Abstract
Vaccination in pregnancy using a tetanus toxoid, reduced dose diphtheria toxoid, and reduced dose acellular pertussis (Tdap) vaccine is important for prevention of severe pertussis disease in young infants. The objectives of this systematic literature review were to search for original research studies evaluating the vaccine effectiveness, immunogenicity, and safety of Adacel®/Adacel-Polio® used during pregnancy to prevent pertussis disease in young infants. Medical databases used included EMBASE, BIOSIS Previews, and Chemical Abstracts, with search terms related to pregnancy, vaccines/immunization, safety, pertussis, effectiveness/efficacy, and immune response; other potentially eligible reports were included where applicable. Search results were restricted to literature published from 1 January 1995 to 26 July 2021. A total of 2021 articles and 4 other reports were identified for primary review. A total of 49 publications qualified for inclusion after primary and secondary reviews. Effectiveness studies of Adacel or Adacel-Polio given in pregnancy consistently showed high levels of protection from pertussis disease in the newborn (vaccine effectiveness: 91–93%). In immunogenicity studies, the response in pregnant women was consistent with that of non-pregnant women. Infants of mothers vaccinated with Adacel or Adacel-Polio in pregnancy had higher anti-pertussis antibody levels at birth and at 2 months of age compared to infants born to women vaccinated with comparator vaccines, placebo, or those not vaccinated during pregnancy. There was evidence of a slightly decreased response to primary pertussis vaccination in infants of mothers vaccinated with Adacel or Adacel-Polio, but this was not thought to be clinically significant. In safety studies, Adacel or Adacel-Polio vaccination was well tolerated by pregnant woman and not associated with pregnancy, postpartum, or neonatal complications. In conclusion, Adacel or Adacel-Polio vaccination in pregnancy is highly effective in protecting young infants from pertussis disease, with a favorable safety profile for both pregnant women and their infants.
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Newborn infants are particularly susceptible to pertussis infection in the period before routine infant vaccination. |
Pertussis vaccination in pregnancy using Tdap vaccines, consisting of tetanus toxoid, reduced dose diphtheria toxoid, and reduced dose acellular pertussis antigens, and the resultant transmission of maternal antibodies to newborn infants provides direct protection against pertussis disease in the early neonatal period. |
Adacel® is a Tdap vaccine and Adacel®-Polio contains the same Tdap antigens as Adacel together with inactivated poliovirus antigens; both are widely used globally for the vaccination of pregnant women, usually in the second or third trimester. |
A systematic literature review, conducted to assess the effectiveness, immunogenicity, and safety of Adacel or Adacel-Polio vaccination during pregnancy, showed that protection against pertussis is conferred in newborn infants with no increased risk of pregnancy complications, adverse birth outcomes, or developmental problems in the newborn. |
Adacel or Adacel-Polio vaccination during pregnancy was highly immunogenic in pregnant women, providing the developing fetus with maternal antibodies that protected against pertussis disease from birth through 2–3 months of age with vaccine effectiveness of over 90% in 5 studies and affording a favorable safety profile for both the mother and infant. |
Introduction
Pertussis poses a high burden of disease globally, with more than 24 million cases and 160,700 deaths estimated in 2014 [1]. Although pertussis affects all age groups, it is most hazardous for infants, who account for nearly all pertussis hospitalizations and deaths, and the highest rates of morbidity and mortality from pertussis disease occur in infants less than 1 year of age [2].
In the pre-vaccination era, prior to the routine use of pertussis vaccines, adults who had had pertussis as children had their acquired immunity boosted regularly by recurrent exposure in the population, and pregnant women then passed protection to their infants through the placental transfer of anti-pertussis antibodies. The routine implementation of infant and childhood pertussis vaccination programs resulted in protection for the newly immunized pediatric group, with an increasing proportion of cases occurring in adolescents and adults who had lost their infection- or vaccine-induced immunity, and who were no longer boosted by exposures in the population. Young infants received lower levels of anti-pertussis antibodies from their mothers during pregnancy, which increased their vulnerability to pertussis during the first few months of life [3]. As a result, manifestations of severe pertussis disease—including hospitalization, intensive care unit admission, and death—are most often seen in the first few months of life, prior to initiation of the primary infant vaccination series [4,5,6,7].
In the United States (US) in 2019, 18,617 cases and 7 pertussis-related deaths were reported, with the highest burden in infants who had not completed their primary vaccination series. Reported pertussis incidence in infants < 6 months of age was 76.5 per 100,000 compared to 5.7 per 100,000 in the entire population. The proportion of hospitalized cases was also higher in infants < 6 months (40.9%) compared to the entire population (6.2%) [8]. From 2004 through 2016 in the US, 54.4% of infants hospitalized with pertussis, and 85.5% of infants who died from pertussis were less than 2 months of age [9]. European surveillance data from 2018 for 30 EU/EEA countries reported 35,627 pertussis cases, of which 33,133 (93%) were classified as confirmed, 1254 (4%) as probable and 1240 (3%) as possible. Five countries (Germany, the Netherlands, Norway, Spain and the UK) accounted for 72% of all notified cases. The highest notification rate was observed among infants below the age of 1 year (44.4 cases per 100,000 population). Infants were the most affected age group in all Member States except for Estonia and Norway. Infants constituted 6% of all cases reported; among those in which the month of age was known (87%), 65% were under six months old and 45% were under 3 months old [10].
In many Asian countries, often with only passive surveillance practices in place, it is likely that pertussis is greatly underreported, which may mask pertussis resurgence. While some countries in Asia have reported increases in incidence in pertussis in recent years (e.g., China, South Korea, Malaysia, and Thailand), this is less apparent in others (e.g., India, Pakistan, the Philippines, and Taiwan), but better surveillance in recent years can confound the year-on-year comparisons [11]. Similarly, the epidemiology of pertussis in Africa is difficult to fully characterize. Improved surveillance is a priority for the accurate assessment of disease burden across the African continent [12], although available data suggest greater prevalence of pertussis disease among younger infants rather than older individuals in Algeria and Tunisia (81.2% and 94.0%, respectively, in children < 6 months of age) [13, 14] and Morocco (57% of infants hospitalized for pertussis reported to be < 2 months of age) [15]. In Latin America, improvements in surveillance that have occurred in the last decade, often following pertussis outbreaks, also make year-on-year comparisons difficult. Generally, most cases and most deaths have occurred in younger infants. In Brazil from 2010 to 2016, 91% of pertussis-related deaths were in infants < 3 months of age. In Peru during 2011 and 2012, 38% of cases were in infants < 1 year of age. In Uruguay (2011–2012), Mexico (2012), and Venezuela (2011) the majority of detected cases occurred in infants < 1 year of age [16].
Various indirect protection strategies have been used to try to control pertussis infection in young infants. Cocooning strategies—such as postpartum vaccination, vaccination of parents, or vaccination of all close contacts—may have an impact on disease prevention in some settings, if high coverage could be achieved in a timely manner [17]. However, some studies have shown that in practice cocooning strategies have low to moderate effectiveness in protecting young infants against pertussis disease [18,19,20,21], mostly because they are difficult to implement [18, 20, 22, 23].
Vaccines given during pregnancy, on the other hand, can provide direct protection for the newborn through the transfer of maternal antibodies to the developing fetus. Pertussis antibody concentrations in infants of Tdap-vaccinated mothers are higher during the first 2–4 months of life than in infants of unvaccinated mothers [24, 25]. These antibodies transferred from the mother’s immune response to Tdap vaccination in pregnancy can subsequently protect infants regardless of the source of infection. Several studies assessing the effectiveness of Tdap vaccination in pregnancy have confirmed the protective effect of this intervention [24,25,26,27]. Moreover, vaccination of the pregnant woman can reduce the risk of maternal pertussis infection, which could be a source of transmission to the newborn, thus providing a further measure of indirect protection for the infant [28]. This dual effect ensures robust protection of infants who are too young to be vaccinated during the time they are at highest risk of pertussis infection. Therefore, vaccination in pregnancy is a feasible option to close this ‘immunity gap’ [29].
Recommendations for Tdap vaccination in pregnancy were enacted by many recommending bodies after major outbreaks reported globally between 2008 and 2016. After implementation of recommended Tdap in pregnancy vaccination programs, there soon were myriad publications available assessing the effectiveness, immunogenicity, and safety of such vaccination. Data from randomized, controlled trials and observational studies available in the biomedical literature provide strong evidence for the effectiveness, immunogenicity, and safety of Tdap vaccines in infants born to women vaccinated during pregnancy. The World Health Organization recommends 1 dose of Tdap vaccine in the second or third trimester and preferably at least 15 days before the end of pregnancy [17] and pertussis programs in pregnancy are widely recommended in high-income and low- to middle-income countries [30].
In this review, we collate the safety and immunogenicity data for pregnant women—and for the infants born to them—of vaccination in pregnancy using Adacel or Adacel-Polio. We also collate the effectiveness of this intervention at preventing pertussis disease in these infants.
Methods
Adacel is a Tdap vaccine with five pertussis components [pertussis toxoid (PT), filamentous hemagglutinin (FHA), pertactin (PRN), and fimbriae types 2 and 3 (FIM)] [31]; Adacel-Polio also includes IPV containing Mahoney (Type 1), MEF-1 (Type 2), and Saukett (Type 3) strains [32].
We used the Cochrane methodology for systematic review of interventions [33] to conduct a systematic literature review (SLR) to evaluate the effectiveness of Adacel or Adacel-Polio vaccination during pregnancy in the prevention of pertussis disease in young infants, the immune response to Adacel or Adacel-Polio vaccination during pregnancy in pregnant women and their infants, and the safety of Adacel or Adacel-Polio vaccination during pregnancy in pregnant women and their infants. The following databases were searched: EMBASE, BIOSIS Previews, and Chemical Abstracts. In addition, other potentially eligible clinical trials or ancillary publications were identified by searching the reference lists of retrieved studies, systematic reviews, and through direct contact with experts. Since Tdap vaccines were initially developed in the mid-1990s, the search was restricted to literature published from 1 January 1995, while the end date for the search was 26 July 2021.
The search terms related to pregnancy, vaccines/immunization, safety, pertussis, effectiveness/efficacy, and immune response, and the search strategy was designed to assure a search broad enough to capture all relevant and up-to-date data to address the defined objectives. A 2-phase search strategy was employed for the largest database, EMBASE. The first search strategy included publications related to safety/adverse events (AEs) associated with Tdap vaccination during pregnancy, and the second search strategy included publications related to immunogenicity/effectiveness of Tdap vaccination in pregnancy. The search strategy for BIOSIS Previews and Chemical Abstracts was combined to assess safety/AEs and immunogenicity/effectiveness and aimed to exclude publications already identified in EMBASE. The eligibility criteria for the 2 phases are summarized below.
First Review
Inclusion Criteria
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Original research studies reporting outcomes related to effectiveness, immunogenicity, and/or safety in women who received Adacel or Adacel-Polio in pregnancy or in their infants.
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All study designs (randomized, non-randomized studies, interventional, observational).
Exclusion Criteria
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Publications that were not primary research studies (e.g., reviews, meta-analyses, letters to editors, modeling studies, studies on vaccination program improvements, vaccine uptake increase, vaccine acceptability and perception studies, cost-effectiveness, and health economic studies).
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Studies not related to effectiveness, immunogenicity, or safety of Tdap/Tdap-IPV vaccination in pregnancy.
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Animal studies.
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Studies with no relevant effectiveness, immunogenicity, safety data on outcomes assessed.
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Posters or abstracts for which fully published results are included in the review.
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Duplicates.
Second Review
Inclusion Criteria
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Immunogenicity and/or effectiveness studies in which Adacel or Adacel-Polio was used in a minimum of 75% of the Tdap vaccine recipients. The discretionary threshold of 75% was chosen so that the immunogenicity and effectiveness results would be more likely to be driven by responses to Adacel or Adacel-Polio than by those to other Tdap or Tdap-IPV vaccines.
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Safety studies that included any recipients of Adacel or Adacel-Polio and those in which the Tdap vaccine used was unknown.
Exclusion Criteria
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Safety studies exclusively using other brands of Tdap or Tdap-IPV vaccine (as this SLR was designed to specifically assess the effectiveness, immunogenicity, and safety of Adacel or Adacel-Polio).
Each selected article was assessed for its level and quality of evidence based on the criteria proposed by the US Preventive Services Task Force (USPTF) [34] by two or three independent reviewers. The USPTF evidence level was allocated as: I (at least one properly randomized controlled trial), II-1 (well-designed controlled trials without randomization), II-2 (well-designed cohort or case–control analytic studies, preferably from > 1 center or research group), II-3 (multiple time series with or without the intervention), or III (opinions of respected authorities, based on clinical experience, descriptive studies and case reports, or reports of expert committees). The USPTF level was then used to assign an evidence quality rating of good, fair, or poor to each study based on specific criteria for the type of study.
This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.
Results
Search Results
The initial searches provided 2736 articles and 4 other reports for primary review. Of these, 715 articles were removed before screening (duplicate records). Of the remaining 2021 articles, 1910 were excluded as not relevant to the topic of Tdap in pregnancy or not primary reports of clinical studies (reviews, meta-analyses, case reports, immunization guidelines, opinion pieces, letters to editors, studies on vaccination improvement, vaccine uptake, vaccine acceptability and perception studies, and health economics studies). Secondary review of the remaining 111 articles was designed to assess the more specific study criteria of Tdap vaccine brand used in the study. If the Tdap vaccine used was not specified in the publication, we contacted the corresponding author for additional information about the vaccine brand used, if available. A further 65 articles were subsequently excluded because of the use of a other brands of Tdap or Tdap-IPV (52 studies), unknown brand of Tdap used (11 studies) in immunogenicity or effectiveness studies, or less than of 75% for the proportion of Adacel or Adacel-Polio used in immunogenicity or effectiveness studies (2 studies). An additional 4 reports were identified from organizations (2 reports) and citation searching (2 reports), of which 1 report was subsequently excluded (less than 75% for the proportion of Adacel or Adacel-Polio used in the immunogenicity study). After the primary and secondary reviews, therefore, a total of 49 studies remained for inclusion in the SLR (Fig. 1).
Of the 49 articles that remained for inclusion in the SLR (Fig. 1), 5 publications [26, 27, 35, 36, 37] reported effectiveness (Table 1), 18 publications reported immunogenicity (Table 2) [24, 25, 38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53], 24 publications reported safety of Adacel or Adacel-Polio (Table 3) [24, 25, 40, 46, 53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72], and 7 publications reported safety of unspecified Tdap (Table 4) [73,74,75,76,77,78,79]. Five of these publications reported both safety and immunogenicity data [24, 25, 40, 46, 53].The characteristics of the selected studies and the USPSTF evidence level and evidence quality for each study are presented in Tables 1, 2, 3, 4, 5.
Data were collected from women (pregnant or non-pregnant) and newborn infants (see Tables 1, 2, 3, 4 for details). In the majority of studies, vaccination was in the second or third trimester of pregnancy.
Effectiveness
Vaccine effectiveness of Tdap vaccination in pregnancy to prevent pertussis in infants was evaluated in two studies for Adacel [27, 37] and in three studies for Adacel-Polio [26, 35, 36] (Table 1). These five studies consistently showed protection in the newborn from pertussis disease following Adacel or Adacel-Polio given in pregnancy, with vaccine effectiveness (VE) rates between 90 and 93% for the prevention of pertussis disease in infants up to 3 months of age (Table 5). The VE estimates for these studies were derived using different methodologies but demonstrated consistency of the estimates across the studies.
The effectiveness studies were conducted in women who had been vaccinated during the third trimester of pregnancy according to the recommendations in the United Kingdom (UK) and the US at the beginning of their respective Tdap vaccination in pregnancy programs. It is also important to note that these VE assessment studies were carried out during major pertussis outbreaks in these countries, therefore providing strong support for the utility of this intervention during a period when young infants were most at risk.
Two of these studies to evaluate the VE of Adacel were conducted in the US. One was a retrospective cohort study conducted in a large managed care organization in California [27] and the other was a case–control study conducted in 6 states across the US [37]. The retrospective cohort study modeled the risk of pertussis in the infant in relation to whether the mother received Tdap during pregnancy. Stratified Cox regression estimated the pertussis hazard ratio (HR) in infants of women vaccinated with Tdap versus women who were unvaccinated during pregnancy with VE calculated as 1–HR. This study found the VE of Tdap vaccine (> 99% Adacel) during pregnancy when given ≥ 8 days before birth was 91.4% (95% CI 19.5–99.1%) during the first 2 months of life.
The case–control study found the effectiveness of Adacel in preventing pertussis in infants < 2 months of age whose mothers were vaccinated between 27 and 36 weeks gestation was 92.5% (95% CI 38.5–99.1%). Vaccine effectiveness was estimated as 1–odds ratio (OR) × 100%.
Two case-coverage studies were conducted in the UK to monitor the effectiveness of the Tdap-IPV immunization program in preventing pertussis disease in infants up to 2–3 months of age [26, 35]. For these studies, the authors calculated VE using the screening method (also known as case-coverage), in which VE is one minus the odds of maternal vaccination in cases divided by the odds of vaccination in the population. At the time of the initial assessment in 2013, the VE in infants < 3 months of age after vaccination in pregnancy with Adacel-Polio ≥ 7 days before birth was 91% (95% CI 84–95%) [35], and an analysis for vaccination ≥ 7 days before birth in infants < 2 months of age gave a VE of 90% (95% CI 82–95%) [35]. For the second assessment (in 2015), the VE of Adacel-Polio for preventing pertussis disease in infants < 3 months of age was 93% (95% CI 89–95%) [26].
In another case–control study in the UK [36] the effectiveness in infants < 2 months of age after vaccination in pregnancy found the unadjusted VE to be 91% (95% CI 77–97%). The unadjusted VE was calculated as 1–OR, where OR is the odds ratio for vaccination in pregnancy, between cases and controls. After adjustment for sex, geographical area, and birth period, the VE was 93% (95% CI 81–97%).
These high VE estimates of Adacel/Adacel-Polio vaccination during pregnancy were seen when vaccines were given in the third trimester at least 7–8 days before birth in the retrospective cohort study [27] and the two case-coverage studies [26, 35], or at least 14 days before birth in the US case–control study [37]. Vaccine effectiveness remained high when the analysis was restricted to women vaccinated from 28 days to more than 7 weeks before birth in 1 case-coverage study and in the case–control study [35, 36], indicating that there was no increase in VE related to the earlier administration of the vaccine in the third trimester. Yet, VE was lower when vaccination occurred between 6 days before birth and 14 days postpartum in the other case-coverage study [26], and between more than 14 days before birth and postpartum in the US case–control study [37]. Optimally, 2 weeks are needed for pregnant women to mount a sufficient immune response to Adacel or Adacel-Polio vaccination [80], and vaccination closer to delivery did not allow sufficient time for the maternal antibodies to rise and be transferred through the placenta to the fetus.
Two of the effectiveness studies also found that infants of women vaccinated with Adacel or Adacel-Polio during pregnancy remained better protected throughout the first year of life than infants of unvaccinated women [26, 27]. Infants of vaccinated women had positive relative VE estimates after the infant doses of pediatric diphtheria, tetanus, or acellular pertussis (DTaP). The retrospective cohort study [27] found that maternal Tdap vaccination conferred a significant amount of protection against pertussis over the entire first year of life (69%), even after infants were immunized with DTaP. One of the case-coverage studies [26] found high relative VE conferred through maternal immunization after the first and second DTaP doses (82% and 69%, respectively) and lower VE after the third dose (29%). The infants of these Adacel and Adacel-Polio vaccinated mothers were more protected over the first year of life than infants whose mothers did not receive vaccination during pregnancy.
These studies demonstrate that vaccination of pregnant women with Adacel or Adacel-Polio results in protection from pertussis disease in newborns and in infants up to 2–3 months of age, and that this protection may continue through the first year of life and supplement the effect of the primary vaccination series.
Immunogenicity
Pregnant Women
Thirteen studies (five randomized controlled trials [RCTs], six cohort [one retrospective, five prospective], and two prospective observational) assessed the immune response of pregnant women vaccinated with Adacel. The pregnant women in these studies had likely received wP vaccine as infants, based on their ages and the timing of the studies. These 13 studies measured antibody concentrations of pregnant women at various time points, including pre-vaccination (7 studies) [24, 25, 40, 45, 46, 52, 53], 2–4 weeks post-vaccination (6 studies) [25, 40, 45, 46, 52, 53], at delivery (9 studies) [24, 25, 38, 39, 42, 43, 45,46,47], and post-delivery (2 studies) [24, 25] (Table 6). The comparator groups in the RCTs included pregnant women who received placebo, Td adsorbed, or tetanus toxoid. In the cohort studies with a comparator group, the comparator groups were unvaccinated pregnant women. Anti-PT, anti-FHA, anti-PRN, and anti-FIM antibody geometric mean concentrations (GMCs) from these studies are summarized in Table 6.
One RCT [25] and 1 observational study [40] compared responses to Adacel given in pregnancy with responses in non-pregnant women of reproductive age. The antibody responses to vaccination with Adacel were robust in both pregnant and non-pregnant women. The antibody concentrations pre-vaccination and post-vaccination in pregnant and non-pregnant women were similar, but were slightly higher pre-vaccination and significantly higher post-vaccination in non-pregnant versus pregnant women for PT and FHA but not for FIM or PRN.
The most comprehensive data on immunogenicity in pregnant women are from the five RCTs [24, 25, 46, 47, 53]. In each of these studies the vaccination was in the third trimester. Pre-vaccination GMCs for pertussis antigens were similar for participants in the Adacel or Adacel-Polio groups and the comparator groups, and were higher at delivery for those receiving Adacel or Adacel-Polio than in the comparator vaccine group in four of the RCTs (comparator groups of placebo [25, 53], Td adsorbed vaccine [24], or tetanus vaccine [46]. In one RCT that assessed immunogenicity of Adacel in comparison with a 3aP Tdap vaccine given in pregnancy, maternal GMCs at delivery were higher in the Adacel group for anti-FIM, lower for anti-FHA, and similar for anti-PT and anti-PRN [47]. At 1–2 months post-delivery, where measured, antibody levels remained similar to those at delivery (Table 6).
The data from the remaining cohort studies (Table 6) [39, 41,42,43, 52] did not include pre- and post-vaccination antibody concentration data, but provided these data at delivery in vaccinated and non-vaccinated women. All these studies showed higher pertussis antibody levels in pregnant women vaccinated with Adacel compared to unvaccinated pregnant women.
Some studies evaluated the impact of the timing of Tdap vaccination in relation to pregnancy on the maternal pertussis antibody responses. One study [25] evaluated anti-PT, anti-FHA, anti-PRN, and anti-FIM antibody responses to Adacel in pregnant women vaccinated in the third trimester compared to women vaccinated in the post-partum period. These data showed no differences in the antibody responses between the groups at 2 months after delivery. Another study [39] reported a tendency towards lower antibody levels at delivery in women vaccinated before 20 weeks gestation, but another study [43] showed no difference in antibody levels at delivery in women vaccinated in early pregnancy (first or second trimester) and those vaccinated within 2 years prior to pregnancy. A further study [38] showed similar anti-PT antibody levels at delivery following vaccination during 27–30 weeks and 31–35 weeks of gestation.
One study assessed the pertussis antibody response to ante-partum Tdap vaccination at 12 months after delivery [24], and showed a linear decline for the response to each pertussis antigen of approximately 50% in women who had received Adacel in the last trimester.
Infant
A total of 17 studies in the SLR (6 RCTs, 4 cohort [1 retrospective, 3 prospective], and 7 observational) reported results for immunogenicity in newborns and infants of women vaccinated with Adacel or Adacel-Polio during pregnancy. These 17 studies measured antibody concentrations at various time points, including birth (14 studies) [24,25,26, 36, 38, 39, 41,42,43,44,45,46,47, 51], 2, 4, 6 months (2 studies) [24, 53], 2, 4, 6, 5/6/7, 12/13 months (1 study) [24], 2, 5/6/7 months (6 studies) [25, 42, 46,47,48,49], and 2 months (1 study) [45]; additionally, 3 studies reported antibody concentration data after a booster vaccination in the second year of life [24, 25, 42]. The comparator groups in the RCTs included pregnant women who received placebo, Td adsorbed, or tetanus toxoid. In the cohort observational studies with a comparator group, the comparator groups were unvaccinated pregnant women. Antibody GMCs against pertussis antigens from these studies are summarized in Table 7.
The RCTs generally showed higher pertussis antibody concentrations in the cord blood of infants born to mothers vaccinated with Adacel than in those whose mothers received the comparator vaccine or were unvaccinated. These results were also seen in the cohort studies.
At delivery, the ratios of infant cord blood antibodies to maternal antibodies were > 1 for pertussis antibodies, as reported in three RCTs [24, 25, 47], suggesting active transport of antibody across the placenta. Additionally, three prospective cohort studies and one prospective observational study reported higher ratios of transplacental antibodies at delivery [38, 43, 45, 52].
Antibody responses in infants of women vaccinated with Adacel during pregnancy and infants in the comparator groups are summarized in Table 7. Six studies [38, 39, 43, 45, 51, 52] did not include a comparator. Five RCTs [24, 25, 46, 50, 53], one retrospective cohort study [41], and two prospective cohort studies [42, 44] reported higher antibody concentrations against all measured pertussis antigens at birth in infants of mothers vaccinated with Adacel compared to the infants of mothers in the control groups (Table 7). The RCTs and the prospective cohort studies also reported that the antibody concentrations decreased in the first 2 months of life but remained higher in infants of women vaccinated with Adacel compared to those of women vaccinated with non-pertussis containing comparator vaccines, placebo, or those who were unvaccinated. Additionally, one RCT [47] and one observational study [48] reported higher antibody concentrations against all measured pertussis antigens at 2 months of age in infants of mothers vaccinated with Adacel-Polio compared to infants of unvaccinated mothers.
In most studies reviewed, infant primary pertussis vaccination started at 2 months of age, using 3 + 1 vaccination schedules. Several studies sought to assess the immune response to the infant pertussis vaccination series in infants of women vaccinated with Adacel or Adacel-Polio during pregnancy. At 4 months of age, prior to the second pertussis vaccination in the primary series, antibody concentrations for anti-PT in two RCTs [24, 53] were equivalent or lower in infants of women vaccinated with Adacel compared with infants of women in the comparator groups (Td adsorbed, placebo), yet concentrations for anti-FHA, anti-PRN, and anti-FIM remained higher in the infants of women vaccinated with Adacel. In one of these RCTs, at 6 months of age prior to the third dose of the primary infant series, lower antibody concentrations were reported for all pertussis antigens in infants of women vaccinated with Adacel during pregnancy [24]. Results were similar in the other RCT except concentrations of anti-PRN which remained higher for infants of women vaccinated with Adacel [53]. Pertussis antibody concentrations 1 month after the completion of the 3-dose primary vaccination series, at approximately 7 months of age, were somewhat lower for one or more antigens in infants of mothers vaccinated with Adacel compared to infants of unvaccinated mothers [24, 25, 42, 50].
Similar results were seen in 1 RCT and 2 observational studies from the UK using Adacel-Polio. The UK employs a 2-/3-/4-month 3-dose primary pertussis vaccination regimen for infants. Pertussis antibody concentrations at 5 months of age after completion of the primary series were lower in infants of mothers vaccinated with Adacel-Polio than in infants of unvaccinated mothers [47,48,49].
Post-primary series and post-booster antibody concentrations for most pertussis antigens were either equivalent or lower in infants of women vaccinated with Adacel or Adacel-Polio when compared to infants of women vaccinated with comparator vaccines, placebo, or unvaccinated women, indicating a lower boosting of the infant immune response related to maternal antigens. There does not appear to be any immediate clinical impact from this modification of the immune response.
Several studies sought to assess the impact of the timing of vaccination during pregnancy on infant pertussis antibody concentrations. In a prospective observational study [39], there was a tendency towards lower antibody levels at delivery in women vaccinated before 20 weeks of pregnancy, but there were no significant differences between maternal or cord serum antibody levels based on the timing of Adacel vaccination in pregnancy. Also, in a prospective cohort study, there was no difference in antibody levels to pertussis antigens in maternal delivery sera for women vaccinated before (within 2 years) or during early pregnancy (the majority before 20 weeks) in the US [43].
Safety
Pregnant Women
Eighteen studies [four RCTs, two US Vaccine Adverse Event Reporting System (VAERS) reviews, five retrospective cohort, one prospective cohort, and six observational (two retrospective cohort, two prospective cohort, one cohort, one safety)] that included women vaccinated with Adacel or Adacel-Polio during pregnancy provide evidence of the safety [local and systemic reactions, serious AEs (SAEs), and pregnancy complications] of Adacel and Adacel-Polio in pregnant women (Table 8). The comparator groups in the RCTs included pregnant women who received placebo, Td adsorbed, or tetanus toxoid. In the five retrospective cohort studies and the three observational studies (two retrospective cohort, one cohort) with a comparator group, the comparator groups were unvaccinated pregnant women.
AEs in pregnant women vaccinated with Adacel were similar to those in non-pregnant, reproductive age women. One RCT reported a similar proportion of injection site reactions (pain, erythema/redness, and/or induration/swelling) in pregnant and non-pregnant women (78.8% pregnant women vs. 78.1% non-pregnant women) [25]. These reactions were mostly pain at the injection site. Similarly, in a prospective cohort study, compared with non-pregnant women, pregnant women were more likely to experience moderate/severe pain at the injection site (17.9% vs. 11.1% in pregnant and non-pregnant women, respectively) [40]. The RCT found that the proportion of participants with any systemic symptom was 36.4% in women immunized during pregnancy and 53.1% in non-pregnant women, but this difference was not found to be statistically significant [25]. The prospective cohort study [40] found that the occurrence of other moderate/severe and all severe local and systemic reactions assessed were not different between pregnant and non-pregnant women.
There were no unexpected AEs in pregnant women following vaccination with Adacel or Adacel-Polio. The most frequently reported AEs were mild or moderate injection site reactions with incidences in randomized controlled studies of 25.5% [53], 45% [46], and approximately 80% [24, 25]. Most injection site reactions resolved with 72 h, and the most common was injection site pain. The incidence of injection site reactions was similar in an observational study (10–80%) [71] and a prospective observational study (65%) [66], but lower in another prospective cohort study (approximately 2%) [57], in retrospective cohort studies (3.4/10,000) [61] and in two VAERS reviews (4.5% [72] and 11.9% [64]). In another observational study, the incidence of moderate or severe injection site reactions ranged from 5.6% (erythema) to 19.0% (tenderness) [40]. The incidence rates of injection site reactions were consistent with those specified in the product labels. Injection site reactogenicity was not reported in the other studies, and, where evaluated, there were no differences in incidence between women vaccinated with Adacel or Adacel-Polio and the comparator groups.
Systemic AEs were generally reported at similar rates in pregnant women who received Adacel or Adacel-Polio in pregnancy and in those in the comparator groups who received non-pertussis containing vaccines. The overall incidence of systemic AEs was generally lower than injection site AEs, and, in the RCTs [24, 25, 46, 53] ranged from 3.5% [53] to approximately 40% [25, 46]. In one of these studies [25], the incidence of systemic symptoms was lower in women vaccinated during pregnancy (36%) compared to those vaccinated postpartum (73%) or while not pregnant (53%), and the frequency of fever in Tdap-vaccinated pregnant women was similar to placebo and to that in Tdap-vaccinated non-pregnant women. In another of the RCTs [24], in pregnant women, Adacel was associated with a lower incidence of mild muscle ache and fatigue, whereas severe muscle aches were more common in pregnant women who had received Adacel compared to those who had received Td adsorbed vaccine. In the other RCTs [46, 53], there was no difference in systemic AE incidence between Adacel and the comparator vaccine in pregnant women. In the cohort studies, with the exception of one study that showed a slightly higher incidence of fever for Adacel than the comparator vaccine [61], there were no differences between Adacel or Adacel-Polio and the comparator groups that were considered to be consistent or of clinical importance. Additionally, in one observational study, there was no difference in the incidence of systemic reactions to Adacel in pregnant or non-pregnant women [40].
The larger database studies from the US VAERS [64, 72] and the Vaccine Safety Datalink [61] contained some reports of fever and other systemic symptoms such as headache in pregnant women vaccinated with Adacel or Tdap during pregnancy, but the percentages of reports were low (< 5%). In the observational retrospective cohort study using data from the VSD [61], there was no increase in maternal safety outcomes (i.e., neurologic events, proteinuria, and venous thromboembolism in the vaccinated cohort compared to the unvaccinated cohort) within 42 days after vaccination. However, fever within 3 days was more common in the vaccinated cohort than in the unvaccinated cohort. The reports of fever in pregnant women were consistent with the manufacturer’s AE profile and did not result in adverse pregnancy or birth outcomes. One of the VAERS reviews included 2.3% of reports related to headache or fever and abdominal pain [72], while in the other 4.3% of reports included fever and chills [64].
There were no SAEs that were considered to be related to Adacel or Adacel-Polio and no relevant differences in incidence compared to the control groups in any study. There was a low percentage of reports of SAEs to the US VAERS during the time periods studied: 0.8% of the US VAERS reports between 2005 and 2010 contained information on SAEs in pregnant woman [72] and a combined percentage of 6.9% of the US VAERS reports between 2011 and 2015 (after recommendations had been issued) for SAEs in either pregnant women or their infants [64]. In the observational retrospective cohort study using data from the VSD [61], there was no increased risk for gestational diabetes, thrombocytopenia, venous thromboembolism, or predefined cardiac events within 42 days of vaccination in the subset of women receiving Tdap vaccine at ≥ 20 weeks of gestation compared to matched controls.
Pregnancy/delivery complications were reported in several studies but were generally similar for women vaccinated with Adacel or Adacel-Polio and the comparator groups. One RCT [24] described 17 serious complications of pregnancy/labor [8 in Adacel recipients and 9 in the comparator group (Td adsorbed vaccine)], including 1 event in the Adacel recipients that was assessed as possibly vaccine-related (gestational hypertension). However, the authors concluded that there was no difference in the few serious complications of pregnancy/labor between pregnant women vaccinated with Adacel and those vaccinated with the comparator. Another RCT [25] reported five serious complications of pregnancy/labor, four (12%) in Adacel recipients and one (7%) in the comparator group (tetanus-only vaccine), but none of the events in the Adacel group were deemed to be vaccine-related. In an observational cohort study [57], there was no increased risk of stillbirth, maternal death, pre-eclampsia, eclampsia, antepartum or postpartum hemorrhage, fetal distress, uterine rupture, placenta previa, vasa previa, or Caesarean delivery in pregnant women vaccinated with Adacel-Polio. There was no evidence that vaccination with Adacel-Polio accelerated the time to delivery or increased the risk of maternal complications of pregnancy or delivery.
One retrospective cohort study and one observational retrospective cohort study specifically assessed birth and infant outcomes in women vaccinated with Tdap in pregnancy. In the observational retrospective cohort study [60], Tdap vaccination during pregnancy was not associated with increased risk of preterm delivery, small for gestation age (SGA) birth, or with hypertensive disorders of pregnancy, although a small but statistically significant increased risk of being diagnosed with chorioamnionitis was observed. However, the authors suggested that these results should be interpreted with caution due to the small size of the risk and there being no associated increased risk of preterm birth, a major sequela of chorioamnionitis, and concluded that the observed risk may be due to residual confounding. Furthermore, another retrospective cohort study that primarily studied infant outcomes after vaccination during pregnancy reported no increased risk of chorioamnionitis in pregnant women vaccinated with Adacel [63].
Infant
Sixteen studies [three RCTs, two US VAERS reviews, two case–control, seven retrospective cohort, and two observational (one retrospective cohort, one cohort)] in newborns and infants of women vaccinated with Adacel or Adacel-Polio during pregnancy provide evidence of the safety of Adacel and Adacel-Polio in newborns and infants. As for the previously described studies that included pregnant women, the comparator groups in the RCTs included pregnant women who received placebo, Td adsorbed, or tetanus toxoid. In the six retrospective cohort studies with a comparator group and the two observational studies, the comparator groups were unvaccinated pregnant women.
Birth outcomes, AEs, SAEs, and developmental data in infants are summarized in Table 9.
In all studies, where reported, most infants were born live, at term, and without congenital abnormalities. There were no significant differences in the infants’ gestational ages, birth weights, Apgar scores, neonatal examinations, or neonatal complications between the Adacel or Adacel-Polio and the comparator groups in the RCTs. Where a comparator group was available, the incidence of stillbirth, prematurity, or congenital abnormalities in infants born to mothers who had received Adacel or Adacel-Polio during pregnancy was similar to that in infants from mothers who had received the comparator vaccine, and there was no association between stillbirth and the receipt of Adacel or Adacel-Polio in pregnancy. In one retrospective cohort study [63], infants of mothers vaccinated with Adacel during pregnancy had higher birth weight and were less likely to be born preterm compared to infants of mothers who had not been vaccinated.
Regarding developmental outcomes, where assessed, there were no differences detected between infant groups [24, 25, 54, 55, 59, 68]. In particular, Tdap vaccination in pregnancy had no effect on the incidence of autism spectrum disorder [54], attention-deficit hyperactivity disorder [55], infant growth problems [59], or hospitalization and death rates in the first 6 months of life [68]. Additionally, one study showed an inverse association of Tdap vaccination in pregnancy with infant upper respiratory infection, gastrointestinal infection, and urgent/inpatient healthcare use [62], and, in another study, the incidence of respiratory hospitalization was shown to be higher in infants without Tdap vaccination in pregnancy [68]. No cases of pertussis illness occurred in mothers or infants according to the study reports.
Further to reports of a slightly higher relative risk reported for chorioamnionitis in women vaccinated with Tdap vaccine during pregnancy [60], a retrospective cohort study was performed to assess infant outcomes that may be related to a diagnosis of chorioamnionitis in the mother [56]. In this study, infants of these women did not show an increased risk of conditions often associated with chorioamnionitis (including transient tachypnoea of the newborn, neonatal sepsis, neonatal pneumonia, respiratory distress syndrome, or newborn convulsions) [56].
Overall, there was no evidence of fetal, newborn, or infant harm after administration of Adacel or Adacel-Polio in pregnancy, and some studies have shown a benefit particularly in terms of respiratory morbidity.
Concomitant Administration with Other Vaccines and Repeat Dosing of Tetanus-Containing Vaccines
Three studies (two retrospective cohort and one prospective cohort) reported the concomitant use of Adacel and Adacel-Polio with other vaccines during pregnancy and repeat dosing of tetanus-containing vaccines [67, 69, 70]. These studies are summarized in Table 10.
In one retrospective cohort study [69], concomitant administration of Tdap and influenza vaccines during pregnancy was not associated with a higher risk of fever, acute reactions, or birth outcomes compared with sequential vaccination. In the prospective cohort study [67], there was a slight increase in mild injection site reactions following Tdap vaccine versus influenza vaccines, and a low incidence of fever and other systemic reactions reported by recently immunized pregnant women following Tdap or influenza vaccines administered exclusively or in combination. Both studies support the safety of concomitant use of Tdap vaccine with influenza vaccine.
Also in the prospective cohort study [67], a small subset of the study population had received a previous Tdap vaccine 3–4 years prior to receipt of their current Tdap vaccine in pregnancy. These women more frequently reported AEs overall than women who had no previous recent dose and were also more likely to visit a general practitioner for treatment.
In the other retrospective cohort study [70], there was no increased risk of acute AEs and allergic reactions or adverse birth outcomes for women who had been previously vaccinated less than 2 years before, or 2–5 years before vaccination in pregnancy, compared with those who had been vaccinated more than 5 years before.
While there may be an increased risk of injection site reactions in those who have received recent Td/Tdap vaccines, overall these studies support the safety of Tdap in pregnant women previously vaccinated with tetanus-containing vaccines.
Discussion
This review includes an evaluation of literature from a period of more than 26 years, from 1995 to 2021, and was conducted to assess the available data supporting the effectiveness, immunogenicity, and safety of Adacel/Adacel-Polio used during pregnancy to prevent pertussis disease in young infants. Adacel and Adacel-Polio were considered to be equivalent vaccines for protection against pertussis since their pertussis antigen components are identical and they have been shown to have equivalent immunogenicity in several studies [81, 82].
Newborn infants are particularly susceptible to pertussis infection in the period until the first infant vaccination, usually at 6–8 weeks of age [17]. The importance of Tdap vaccination in pregnancy is primarily to provide protection against pertussis disease in infants who are too young to be vaccinated, i.e., during the vulnerable weeks from birth prior to the first infant vaccination.
Vaccine Effectiveness
Vaccine effectiveness data from this SLR showed that Adacel or Adacel-Polio vaccination during pregnancy results in protection of the newborn from pertussis disease. The five vaccine effectiveness studies showed high effectiveness (VE point estimates > 90%) in the prevention of pertussis disease in young infants for the first 2–3 months of life. These VE data support the many national recommendations for Tdap vaccination in pregnancy to prevent hospitalization and death from pertussis in young infants. Additionally, one study showed that infants without Tdap vaccination in pregnancy were more likely to be hospitalized due to respiratory symptoms [68], and another showed an inverse relationship between Tdap vaccination during pregnancy and infant upper respiratory tract infections [62]. The impact of vaccination with Adacel and Adacel-Polio during pregnancy continues through the first year of life, even after the infant’s primary DTaP vaccination series.
Immunogenicity
Adacel and Adacel-Polio have been shown to induce anti-pertussis immunity in pregnant women, with the immune response being comparable to that in nonpregnant women. Women vaccinated during pregnancy with Adacel or Adacel-Polio produce antibodies that are transferred through the placenta to the developing fetus. After birth, the pertussis antibody concentrations in the newborn’s cord blood are higher than the maternal antibody concentrations at delivery, indicating efficient transplacental antibody transfer.
As the women in these studies were mostly likely to have received primary vaccination with wP vaccine, it is unclear whether the results seen in these studies would be the same in women who received primary vaccination with aP vaccines. This important question should be assessed as these aP-primed women enter their reproductive years.
Anti-pertussis antibody levels were higher in newborn infants of mothers vaccinated with Adacel or Adacel-Polio than those born to unvaccinated mothers, from birth through the first 2–4 months of life. These higher antibody levels provide the protection that results in the high VE that was seen in the effectiveness studies.
Protection against pertussis is affected not only by the quantity but also the quality of circulating antibodies [83]. Antibody avidity is a measure of functional affinity and, thus, of the quality of the antibodies. It is used as a surrogate marker for the long-term humoral immune response. It is important to also note that none of the studies from the SLR assessed the quality or functionality of the pertussis antibodies after Tdap5 vaccination during pregnancy. although the high VE in the first few months of life in infants of vaccinated mothers supports the ability of the maternal antibodies to protect the infant during the vulnerable newborn period.
Most studies reporting infant vaccination immunogenicity showed a lower amount of boosting of the anti-pertussis antibody response in infants of mothers vaccinated during pregnancy, after receipt of the infant DTaP primary vaccination series. The infants responded to their infant vaccination series, but the response was less augmented when compared to infants of unvaccinated mothers. However, since there is no single, broadly agreed upon correlate of protection for pertussis [84, 85] it is difficult to determine whether this modification of the immune response is meaningful in terms of protection against pertussis. Similar immune modification has been described for diphtheria and poliovirus responses, without any change in protection [42, 48,49,50]. Despite the lower pertussis antibody levels, there does not seem to be any evidence of increased susceptibility to pertussis disease after 6 months of life. In fact, two effectiveness studies [26, 27] and two recent publications of Tdap in pregnancy [86, 87] have shown that infants of women vaccinated with Adacel or Adacel-Polio (or unspecified Tdap) remain better protected throughout the first year of life than infants of unvaccinated women.
Timing of Vaccination
The effectiveness studies were conducted in women who had received Adacel/Adacel-Polio during the very late second trimester and third trimester [26, 27, 35, 36], which was consistent with the recommendations at the time of these studies in the UK and US [27, 35]. Most of the immunogenicity studies were conducted in the second and third trimesters [24, 25, 38, 39, 46, 48, 49, 51, 53], but some included data from the first trimester [42, 43]. One immunogenicity study also compared Adacel administered at 27–30 weeks of pregnancy versus 31–35 weeks of pregnancy [38].
The majority of these data support vaccination during the late second or third trimesters, although the data following vaccine administration in the early and mid-second trimesters are also encouraging. In the studies included in this SLR, no differences were seen in antibody levels when mothers were vaccinated in the second or third trimesters [39, 49, 51]; the data for vaccination in the first trimester are less abundant and less robust.
The studies that were reviewed also indicated that the timing of Adacel/Adacel-Polio vaccination prior to delivery is important. Since at least 2 weeks are needed for the mother to mount a sufficient immune response [80], the main analyses were limited to those vaccinated a minimum of 14 days prior to delivery [24,25,26,27, 35, 36, 49, 51]. One observational study [26] compared VE after vaccination > 28 days prior to delivery, 7–27 days prior to delivery, and 0–6 days prior to delivery to 1–13 days postpartum, and showed that VE decreased significantly when vaccination occurred < 7 days prior to delivery [26].
Safety
Both Adacel and Adacel-Polio were well tolerated in pregnant women. Injection site reactions were common but comparable in frequency to those seen in nonpregnant women vaccinated with Adacel. Systemic reactions were also comparable to those seen in nonpregnant women or women vaccinated with other vaccines during pregnancy. Serious AEs were rare in pregnant women, and there was no evidence of a relationship between these events and Adacel vaccination.
The finding of a slightly increased risk of chorioamnionitis in women who received Tdap vaccine (> 80% Adacel) during pregnancy was not associated with a corresponding increase in infant conditions related to chorioamnionitis in two studies that assessed infant outcomes. A recently published follow-up study reassessed the risk of chorioamnionitis in women who received Tdap vaccine during pregnancy in a large cohort of pregnant women and found no increased risk of chorioamnionitis, preterm birth, or adverse infant outcomes. The authors attributed the previous chorioamnionitis findings to the imprecision of using ICD-10 codes for chorioamnionitis since they lack specificity for clinical chorioamnionitis [88].
Overall, the review of the safety data showed no evidence that Adacel or Adacel-Polio vaccination increases the risk of adverse pregnancy outcome or delivery complications.
Birth weight, gestational age at delivery, and the rate of congenital abnormalities were similar between infants of mothers who were vaccinated with Adacel or Adacel-Polio during pregnancy and infants of mothers who received neither of these vaccines during pregnancy.
Concomitant use of Tdap and influenza vaccines does not increase the risk of adverse maternal, pregnancy, or birth outcomes. Also, relatively recent receipt of a prior tetanus-containing vaccine did not appear to increase the risk of AEs after Tdap vaccination in pregnancy.
Limitations
Limitations of this SLR include the potential for publication bias, with the possibility that the inclusion of data only from peer-reviewed, published studies could bias the results in favor of studies with positive findings. However, it is unlikely that studies suggesting safety issues or concerns about effectiveness or immunogenicity would not be published, due to the novelty of the area of research and the need for accurate and well-designed studies to assure the effectiveness, immunogenicity, and safety of this intervention in this unique population. Additionally, per Good Publication Practice, all data (including negative findings) should be published, and therefore included in the SLR.
Another limitation is the variability of methodology, study populations, datasets, laboratory methods, and antibody testing between studies in the studies included in the SLR, which precluded inter-study comparisons and meta-analyses. The studies also had differences in evidence level and quality in review. Nevertheless, the findings in the multiple studies of effectiveness, immunogenicity, and safety showed consistent results that support the use of Adacel and Adacel-Polio in pregnancy.
Lastly, the findings of individual studies may not be generalizable to all populations. However, the variety of studies included in the SLR support the consistent effectiveness, immunogenicity, and safety of Adacel and Adacel-Polio for use in pregnancy in a range of different populations.
Conclusion
Both Adacel and Adacel-Polio have been shown to be highly effective in preventing pertussis disease in young infants prior to the start of their primary pertussis vaccination series. This high VE is the result of transplacental antibody transfer from the mother to the fetus, resulting in higher pertussis antibody levels in infants of women vaccinated with Adacel/Adacel-Polio during pregnancy compared to those not vaccinated. Additionally, both Adacel and Adacel-Polio were well tolerated in pregnant women and not associated with any increased risk of pregnancy complications, adverse birth outcome, or AEs in the newborn.
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Acknowledgements
The authors would like to thank Dr Vitali Pool (Sanofi) for his indispensable assistance with updates to the systematic literature review and for his valuable input during the development of this article.
Funding
The work, journal Rapid Service Fee, and medical writing assistance were funded by Sanofi, Lyon, France.
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Dr Andrew Lane (Lane Medical Writing) provided medical writing assistance, funded by Sanofi, in the preparation and development of the manuscript in accordance with the European Medical Writers Association guidelines and Good Publication Practice. The authors also thank Roopsha Brahma, PhD for editorial assistance and manuscript coordination on behalf of Sanofi.
Author Contributions
Liana R. Clark and David R. Johnson developed the idea for this review. Liana R. Clark performed the literature search and data analysis. Liana R. Clark and David R. Johnson drafted and/or critically revised the work.
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Liana R. Clark and David R. Johnson are employees of Sanofi.
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This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.
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Clark, L.R., Johnson, D.R. Safety and Clinical Benefits of Adacel® and Adacel®-Polio Vaccination in Pregnancy: A Structured Literature Review. Infect Dis Ther 12, 1955–2003 (2023). https://doi.org/10.1007/s40121-023-00847-5
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DOI: https://doi.org/10.1007/s40121-023-00847-5