Objective
Severe pertussis infection has been reported in infants before receiving routine immunization series. This problem could be solved by vaccinating mothers during pregnancy or children at birth. This study aimed to conduct a systematic review and meta-analysis of randomized controlled trials (RCTs) and real-world evidence to evaluate the optimal strategy for pertussis vaccination.
Data Sources
PubMed, Embase, and the Cochrane Library databases were searched until December 2020.
Study Eligibility Criteria
RCTs, cohort studies, case-control studies, and case series were included if they investigated the efficacy, immunogenicity, and safety of acellular pertussis vaccine during pregnancy and at birth.
Methods
Number of pertussis cases, severe adverse events (SAEs), and pertussis antibody concentration in infants before and after they receive routine vaccination series were extracted and random-effect model was used to pool the analyses.
Results
Overall, 29 studies were included. Our meta-analysis revealed that pertussis immunization during pregnancy significantly increased the concentrations of 3 pertussis antibodies and reduced the incidence rates of infected infants below 3 months of age (odds ratio, 0.22; 95% confidence interval, 0.14–0.33). Similarly, infants vaccinated at birth had higher levels of pertussis antibody than those who were not. No significant difference in rates of severe adverse events was seen in all vaccination groups (during pregnancy [risk ratio, 1.18; 95% confidence interval, 0.76–1.82] and at birth [risk ratio, 0.72; 95% confidence interval, 0.34–1.54]).
Conclusion
Pertussis vaccination during pregnancy could protect infants against pertussis disease before the routine vaccination. Pertussis immunization at birth would be an alternative for infants whose mothers did not receive pertussis vaccines during pregnancy.
Why was this study conducted?
Severe pertussis infection has been reported in infants before receiving routine immunization series. This study aimed to evaluate the efficacy, immunogenicity, and safety of pertussis vaccination during pregnancy and at birth.
Key findings
Administering the pertussis vaccine during pregnancy and at birth was safe and significantly increased pertussis antibody concentration in infants before the primary vaccination schedule. Maternal immunization significantly reduced the incidence of pertussis in infants aged <3 months.
What does this add to what is known?
A national maternal immunization program could be considered to protect infants against pertussis before routine vaccinations. Furthermore, neonatal immunization could be an alternative for infants of mothers who did not receive a pertussis vaccine during pregnancy.
Introduction
Pertussis is a highly contagious disease caused by Bordetella pertussis . It is endemic worldwide, especially in developing countries. Unfortunately, despite routine immunization programs considerably reducing the number of cases and mortality rates, the incidence rates and number of severe cases remain high in infants who are yet to receive the primary vaccination series—more than 1000 cases per 100,000 infants during outbreaks. According to the Global Burden of Disease Study, approximately 400 pertussis-associated deaths per million live births occurred among infants aged <1 year in 2013. Furthermore, during the 2010 pertussis outbreak in the United States, 10 deaths among 9000 pertussis infections occurred in infants <3 months of age.
Several strategies, such as cocooning or vaccination during pregnancy, during the postpartum period, or at birth, have been introduced to prevent pertussis in infants before they receive their first doses of routine vaccines. The efficacy of cocooning immunization remains uncertain because of the lack of cost-effectiveness and need to vaccinate several caregivers around the vulnerable infant. Furthermore, postpartum vaccination only protects the mother and fails to induce the infant’s immunity. Earlier implementation of vaccine, that is, during pregnancy, could increase the child’s level of antibodies and reduce hospitalizations, but many controversies surrounding the optimal timing, safety, and interference of maternal antibodies, have remained. Finally, little evidence exists for the efficacy and safety of vaccination at birth. Although Provenzano et al and Halsey et al have suggested using whole-cell vaccines to induce immune tolerance and limit maternal immunologic responses, other studies have demonstrated adequate immunogenicity among infants receiving the acellular vaccines.
Nevertheless, vaccinating mothers and their children at birth could potentially prevent early severe pertussis cases and was the focus of this study. Although a randomized controlled trial (RCT) is generally considered to be the most reliable study design to report intervention effectiveness, it lacks the ability to represent the wider and more heterogeneous population of pertussis cases, whose evidence is found in real-world data, such as cohort studies and case-control studies. Therefore, we conducted a systematic review, a meta-analysis of RCTs, and real-world data study to investigate the efficacy, immunogenicity, and safety of acellular pertussis vaccine during pregnancy and at birth.
Methods
Search strategy
PubMed or MEDLINE, Embase, and the Cochrane Library databases were searched using a combination of medical subject headings and key words (Methods in Supplemental data ). In addition, we searched ClinicalTrials.gov and relevant papers manually for further studies. The search started from the inception of the study to December 2020. This study was registered a priori in the online International Prospective Register of Systematic Reviews (registration number: CRD42020160746).
Selection criteria
RCTs, cohort studies, case-control studies, and case series were included in this analysis when (1) efficacy, (2) immunogenicity, or (3) severe adverse events (SAEs) of pertussis vaccination were evaluated in either of the 2 following scenarios. First, they were compared between infants whose mothers received pertussis vaccines during pregnancy and infants whose mothers did not (comparison number 1). Second, they were compared between infants vaccinated at birth and those who were not (comparison number 2). All infants received pertussis vaccines from 2 or 3 months of age according to the routine immunization program. Non-English studies were included in our analysis. We excluded studies on nonhuman cases, preterm newborns, or those that did not report on the 3 aforementioned measurements.
Data extraction
Here, 2 researchers (H.S.N. and N.P.V.) screened the papers identified and then extracted the baseline and outcome data independently. A third author (K.W.T.) made the final decision in case of any disagreements. The following data were extracted: author, year of publication, period of study, inclusion criteria, primary vaccination schedule, number of participants, intervention, outcome data, and vaccine manufacturer. We contacted the authors for additional information if necessary.
Methodological quality appraisal
Quality appraisal was independently performed by 2 reviewers (H.S.N. and N.P.V.) using the recommendations from the Cochrane Collaboration. The risk of bias for RCTs was assessed using the version 2 of the Cochrane risk-of-bias tool for randomized trials (RoB 2). For nonrandomized studies, the Risk Of Bias In Non-randomized Studies-of Interventions (ROBINS-I) tool was used. The third author (K.W.T.) resolved all disagreements.
Outcomes
The primary outcomes were (1) the immunogenicity of the pertussis vaccine, (2) incidence rates of pertussis, or (3) SAEs between the intervention and control groups. Immunogenicity was defined as the child’s plasma concentrations of antigen-specific antibodies: antipertussis toxin (anti-PT), antifilamentous hemagglutinin (anti-FHA), and antipertactin (anti-PRN) immunoglobulin G (IgG) measured at 3 time points (umbilical cord blood and before and after the primary vaccination schedules). SAEs were defined and classified according to the World Health Organization (WHO) definition. Secondary outcomes were to assess whether antibody concentration in umbilical cord arterial serum varies according to different gestational ages at vaccination (early vs late in the third trimester of pregnancy).
Statistical analyses
This meta-analysis was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The Review Manager software package (RevMan version 5.3, Cochrane Collaboration) was used to analyze the extracted data. The incidence of pertussis was presented as odds ratios (ORs) and 95% confidence intervals (CIs), calculated using the Mantel-Haenszel method. Vaccine efficacy was calculated as 1 minus OR based on the definition from the WHO. As most studies reported the geometric mean concentration for levels of antibodies, we converted these to natural logarithm and, hence, from log-normal to normal distributions for all studies. Moreover, as the studies used different assays to measure antibody levels, the immunogenicity of the pertussis vaccine was reported as standardized mean differences (SMDs) and 95% CIs, calculated using the inverse variance method. Risk ratios (RRs) with 95% CIs were used to evaluate SAEs. The random effect model was used for the pooled estimate of effect sizes.
Heterogeneity among studies was evaluated using both the Cochrane Q tests and I 2 statistics. When I 2 statistics were higher than 50% or the P value was lower than .10, heterogeneity was considered significant. In addition, subgroup analyses were performed for different study designs: RCTs, cohort studies, or case-control studies.
Results
Study selection
The selection procedure and screened studies are presented in a PRISMA flowchart ( Figure 1 ). Overall, the systematic review included 26 studies , comparing pertussis vaccination with no vaccination during pregnancy ( Table 1 ) and 6 studies , , comparing infants vaccinated at birth with those who were not ( Table 2 ). Furthermore, meta-analysis was performed on 29 studies, , , , , , of which 24 studies were carried out in pregnant women , , , and 5 studies in neonates. , , Acellular pertussis vaccine was used for both the intervention and the routine vaccination series groups.
| Author (year) | Place | Inclusion criteria | Primary pertussis vaccination schedule | Number of participants | Intervention | Period of study | Vaccine manufacturer applied in the intervention |
|---|---|---|---|---|---|---|---|
| Randomized control trial study | |||||||
| Barug et al (2019) | The Netherlands | Mother: no pregnancy abnormalities, no pertussis vaccination <5 y, no Td vaccine <2 y, no vaccine <2 wk. Infant: healthy and >37 wk of gestation | 3 and 5 mo | T1: 53 T2: 50 | T1: Tdap vaccination at 30–32 wk T2: Tdap vaccination within 48 h after delivery | January 2014 to March 2016 | GSK |
| Halperin et al (2018) | Canada | Mother: no pregnancy abnormalities, no pertussis <5 y, no Td or Tdap vaccine <5 y, no vaccine <2 wk. Infants: healthy with no medical condition | 2, 4, and 6 mo | T: 135 C: 138 | T: Tdap vaccination at 30.0–35.7 wk C: Td vaccination at 30.0–35.7 wk | March 2012 to April 2014 | Sanofi Pasteur |
| Hoang et al (2016) | Vietnam | Mother: no Tdap <10 y, no Td <1 mo, no fever <72 h. Infant: healthy with no medical condition | 2, 3, and 4 mo | T: 52 C: 51 | T: Tdap vaccination at 18–32 wk C: vaccinated only Tetanus at 18–32 wk | December 2012 to December 2014 | Sanofi Pasteur |
| Munoz et al (2014) | United States | Mother: no pregnancy abnormalities, no Tdap or Td <2 y, no vaccines <4 wk, no influenza vaccine <2 wk, no fever <72 h | 2, 4, and 6 mo | T1: 33 T2: 15 | T1: Tdap vaccination at 30–32 wk T2: Tdap vaccination after birth | October 2008 to May 2012 | Sanofi Pasteur |
| Perrett et al (2020) | Australia, Canada, Czech Republic, Finland, Italy, Spain | Mother: no pregnancy abnormalities, no Tdap during pregnancy, no pertussis <5 y, no vaccine <30 d, no fever <72 h | 2 and 4 mo in Spain 3 and 5 mo in Finland and Italy 2, 3, and 4 mo in the Czech Republic 2, 4, and 6 mo in Australia, Canada, and Spain | T: 341 C: 346 | T: Tdap vaccination at 27–36 wk C: no aP vaccine during pregnancy | October 2015 to October 2017 | GSK |
| Villarreal Pérez et al (2017) | Mexico | Mother: no pregnancy abnormalities, no Tdap or Td vaccine <2 y, no fever <72 h | 2, 4, and 6 mo | T: 90 C: 81 | T: Tdap vaccination at 30–32 wk C: no aP vaccine during pregnancy | September 2011 to August 2014 | Sanofi Pasteur |
| Prospective cohort study | |||||||
| Abu Raya et al (2014) | Israel | Mother: no pregnancy abnormalities, no pertussis <5 y, no Td or Tdap vaccine <5 y, no vaccine <2 wk. Infants: weight >2000 g | NA | T: 51 C: 20 | T: Tdap vaccination at 23–36 wk C: no aP vaccine during pregnancy | November 2013 to May 2014 | GSK |
| Fallo et al (2018) | Argentina | Mother: no pregnancy abnormalities and no cough that lasted >2 wk. Infants: weight >2000 g | 2, 4, and 6 mo | T: 105 C: 99 | T: Tdap vaccination at 13.2–36.6 wk C: no aP vaccine during pregnancy | 2011 to 2014 | NA |
| Gall et al (2011) | United States | NA | 2, 4, and 6 mo | T: 52 C: 52 | T: Tdap during the second trimester of pregnancy C: no aP vaccine during pregnancy | October 2008 to December 2009 | Sanofi Pasteur |
| Hardy-Fairbanks et al (2013) | United States | Mother: no pregnancy abnormalities Infants: healthy and >37 wk of gestation | 2, 4, and 6 mo | T: 16 C: 54 | T: Tdap vaccination at 16–36 wk C: no aP vaccine during pregnancy | March 2008 to February 2009 | Sanofi Pasteur |
| Healy et al (2018) | United States | Infants: healthy and >37 wk of gestation | 2, 4, and 6 mo | T: 312 C: 314 | T: Tdap vaccination at 27–36 wk and ≥14 d before birth C: no aP vaccine during pregnancy | December 2013 to March 2014 | Sanofi Pasteur |
| Healy et al (2013) | United States | Mother: no pregnancy abnormalities, Tdap vaccine <2 y. Infants: >37 wk of gestation | 2, 4, and 6 mo | T1: 19 T2: 86 | T1: Tdap vaccination at 1–28 wk T2: Tdap vaccination before pregnancy within the prior 2 y | June 2009 to May 2011 | Sanofi Pasteur |
| Hincapié-Palacio et al (2018) | Colombia | Mother: no pregnancy abnormalities, no fever <72 h. Infants: >37 wk of gestation. Pertussis cases: confirmation by PCR or laboratory test + epidemiology or clinical criteria and occurring <6 mo | 2, 4, and 6 mo | T: 745 C: 260 | T: Tdap vaccination at 30–36 wk C: no aP vaccine during pregnancy | December 2015 to April 2016 | Sanofi Pasteur |
| Ladhani et al (2015) | England | Infant: ≥37 wk of gestation | 2, 3, and 4 mo | T: 141 C: 246 | T: Tdap vaccination at 28–38 wk C: no aP vaccine during pregnancy | December 2012 to July 2014 | Sanofi Pasteur |
| Lima et al (2019) | Brazil | Mother: no pregnancy abnormalities and no pertussis vaccination. Infants: healthy with adequate weight for the gestational age | 2, 4, and 6 mo | T: 66 C: 101 | T: Tdap vaccination at 30–36 wk C: no aP vaccine during pregnancy | NA | GSK |
| Maertens et al (2016) | Belgium | Mother: no pregnancy abnormalities, no Tdap vaccine <10 y, no vaccine <4 wk, no fever <72 h. Infants: healthy with no medical condition | 2, 3, and 4 mo | T: 57 C: 42 | T: Tdap vaccination at 22–33 wk C: Tdap vaccination after birth | February 2012 to December 2016 | GSK |
| Naidu et al (2016) | Australia | Mother: no pregnancy abnormalities, no Tdap in pregnancy. Infants: >37 wk of gestation | NA | T1: 53 T2: 62 C: 39 | T1: Tdap vaccination at 28–32 wk T2: Tdap vaccination at 32–36 wk C: no aP vaccine during pregnancy | April 2014 to September 2014 | NA |
| Rice et al (2019) | United Kingdom | Mother: no pregnancy abnormalities | 2, 3, and 4 mo | T: 16 C: 15 | T: vaccinated at 30–32 wk C: no aP vaccine during pregnancy | May 2014 to September 2016 | Sanofi Pasteur or GSK |
| Retrospective cohort study | |||||||
| Baxter et al (2017) | United States | Mothers: born <1996 g. Infants: >37 wk of gestation. Pertussis case: confirmation by PCR and occurring <8 wk and <1 y | 2, 4, and 6 mo | T: 68,168 C: 79,292 | T: Tdap vaccination during pregnancy until ≥8 d before birth C: no aP vaccine during pregnancy | 2006 to 2015 | Sanofi Pasteur or GSK |
| Griffin et al (2018) | New Zealand | Mothers: Mother: >20 wk of gestation. Infants: >400 g and >28 wk of gestation | NA | T: 8178 C: 60,372 | T: Tdap vaccination at 28–38 wk C: no aP vaccine during pregnancy | 2013 | GSK |
| Winter et al (2017) | United States | Mother: no pregnancy abnormalities. Infants: >27 wk of gestation and weighted >500 g. Pertussis case: confirmation by PCR or laboratory test or clinical criteria and occurring <8 wk and <1 y | NA | T1: 42,941 T2: 31,563 | T1: Tdap vaccination at 27–36 wk T2: Tdap vaccination postpartum | 2013 to 2014 | NA |
| Case-control study | |||||||
| Dabrera et al (2015) | United Kingdom | Pertussis case: confirmation by PCR or laboratory test and occurring <8 wk | NA | T: 49 C: 64 | T: Tdap vaccination at 26–38 wk C: no aP vaccine during pregnancy | 2013 to 2014 | NA |
| Bellido-Blasco et al (2017) | Spain | Pertussis case: confirmation by PCR and occurring <12 wk | 2, 4, and 6 mo | T: 46 C: 42 | T: Tdap vaccination at 28–36 wk C: no aP vaccine during pregnancy | March 2015 to February. 2016 | NA |
| Fernandes et al (2019) | Brazil | Infants >36 wk of gestation and weighed >2500 g. Pertussis cases: clinical criteria and occurring <8 wk | 2, 4, and 6 mo | T: 151 C: 139 | T: Tdap vaccination at 18–37 wk C: no aP vaccine during pregnancy | February 2015 to July 2016 | GSK |
| Saul et al (2018) | Australia | Pertussis case: confirmation by PCR or laboratory test or clinical criteria and occurring <12 wk and <6 mo | NA | T: 48 C: 48 | T: Tdap vaccination during pregnancy until ≥8 d before birth C: no aP vaccine during pregnancy | February 2015 to July 2016 | GSK |
| Skoff et al (2017) | Portland | Infants: >37 wk of gestation. Pertussis case: confirmation by PCR or laboratory test or laboratory test + epidemiology or clinical criteria and occurring <8 wk | NA | T: 139 C: 636 | T: Tdap vaccination during pregnancy until ≥8 d before birth C: no aP vaccine during pregnancy | January 2011 to December 2014 | Sanofi Pasteur or GSK |
| Author (year) | Place | Inclusion criteria | Primary pertussis vaccination schedule | Number of participants | Intervention | Period of study | Vaccine manufacturer applied in the intervention |
|---|---|---|---|---|---|---|---|
| Randomized control trial study | |||||||
| Belloni et al (2003) | Italy | Mother: no pregnancy abnormalities. Infant: healthy and 36–42 wk of gestation | 3 and 5 mo | T: 45 C: 46 | T: vaccinated aP on the fourth d of birth C: no aP at birth | January 1999 to August 1999 | Biocine |
| Halasa et al (2008) | United States | Mother: no pregnancy abnormalities. Infant: healthy and ≥36 wk of gestation | 2, 4, and 6 mo | T: 25 C: 25 | T: vaccinated DTaP within 2–14 d of birth C: no aP at birth | February 2004 to August 2004 | Sanofi Pasteur |
| Knuf et al (2008) | Germany | Mother: no pregnancy abnormalities. Infant: healthy and 36–42 wk of gestation | 2, 4, and 6 mo | T: 60 C: 61 | T: vaccinated aP within 2–5 d of birth C: no aP at birth | July 2004 to April 2006 | GSK |
| Wood et al (2018) | Australia | Mother: no pregnancy abnormalities, no Tdap vaccine <5 y, and no pertussis <5 y. Infant: healthy and ≥36 wk of gestation | 1.5, 4.0, and 6.0 mo | T: 221 C: 219 | T: vaccinated aP within 5 d of birth C: no aP at birth | June 2010 to March 2013 | GSK |
| Wood et al (2010) | Australia | Mother: no pregnancy abnormalities. Infant: healthy and ≥36 wk of gestation | 2, 4, and 6 mo | T: 27 C: 26 | T: vaccinated aP within 5 d of birth C: no aP at birth | February 2005 to March 2007 | GSK |
| Prospective cohort study | |||||||
| White et al (2010) | Australia | Infant: healthy with no medical condition | 2, 4, and 6 mo | T: 11 C: 10 | T: vaccinated aP within 5 d of birth C: no aP at birth | NA | GSK |
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