in infants. Results less than the LLOQ were assigned one-half of the LLOQ for calculations of GMC and placental transmission. The proportion of participants with tetanus and diphtheria antibody concentrations of 0.1 IU/mL or greater and 1.0 IU/mL or greater and their 95% CIs were calculated.

The primary analysis of immunogenicity included participants who received 2 injections (1 vaccine and 1 saline placebo) and contributed both prevaccination and postvaccination blood samples for testing and for which valid results were reported. One mother and 4 infants were excluded from immunogenicity analyses because of errors in administration of immunizations to the infants (3 infants), a missing delivery blood sample (1 infant), and a mother receiving the postpartum injection more than 2 months late.

Frequencies were compared using a 2-sided Fisher exact test (2-way comparisons) and the Freeman-Halton extension (3-way comparisons). Two-sided t test was used to compare GMCs between groups. An individual α level of .05 was applied for assigning statistical significance. No imputation was carried out for missing data.

Analyses were performed using SAS version 9.3 (SAS Institute Inc) and R version 2.15.2 (2012-10-26) (R Project for Statistical Computing, http://www.r-project.org/).

Forty-eight healthy pregnant women and their infants and 32 healthy nonpregnant women were enrolled. Thirty-three pregnant women received Tdap vaccine and 15 received placebo during pregnancy (Figure). The mean interval from Tdap immunization to delivery was 52.1 days (SD, 10.5 [95% CI, 48.4-55.8]) and the median interval was 54 days (range, 32-68). Demographic and clinical characteristics of study participants are described in Table 1.

Place holder to copy figure label and caption
Figure.
Consort Flow Diagram

Tdap indicates tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis.aParticipants who did not meet more than 1 eligibility criterion are categorized by the first criterion met.bReceived pharmacy stock vaccine, not study vaccine; included in analysis.

Graphic Jump Location
Table Graphic Jump LocationTable 1.  Demographic and Clinical Characteristics of Study Participants
Safety

The proportion of participants reporting any injection site reactions following Tdap immunization was not different between the groups: 78.8% (95% CI, 61.1%-91.0%) pregnant women, 80.0% (95% CI, 51.9%-95.7%) postpartum women, and 78.1% (95% CI, 60.0%-90.7%) nonpregnant women (P > .99) (Table 2). Following placebo administration, fewer pregnant women (20.0% [95% CI, 4.3%-48.1%]) and postpartum women (18.2% [95% CI, 7.0%-35.5%]) reported injection site reactions. Pain at the injection site was the most common symptom following Tdap immunization, reported in 75.8% (95% CI, 57.7%-88.9%) pregnant women, 73.3% (95% CI, 44.9%-92.2%) postpartum women, and 78.1% (95% CI, 60.0%-90.7%) nonpregnant women (P ≥ .35); swelling and erythema were infrequent. Most symptoms were mild and resolved within 72 hours (eTable 1 in Supplement).

Table Graphic Jump LocationTable 2.  Proportion of Participants With Injection Site and Systemic Reactions After Tdap or Saline Placebo Administration, by Study Group

The proportion of participants with any systemic symptom was 36.4% (95% CI, 20.4%-54.9%) in women immunized during pregnancy, 73.3% (95% CI, 44.9%-92.2%) in women receiving Tdap postpartum, and 53.1% (95% CI, 34.7%-70.9%) in nonpregnant women (P = .055) (Table 2). The frequencies of headache, myalgia, and malaise were not significantly different among the 3 groups (P ≥ .35), headache being more common than myalgia and malaise. The occurrence of fever after receipt of Tdap was significantly different between the 3 groups, with pregnant women (3.0% [95% CI, 0.1%-15.8%]) and nonpregnant women (9.4% [95% CI, 2.0%-25.0%]) reporting it less frequently than postpartum women (26.7% [95% CI, 7.8%-55.1%]) (P = .04). However, the occurrence of fever in women receiving Tdap vaccine postpartum (26.7% [95% CI, 7.8%-55.1%]) was not different from that of postpartum placebo recipients (15.2% [95% CI, 5.1%-31.9%]) (P = .43). There was also no difference in the proportion of participants with fever between recipients of Tdap during pregnancy and nonpregnant women (P = .36). Most systemic symptoms were mild and self-limited (eTable 1 in Supplement).

Serious adverse events were reported by 22 participants, including 7 (21.2% [95% CI, 8.9%-38.9%]) women who received Tdap during pregnancy and 6 (18.1% [95% CI, 7.0%-35.5%]) of their infants; 2 (13.3% [95% CI, 1.7%-40.5%]) women given Tdap postpartum and 6 (40% [95% CI, 16.3%-67.7%]) of their infants; and 1 (3.1% [95% CI, <0.1%-16.2%]) nonpregnant woman (Table 3). None were judged to be attributable to Tdap vaccine. Nonserious adverse events occurred in 63.6% (95% CI, 45.1%-79.6%) of women given Tdap during pregnancy, 73.3% (95% CI, 45.0%-92.2%) of women given Tdap postpartum, and 28.1% (95% CI, 13.7%-46.7%) of nonpregnant women, as well as in 84.8% (95% CI, 68.1%-94.9%) of infants born to women vaccinated with Tdap antepartum and 93.3% (95% CI, 68.1%-99.8%) of infants born to women receiving Tdap postpartum. All resolved without sequelae.

Table Graphic Jump LocationTable 3.  Serious Adverse Events in Study Participants Receiving Tdap, by Study Group and Severity

All infants were live born, mostly at term and by vaginal delivery (Table 1). There were no significant differences in the infants’ gestational ages, birth weights, Apgar scores, neonatal examinations, or complications. There were no differences in the infants’ growth and development (eTable 2 and eTable 3 in Supplement), and no cases of pertussis illness occurred in mothers or infants.

Immunogenicity

At baseline, the antibody concentration to each of the vaccine antigens was low and comparable among the study groups. Antibody responses to Tdap vaccine in pregnant women were not different than those of nonpregnant women and women immunized postpartum (Table 4, eFigure 1 in Supplement). Women immunized with Tdap during pregnancy had significantly higher concentrations of antibodies to all vaccine antigens at delivery than women immunized postpartum (Table 4, eFigure 2 in Supplement). Infants born to mothers who received Tdap during pregnancy had significantly higher concentrations of pertussis antibodies at birth and at age 2 months (Table 4). The concentration of pertussis antibodies in cord blood was higher than in maternal serum at delivery, with linear correlation between maternal and infant concentrations (Table 5, eFigure 3 in Supplement). The ratio of the concentrations of antibodies to Tdap antigens remaining at 2 months in infants is shown in Table 5.

Table Graphic Jump LocationTable 4.  Geometric Mean Concentration of Antibodies to Tdap Vaccine Antigens in Sera From Mothers and Infants, and Nonpregnant Women, by Study Group and Time of Sample Collection
Table Graphic Jump LocationTable 5.  Transplacental Transfer of Antibodies (Ratio of Infant Cord Blood Antibodies to Maternal Antibodies) and Antibody Concentrations in Infants at 2 Months of Age Compared With Concentrations at Birth (Ratio of Infant 2-Month Antibodies to Cord Blood Antibodies)

At 7 months of age, after receipt of 3 doses of DTaP, infants of women who received Tdap during pregnancy achieved equivalent concentrations of antibodies to pertactin, pertussis toxin, and fimbriae types 2 and 3 and significantly lower concentrations of antibodies to filamentous hemagglutinin compared with infants whose mothers received placebo during pregnancy (40.6 EU/mL [95% CI, 30.6-54.0] vs 78.6 EU/mL [95% CI, 52.9-116.7], respectively; P < .01) (Table 4). However, at age 13 months, 1 month after the fourth dose of DTaP, the concentrations of pertussis antibodies were not statistically significantly different in the 2 infant groups (Table 4). Among infants born to women immunized with Tdap during pregnancy, no correlation was observed between cord antibody levels and antibody concentrations achieved after the third DTaP immunization. Among infants of women receiving Tdap postpartum, infants with higher filamentous hemagglutinin antibody levels at birth had lower concentrations at age 7 months (Spearman correlation, 0.55; P = .042) (Table 4). Tetanus and diphtheria antibody responses and protective levels achieved after the third and fourth DTaP doses were in general not statistically significantly different in the 2 infant groups (Table 4 and eTable 4 in Supplement).

In 2012, the United States experienced the most severe pertussis epidemic in more than half a century, with nearly 42 000 reported cases.12 The highest incidence of pertussis and its associated complications continue to occur among infants.12,13 The majority of pertussis-related deaths occur in infants too young to be immunized (ages <2 months) or those incompletely immunized (ages <6 months).1,12,13 In 2008, postpartum Tdap immunization of mothers and all contacts of infants (ages <12 months) was recommended to create a protective “cocoon” and prevent pertussis in this population.7 However, this strategy proved to be challenging to implement, and maternal postpartum immunization alone was not effective in reducing the burden of infant disease.14,15 Newborns are unlikely to have protective levels of pertussis antibodies at birth if their mothers have not received a recent dose of a pertussis-containing vaccine.24 Evidence of rapid decline of pertussis antibody levels in adults and postpartum women immunized with Tdap, the ongoing burden of infant disease, and the increasing severity of pertussis outbreaks in the United States led to the 2012 ACIP recommendation to immunize all pregnant women with Tdap during every pregnancy.9

We report for the first time, to our knowledge, in a randomized controlled trial, that Tdap immunization of pregnant women in the third trimester was well tolerated and elicited immune responses similar to those elicited with immunization of nonpregnant women. Among primary outcomes, injection site and systemic reactogenicity rates in pregnant women were not significantly different than those observed among postpartum or nonpregnant women, and no Tdap vaccine–related adverse events or adverse pregnancy outcomes were observed. The safety of Tdap immunization in pregnancy also has been documented through passive surveillance by a Centers for Disease Control and Prevention Vaccine Adverse Event Report System review and in a 6-year report of the Adacel vaccine pregnancy registry.16,17

Secondary outcome assessments showed that Tdap administration at 30 through 32 weeks’ gestation resulted in high pertussis antibody concentrations in maternal sera at delivery that persisted 2 months postpartum, potentially providing protection to the mother during pregnancy and in the postpartum period. Our findings suggest that third-trimester maternal immunization with Tdap results in efficient placental transfer of pertussis antibodies to the fetus and higher antibody concentrations in infants’ cord blood than in maternal serum at delivery.24,18

An important finding from our study was that concentrations of vaccine-induced pertussis antibodies in sera from infants born to mothers immunized with Tdap during pregnancy were significantly higher at birth and at age 2 months than in infants whose mothers were immunized postpartum. This suggests that infant protection could occur during the period of highest risk of pertussis-associated mortality and morbidity. Although serum concentrations of pertussis antibodies that correlate with protection remain uncertain, high concentrations of antibodies to pertussis toxin, filamentous hemagglutinin, pertactin, and fimbriae types 2 and 3 are known to be protective.19,20 Considering the accumulating evidence that the protective efficacy of Tdap immunization wanes rapidly, most women of childbearing age are likely to be similar to our study participants in their susceptibility to pertussis.11,21

Importantly, although infants born to mothers immunized with Tdap during pregnancy did manifest lower pertussis antibody concentrations to filamentous hemagglutinin following receipt of the third dose of DTaP vaccine, the reduction was modest (48.3%) and disappeared following receipt of the fourth dose of DTaP, suggesting that priming and memory immune responses remained unaltered. Although the presence of maternal antibodies could result in a decreased response to active immunization in infants,22 maternal pertussis antibodies have not been shown to interfere with immunization with acellular pertussis vaccines in young infants.4,23 A recent observational study of 16 Tdap-immunized pregnant women also found only modest reductions in infant pertussis antibody levels following the third dose of DTaP vaccine.24

Our study has several potential limitations. First, the small number of participants potentially limited the ability to detect the occurrence of rare vaccine-related adverse events, which may only be detected in large population-based studies. Similarly, the small sample size limited the statistical power to detect differences in antibody responses in infants, particularly after administration of the third dose of DTaP vaccine. However, infant immune responses to the fourth dose of DTaP were robust and consistent with a good anamnestic response. Although a larger study might reveal a lower overall response to the primary series of DTaP in infants of women immunized during pregnancy, the biological significance would be uncertain and must be weighed against the potentially lifesaving protection provided by significantly higher concentrations of pertussis antibodies in the first 2 months of life. Second, we did not measure antibody concentrations in infants after the first dose of DTaP, but given the high concentrations present at birth and at 2 months, we would anticipate that high concentrations persisted beyond the second month of life. Last, this study was not designed to evaluate the efficacy of maternal immunization with Tdap to protect mothers or infants against pertussis disease, but our clinical surveillance did not identify any clinical cases of pertussis in study participants. Large prospective studies are needed to determine the effectiveness of Tdap vaccination during pregnancy in preventing pertussis illness among young infants. Until definitive evidence is obtained, our findings support current ACIP recommendations to immunize pregnant women with Tdap during pregnancy to protect infants against pertussis.

This preliminary evaluation did not find an increased risk of adverse events (primary outcome) among women who received Tdap vaccine at 30 through 32 weeks’ gestation or their infants. Secondary outcomes assessments showed that maternal immunization with Tdap resulted in significantly higher concentrations of antibodies to all vaccine antigens in infants from birth until initiation of immunization with DTaP at age 2 months and did not substantially alter infant responses to DTaP. Further research is needed to provide definitive evidence of the safety and efficacy of Tdap immunization during pregnancy.

Corresponding Author: Flor M. Munoz, MD, Departments of Pediatrics and Molecular Virology and Microbiology, Baylor College of Medicine, One Baylor Plaza, Ste 221-D, BCM-280, Houston, TX 77030 (florm@bcm.edu).

Author Contributions: Drs Munoz and Baker had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Munoz, Ferreira, Baker.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Munoz, Bond, Jackson, Edwards, Ferreira, Baker.

Critical revision of the manuscript for important intellectual content: Munoz, Maccato, Pinell, Hammill, Swamy, Walter, Jackson, Englund, Healy, Petrie, Ferreira, Goll, Baker.

Statistical analysis: Munoz, Ferreira, Goll, Baker.

Obtained funding: Munoz, Walter, Englund.

Administrative, technical, or material support: Munoz, Bond, Maccato, Pinell, Hammill, Walter, Jackson, Englund, Edwards, Petrie, Baker.

Study supervision: Munoz, Walter, Jackson, Englund, Baker.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Munoz reported serving as a speaker for Sanofi Pasteur; serving as a consultant for Novartis, GlaxoSmithKline, and Novavax; and conducting clinical trials sponsored by Hoffmann-LaRoche, GlaxoSmithKline Biologicals, and Gilead Sciences. Dr Swamy reported receiving consulting and lecturing fees, grant support for vaccine-related studies, and payment for advisory board service, lectures, and development of educational presentations from GlaxoSmithKline; and receiving grant funding from GlaxoSmithKline specific to influenza vaccine and human papillomavirus infection. Dr Walter reported serving as a consultant and advisor for Merck; serving as a speaker for Sanofi Pasteur; and conducting clinical trials sponsored by GlaxoSmithKline, Merck, Novartis, and Pfizer. Dr Englund reported receiving research support from Novartis, Gilead, Chimerix, and Roche; serving as a consultant for GlaxoSmithKline in 2012-2013; serving on a GlaxoSmithKline data and safety monitoring board in 2012-13; and receiving travel expenses from Abbvie (part of Abbot) in 2013. Dr Edwards reported serving as consultant for and receiving grants from Novartis Vaccines. Dr Healy reported conducting trials with grants from Sanofi Pasteur and Novartis and serving as advisor for Novartis Vaccines. Dr Baker reported serving as consultant and advisory board member to Novartis Vaccines and as an advisory board member for Pfizer Inc. No other disclosures are reported.

Funding/Support: This study was supported by Division of Microbiology and Infectious Diseases Contracts N01AI80002C (Baylor College of Medicine, Houston, Texas), HHSN272200800004C (Group Health Research Institute, Seattle, Washington), and HHSN272200800057C (Duke University School of Medicine, Durham, North Carolina). Dr Englund was also supported in Seattle by the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health, through grant UL1RR025014. Ms Petrie, Ms Ferreira, and Mr Goll performed this work supported by National Institute for Allergy and Infectious Diseases–Division of Microbiology and Infectious Diseases(DMID) contract (Clinical Research in Infectious Disease [CRID], HHSN272200800013C).

Role of the Sponsors: The National Institutes of Health and the DMID had a supervisory role in the design and conduct of the study but had no direct role in the collection, management, analysis, and interpretation of the data; the preparation, review, and approval of the manuscript; or the decision to submit the manuscript for publication.

Previous Presentation: Partial results of this study were presented by Dr Munoz at the Second International Neonatal and Maternal Immunization Meeting in Antalya, Turkey, March 3-5, 2013.

Additional Contributions: We gratefully acknowledge the women and infants who participated in this study, their obstetric and pediatric providers for contributing to the success of the trial, the physician assistants, nurses, coordinators, pharmacists, and administrative personnel at each of the participating Vaccine and Treatment Evaluation Units sites, the hospitals where study participants delivered, the members of the data and safety monitoring board and local safety monitors, and the team at National Institutes of Health/DMID and the EMMES Corporation (Gina Simone and Cyrille Amegashie) who supported this trial. We would also like to acknowledge W. Paul Glezen, MD, and Wendy A. Keitel, MD, from Baylor College of Medicine and Michael D. Decker, MD, MPH, David P. Greenberg, MD, and David R. Johnson, MD, MPH, from Sanofi Pasteur, for providing scientific guidance and expertise throughout the conduct of the study and manuscript preparation; Marcia A. Rench, BSN, Baylor College of Medicine, who assisted during the initial protocol design, and Susan Bobbitt, RN, study coordinator at the Baylor College of Medicine site. No compensation was received by any individual for assistance in the conduct of this study.

Vitek  CR, Pascual  FB, Baughman  AL, Murphy  TV.  Increase in deaths from pertussis among young infants in the United States in the 1990s. Pediatr Infect Dis J. 2003;22(7):628-634.
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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(2):59-61.
PubMed   |  Link to Article
Van Savage  J, Decker  MD, Edwards  KM, Sell  SH, Karzon  DT.  Natural history of pertussis antibody in the infant and effect on vaccine response. J Infect Dis. 1990;161(3):487-492.
PubMed   |  Link to Article
Broder  KR, Cortese  MM, Iskander  JK,  et al; Advisory Committee on Immunization Practices (ACIP).  Preventing tetanus, diphtheria, and pertussis among adolescents: use of tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccines recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2006;55(RR-3):1-34.
PubMed
Kretsinger  K, Broder  KR, Cortese  MM,  et al; Centers for Disease Control and Prevention; Advisory Committee on Immunization Practices; Healthcare Infection Control Practices Advisory Committee.  Preventing tetanus, diphtheria, and pertussis among adults: use of tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine recommendations of the Advisory Committee on Immunization Practices (ACIP) and recommendation of ACIP, supported by the Healthcare Infection Control Practices Advisory Committee (HICPAC), for use of Tdap among health-care personnel. MMWR Recomm Rep. 2006;55(RR-17):1-37.
PubMed
Murphy  TV, Slade  BA, Broder  KR,  et al; Advisory Committee on Immunization Practices (ACIP) Centers for Disease Control and Prevention (CDC).  Prevention of pertussis, tetanus, and diphtheria among pregnant and postpartum women and their infants recommendations of the Advisory Committee on Immunization Practices (ACIP) [published correction appears in MMWR Recomm Rep. 2008;57(26):723]. MMWR Recomm Rep. 2008;57(RR-4):1-51.
PubMed
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 and persons who have or anticipate having close contact with an infant aged <12 months—Advisory Committee on Immunization Practices (ACIP), 2011. MMWR Morb Mortal Wkly Rep. 2011;60(41):1424-1426.
PubMed
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(7):131-135.
PubMed
Kapasi  A, Meade  BD, Plikaytis  B,  et al.  Comparative study of different sources of pertussis toxin (PT) as coating antigens in IgG anti-PT enzyme-linked immunosorbent assays. Clin Vaccine Immunol. 2012;19(1):64-72.
PubMed   |  Link to Article
Klein  NP, Bartlett  J, Rowhani-Rahbar  A, Fireman  B, Baxter  R.  Waning protection after fifth dose of acellular pertussis vaccine in children. N Engl J Med. 2012;367(11):1012-1019.
PubMed   |  Link to Article
Centers for Disease Control and Prevention. Pertussis Surveillance Report.http://www.cdc.gov/pertussis/surv-reporting.html. Accessed June 30, 2013.
Winter  K, Harriman  K, Zipprich  J,  et al.  California pertussis epidemic, 2010. J Pediatr. 2012;161(6):1091-1096.
PubMed   |  Link to Article
Castagnini  LA, Healy  CM, Rench  MA, Wootton  SH, Munoz  FM, Baker  CJ.  Impact of maternal postpartum tetanus and diphtheria toxoids and acellular pertussis immunization on infant pertussis infection. Clin Infect Dis. 2012;54(1):78-84.
PubMed   |  Link to Article
Halperin  BA, Morris  A, Mackinnon-Cameron  D,  et al.  Kinetics of the antibody response to tetanus-diphtheria-acellular pertussis vaccine in women of childbearing age and postpartum women. Clin Infect Dis. 2011;53(9):885-892.
PubMed   |  Link to Article
Zheteyeva  YA, Moro  PL, Tepper  NK,  et al.  Adverse event reports after tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccines in pregnant women. Am J Obstet Gynecol. 2012;207(1):e1-e7.
PubMed
 Abstracts of the 27th International Conference on Pharmacoepidemiology & Therapeutic Risk Management. Chicago, Illinois, USA. August 14-17, 2011. Pharmacoepidemiol Drug Saf. 2011;20(suppl 1):S1-S364.
PubMed   |  Link to Article
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(4):e1-e5.
PubMed
Taranger  J, Trollfors  B, Lagergård  T,  et al.  Correlation between pertussis toxin IgG antibodies in postvaccination sera and subsequent protection against pertussis. J Infect Dis. 2000;181(3):1010-1013.
PubMed   |  Link to Article
Heininger  U, Riffelmann  M, Bär  G, Rudin  C, von König  CH.  The protective role of maternally derived antibodies against Bordetella pertussis in young infants. Pediatr Infect Dis J. 2013;32(6):695-698.
PubMed   |  Link to Article
Klein  NP, Bartlett  J, Fireman  B, Rowhani-Rahbar  A, Baxter  R.  Comparative effectiveness of acellular versus whole-cell pertussis vaccines in teenagers. Pediatrics. 2013;131(6):e1716-e1722.
PubMed   |  Link to Article
Glezen  WP.  Effect of maternal antibodies on the infant immune response. Vaccine. 2003;21(24):3389-3392.
PubMed   |  Link to Article
Englund  JA, Anderson  EL, Reed  GF,  et al.  The effect of maternal antibody on the serologic response and the incidence of adverse reactions after primary immunization with acellular and whole-cell pertussis vaccines combined with diphtheria and tetanus toxoids. Pediatrics. 1995;96(3, pt 2):580-584.
PubMed
Hardy-Fairbanks  AJ, Pan  SJ, Decker  MD,  et al.  Immune responses in infants whose mothers received Tdap vaccine during pregnancy. Pediatr Infect Dis J. 2013;32(11):1257-1260.
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
Figure.
Consort Flow Diagram

Tdap indicates tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis.aParticipants who did not meet more than 1 eligibility criterion are categorized by the first criterion met.bReceived pharmacy stock vaccine, not study vaccine; included in analysis.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1.  Demographic and Clinical Characteristics of Study Participants
Table Graphic Jump LocationTable 2.  Proportion of Participants With Injection Site and Systemic Reactions After Tdap or Saline Placebo Administration, by Study Group
Table Graphic Jump LocationTable 3.  Serious Adverse Events in Study Participants Receiving Tdap, by Study Group and Severity
Table Graphic Jump LocationTable 4.  Geometric Mean Concentration of Antibodies to Tdap Vaccine Antigens in Sera From Mothers and Infants, and Nonpregnant Women, by Study Group and Time of Sample Collection
Table Graphic Jump LocationTable 5.  Transplacental Transfer of Antibodies (Ratio of Infant Cord Blood Antibodies to Maternal Antibodies) and Antibody Concentrations in Infants at 2 Months of Age Compared With Concentrations at Birth (Ratio of Infant 2-Month Antibodies to Cord Blood Antibodies)

References

Vitek  CR, Pascual  FB, Baughman  AL, Murphy  TV.  Increase in deaths from pertussis among young infants in the United States in the 1990s. Pediatr Infect Dis J. 2003;22(7):628-634.
PubMed
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(2):335-340.
PubMed   |  Link to Article
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(2):59-61.
PubMed   |  Link to Article
Van Savage  J, Decker  MD, Edwards  KM, Sell  SH, Karzon  DT.  Natural history of pertussis antibody in the infant and effect on vaccine response. J Infect Dis. 1990;161(3):487-492.
PubMed   |  Link to Article
Broder  KR, Cortese  MM, Iskander  JK,  et al; Advisory Committee on Immunization Practices (ACIP).  Preventing tetanus, diphtheria, and pertussis among adolescents: use of tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccines recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2006;55(RR-3):1-34.
PubMed
Kretsinger  K, Broder  KR, Cortese  MM,  et al; Centers for Disease Control and Prevention; Advisory Committee on Immunization Practices; Healthcare Infection Control Practices Advisory Committee.  Preventing tetanus, diphtheria, and pertussis among adults: use of tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine recommendations of the Advisory Committee on Immunization Practices (ACIP) and recommendation of ACIP, supported by the Healthcare Infection Control Practices Advisory Committee (HICPAC), for use of Tdap among health-care personnel. MMWR Recomm Rep. 2006;55(RR-17):1-37.
PubMed
Murphy  TV, Slade  BA, Broder  KR,  et al; Advisory Committee on Immunization Practices (ACIP) Centers for Disease Control and Prevention (CDC).  Prevention of pertussis, tetanus, and diphtheria among pregnant and postpartum women and their infants recommendations of the Advisory Committee on Immunization Practices (ACIP) [published correction appears in MMWR Recomm Rep. 2008;57(26):723]. MMWR Recomm Rep. 2008;57(RR-4):1-51.
PubMed
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 and persons who have or anticipate having close contact with an infant aged <12 months—Advisory Committee on Immunization Practices (ACIP), 2011. MMWR Morb Mortal Wkly Rep. 2011;60(41):1424-1426.
PubMed
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(7):131-135.
PubMed
Kapasi  A, Meade  BD, Plikaytis  B,  et al.  Comparative study of different sources of pertussis toxin (PT) as coating antigens in IgG anti-PT enzyme-linked immunosorbent assays. Clin Vaccine Immunol. 2012;19(1):64-72.
PubMed   |  Link to Article
Klein  NP, Bartlett  J, Rowhani-Rahbar  A, Fireman  B, Baxter  R.  Waning protection after fifth dose of acellular pertussis vaccine in children. N Engl J Med. 2012;367(11):1012-1019.
PubMed   |  Link to Article
Centers for Disease Control and Prevention. Pertussis Surveillance Report.http://www.cdc.gov/pertussis/surv-reporting.html. Accessed June 30, 2013.
Winter  K, Harriman  K, Zipprich  J,  et al.  California pertussis epidemic, 2010. J Pediatr. 2012;161(6):1091-1096.
PubMed   |  Link to Article
Castagnini  LA, Healy  CM, Rench  MA, Wootton  SH, Munoz  FM, Baker  CJ.  Impact of maternal postpartum tetanus and diphtheria toxoids and acellular pertussis immunization on infant pertussis infection. Clin Infect Dis. 2012;54(1):78-84.
PubMed   |  Link to Article
Halperin  BA, Morris  A, Mackinnon-Cameron  D,  et al.  Kinetics of the antibody response to tetanus-diphtheria-acellular pertussis vaccine in women of childbearing age and postpartum women. Clin Infect Dis. 2011;53(9):885-892.
PubMed   |  Link to Article
Zheteyeva  YA, Moro  PL, Tepper  NK,  et al.  Adverse event reports after tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccines in pregnant women. Am J Obstet Gynecol. 2012;207(1):e1-e7.
PubMed
 Abstracts of the 27th International Conference on Pharmacoepidemiology & Therapeutic Risk Management. Chicago, Illinois, USA. August 14-17, 2011. Pharmacoepidemiol Drug Saf. 2011;20(suppl 1):S1-S364.
PubMed   |  Link to Article
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(4):e1-e5.
PubMed
Taranger  J, Trollfors  B, Lagergård  T,  et al.  Correlation between pertussis toxin IgG antibodies in postvaccination sera and subsequent protection against pertussis. J Infect Dis. 2000;181(3):1010-1013.
PubMed   |  Link to Article
Heininger  U, Riffelmann  M, Bär  G, Rudin  C, von König  CH.  The protective role of maternally derived antibodies against Bordetella pertussis in young infants. Pediatr Infect Dis J. 2013;32(6):695-698.
PubMed   |  Link to Article
Klein  NP, Bartlett  J, Fireman  B, Rowhani-Rahbar  A, Baxter  R.  Comparative effectiveness of acellular versus whole-cell pertussis vaccines in teenagers. Pediatrics. 2013;131(6):e1716-e1722.
PubMed   |  Link to Article
Glezen  WP.  Effect of maternal antibodies on the infant immune response. Vaccine. 2003;21(24):3389-3392.
PubMed   |  Link to Article
Englund  JA, Anderson  EL, Reed  GF,  et al.  The effect of maternal antibody on the serologic response and the incidence of adverse reactions after primary immunization with acellular and whole-cell pertussis vaccines combined with diphtheria and tetanus toxoids. Pediatrics. 1995;96(3, pt 2):580-584.
PubMed
Hardy-Fairbanks  AJ, Pan  SJ, Decker  MD,  et al.  Immune responses in infants whose mothers received Tdap vaccine during pregnancy. Pediatr Infect Dis J. 2013;32(11):1257-1260.
PubMed   |  Link to Article
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Multimedia

Supplement.

eAppendix. Inclusion/Exclusion Criteria

eTable 1. Injection Site and Systemic Reactions

eTable 2. Summary of Infant Weight, Length, and Fronto-occipital Circumference (FOC) Measurements

eTable 3. Summary of Infant Bayley III Screening Test Results

eTable 4. Frequency and Proportion of Women and Infants With Diphtheria and Tetanus Antibody Concentrations =0.1 and =1.0 IU/mL and their 95% 2-Sided Confidence Intervals by Study Group, Study Day, and Antigen

eFigure 1. Reverse Cumulative Distribution Curves: Geometric Mean Concentration (GMC) of Antibodies to Vaccine Antigens in Women and Infants

eFigure 2. Geometric Mean Concentration (GMC) Antibodies in Mothers and Infants

eFigure 3. Transplacental Transfer of Vaccine-Specific Antibodies and Correlation of Maternal and Infant Geometric Mean Concentration (GMC) at Delivery

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