Circulation of Bordetella pertussis in the Caribbean Netherlands: a population-based seroepidemiological study

Open AccessPublished:August 15, 2021DOI:https://doi.org/10.1016/j.ijid.2021.08.025

      Highlights

      • B. pertussis circulation in the Caribbean Netherlands is vastly underestimated
      • 8.2% of residents aged ≥ 9 years were infected with B. pertussis in the past year
      • The highest frequency of recent B. pertussis infections was on Bonaire (8.6%)
      • Risk factors for infection included age 12–29 years and Dutch Caribbean origin
      • Seroepidemiological studies are essential for monitoring B. pertussis circulation

      Abstract

      Objectives

      Pertussis is a respiratory infectious disease caused by Bordetella pertussis. In the Caribbean Netherlands (CN), comprising the islands Bonaire, St Eustatius, and Saba, registration of cases is mandatory for disease surveillance. However, insufficient laboratory facilities hamper case confirmation, and circulation persists. The aim of this seroepidemiological study was to gain insight into B. pertussis circulation in CN, and to investigate what factors contribute to the risk of infection.

      Methods

      Blood samples and questionnaires were collected for 1829 participants aged 0–90 years. Concentrations of B. pertussis toxin-specific IgG antibodies (anti-Pt) were determined using a bead-based immunoassay to indicate infections within the previous 12 months (based on anti-Pt ≥ 50 IU/mL) in participants without detectable vaccine-induced humoral immunity. Risk factors for recent infection were analyzed using logistic regression models.

      Results

      An estimated 8.2% (95% CI 6.6–10.1) of CN residents aged ≥ 9 years were found to have been recently infected by B. pertussis. Risk factors for a recent infection were age 12–29 years (13.8–14.6%) and Dutch Caribbean or Surinamese origin (10.7%).

      Conclusions

      B. pertussis infections occur frequently among CN residents aged ≥ 9 years, although few clinical pertussis cases are reported. Transmission to vulnerable individuals seems likely and should be taken into account in optimizing vaccination programs.

      Keywords

      Introduction

      Pertussis or whooping cough is a highly contagious respiratory disease caused mainly by the bacterium Bordetella pertussis. Infants too young to be vaccinated are the most vulnerable to severe complications, such as pneumonia, which often leads to hospitalization and sometimes death (
      • van der Maas NA
      • van Aerde K
      • Bont LJ
      • Bekker MN
      • Rots N
      • de Melker HE.
      [Infection prevention in newborns through maternal vaccination: current insights and developments.].
      ;
      • Vegelin AL
      • van Vught AJ
      • Wolfs TF
      • Kimpen JL
      • Geelen SP.
      [Pertussis in young infants].
      ). Such infants depend on placentally transferred maternal antibodies for protection against disease (
      • Amirthalingam G
      • Andrews N
      • Campbell H
      • Ribeiro S
      • Kara E
      • Donegan K
      • et al.
      Effectiveness of maternal pertussis vaccination in England: an observational study.
      ;
      • Winter K
      • Nickell S
      • Powell M
      • Harriman K.
      Effectiveness of prenatal versus postpartum tetanus, diphtheria, and acellular pertussis vaccination in preventing infant pertussis.
      ). In older children and adults, pertussis often manifests mildly and symptoms remain unrecognized, whereas adults with comorbidities and the elderly are at higher risk of severe pertussis complications and hospitalization (
      • Edwards K
      • Freeman DM.
      Adolescent and adult pertussis: disease burden and prevention.
      ;
      • Kandeil W
      • Atanasov P
      • Avramioti D
      • Fu J
      • Demarteau N
      • Li X.
      The burden of pertussis in older adults: what is the role of vaccination? A systematic literature review.
      ;
      • Rothstein E
      • Edwards K.
      Health burden of pertussis in adolescents and adults.
      ). Hence, B. pertussis is known to circulate across all age groups in many countries, despite high vaccination coverage, and is readily transmitted by infected persons showing no typical clinical symptoms (
      • Althouse BM
      • Scarpino SV.
      Asymptomatic transmission and the resurgence of Bordetella pertussis.
      ;
      • de Greeff SC
      • de Melker HE
      • van Gageldonk PG
      • Schellekens JF
      • van der Klis FR
      • Mollema L
      • et al.
      Seroprevalence of pertussis in the Netherlands: evidence for increased circulation of Bordetella pertussis.
      ;
      • de Melker HE
      • Schellekens JF
      • Neppelenbroek SE
      • Mooi FR
      • Rumke HC
      • Conyn-van Spaendonck MA.
      Reemergence of pertussis in the highly vaccinated population of the Netherlands: observations on surveillance data.
      ).
      The Caribbean Netherlands (CN) is situated in the Caribbean Sea and comprises three Dutch special municipalities: Bonaire (one of the three Dutch Leeward Antilles, along with Aruba and Curaçao), St Eustatius, and Saba. The latter two, also described as the Windward Islands, are 30 km apart and about 800 km northeast of Bonaire, near St Maarten.
      Hexavalent vaccines containing B. pertussis-specific antigens are administered to infants in CN at 2, 3, and 4 months (m) of age, with booster doses at 11 m and 4 years (y) of age (

      RIVM. Vaccination schedule Bonaire, Saba and St. Eustatius [in Dutch: Vaccinatieschema Bonaire, Saba en St. Eustatius]; 2018. Available from: https://rijksvaccinatieprogramma.nl/vaccinaties/vaccinatieschema. [Accessed October 29, 2020]

      ). Booster vaccination at the age of 4 y was implemented on Saba in 2008, Bonaire in 2014, and St Eustatius in 2016. In 2017, vaccination coverage for infants younger than 2 y ranged between 93% and 100% on the CN islands (
      • Van Lier EA
      • Geraedts JLE
      • Oomen PJ
      • Giesbers H
      • van Vliet JA
      • Drijfhout IH
      • Zonnenberg-Hoff IF
      • de Melker HE
      ). Pertussis cases must be reported and require laboratory confirmation (

      Schurink-van 't Klooster TM, de Melker HE. The national immunisation programme in the Netherlands — surveillance and developments in 2019–2020. 2020a.

      ). In 2017, six confirmed cases of clinical pertussis were reported on Bonaire, including two unvaccinated neonates, two children aged 1 and 12 y, and two adults (

      Schurink-van 't Klooster TM, de Melker HE. The national immunization programme in the Netherlands 2018–2019. 2020b.

      ). These represented an incidence of 30 per 100 000 on Bonaire (the total number of residents on Bonaire is ∼20 000) versus an average of 2.5 per 100 000 in Latin America in 2000–2015 and 28.7 per 100 000 in the Netherlands in 2017 (
      • Folaranmi T
      • Pinell-McNamara V
      • Griffith M
      • Hao Y
      • Coronado F
      • Briere EC.
      Systematic review and meta-analysis of pertussis epidemiology in Latin America and the Caribbean: 1980–2015.
      ;

      Schurink-van 't Klooster TM, de Melker HE. The national immunisation programme in the Netherlands — surveillance and developments in 2019–2020. 2020a.

      ). St Eustatius and Saba reported some suspected pertussis cases, but these were not confirmed due to a lack of laboratory facilities (

      Schurink-van 't Klooster TM, de Melker HE. The national immunisation programme in the Netherlands — surveillance and developments in 2019–2020. 2020a.

      ). Clinical diagnosis also depends on the awareness among general practitioners of pertussis disease, particularly its mild form, and the reluctance of the public to seek medical attention. Incidence rates based on case reporting are therefore likely to be underestimated (
      • Barkoff AM
      • Grondahl-Yli-Hannuksela K
      • He Q.
      Seroprevalence studies of pertussis: what have we learned from different immunized populations.
      ). These challenges to accurate pertussis disease surveillance emphasize the need for alternative surveillance strategies.
      Antibodies are induced shortly after natural B. pertussis infection or immunization, and wane to half their peak concentration in 12–20 m (
      • Berbers GA
      • van de Wetering MS
      • van Gageldonk PG
      • Schellekens JF
      • Versteegh FG
      • Teunis PF.
      A novel method for evaluating natural and vaccine induced serological responses to Bordetella pertussis antigens.
      ). In recently vaccinated people, high concentrations of IgG against B. pertussis toxin (Pt) reflect a vaccine-induced antibody response. In persons not vaccinated within the previous 5 years, a concentration of anti-Pt IgG ≥ 50 international units (IU)/mL indicates an infection within the previous 12 months (
      • Althouse BM
      • Scarpino SV.
      Asymptomatic transmission and the resurgence of Bordetella pertussis.
      ;
      • Barkoff AM
      • Grondahl-Yli-Hannuksela K
      • He Q.
      Seroprevalence studies of pertussis: what have we learned from different immunized populations.
      ). Lower concentrations of anti-Pt IgG indicate less recent pertussis infections (
      • van der Lee S
      • Stoof SP
      • van Ravenhorst MB
      • van Gageldonk PGM
      • van der Maas NAT
      • Sanders EAM
      • et al.
      Enhanced Bordetella pertussis acquisition rate in adolescents during the 2012 epidemic in the Netherlands and evidence for prolonged antibody persistence after infection.
      ).
      The aims of this seroepidemiological study were to gain knowledge about the circulation of B. pertussis on the islands of CN by tracing the frequencies of recent infections, and to investigate the risk factors for infection with B. pertussis.

      Methods

       Population and setting

      Details of the study design, data collection, and sample size calculation have been described previously (
      • Verberk JDM
      • Vos RA
      • Mollema L
      • van Vliet J
      • van Weert JWM
      • de Melker HE
      • et al.
      Third national biobank for population-based seroprevalence studies in the Netherlands, including the Caribbean Netherlands.
      ). Briefly, on each island an age-stratified random sample of people aged 0–11, 12–17, 18–34, 35–59, and 60–90 y was drawn from the population registry (PIVA-V, January 1, 2017). In total, 8068 residents were invited for participation (Bonaire n = 4798, St Eustatius n = 2135, and Saba n = 1135), based on an age-specific precision ranging between 5.5% and 10%, an alpha of 5%, and an expected response rate of 30%. For each participant, a blood sample was taken by finger prick (or heel prick for infants) and collected as dried blood spots on Whatman® 903 protein-saver cards. Subsequently, a questionnaire and vaccination certificate for each participant were shared with the research staff. If certificates were unavailable, records were requested from the local public health service or hospital. Informed consent was provided by each participant or his/her guardian.

       Laboratory analyses

      Blood samples were transferred to the National Institute for Public Health and the Environment (RIVM) in the Netherlands and stored at −80°C, awaiting analyses. A 3.2 mm punch was taken from each dried blood spot and incubated in assay buffer (PBS supplemented with 3% BSA and 0.1% Tween-20) at 4°C overnight on a shaker to release serum (
      • Hannon WH.
      Blood collection on filter paper for newborn screening programs.
      ;
      • Mei JV
      • Alexander JR
      • Adam BW
      • Hannon WH.
      Use of filter paper for the collection and analysis of human whole blood specimens.
      ). Sera were tested at 1:200 and 1:4000 dilutions. Concentrations of anti-Pt IgG were determined by a fluorescent bead-based immunoassay using a Luminex LX200 machine (
      • van Gageldonk PG
      • van Schaijk FG
      • van der Klis FR
      • Berbers GA.
      Development and validation of a multiplex immunoassay for the simultaneous determination of serum antibodies to Bordetella pertussis, diphtheria and tetanus.
      ). Standard sera and controls were used on each plate, and sera were calibrated against the World Health Organization International Standard Pertussis Antiserum (serum reference 06/140). Native Pt (Netherlands Vaccine Institute, no. peg004) was used. The lower limit of quantification was restricted by the number of dilutions made for the reference line; therefore, 0.85 IU/mL was used in our dataset.

       Statistical analyses

       Age-specific prevalence of increased anti-Pt IgG and geometric mean concentrations (GMC)

      Analyses were performed using R software, version 4.0.4. Anti-Pt IgG concentrations were divided into four categories: ≥ 100 IU/mL; 50 to < 100 IU/mL; 5 to < 50 IU/mL; and < 5 IU/mL. For persons aged 9 y and older and unvaccinated children, these categories indicated recent infection in the previous 6 m (≥ 100 IU/mL), or in the previous 6–12 m (50 to < 100 IU/mL), or no recent infection (5 to < 50 IU/mL and < 5 IU/mL). The cut-offs were based on studies investigating anti-Pt IgG concentrations in relation to waning immunity following vaccination and (re)infection (
      • de Greeff SC
      • de Melker HE
      • van Gageldonk PG
      • Schellekens JF
      • van der Klis FR
      • Mollema L
      • et al.
      Seroprevalence of pertussis in the Netherlands: evidence for increased circulation of Bordetella pertussis.
      ;
      • de Melker HE
      • Versteegh FG
      • Conyn-Van Spaendonck MA
      • Elvers LH
      • Berbers GA
      • van Der Zee A
      • et al.
      Specificity and sensitivity of high levels of immunoglobulin G antibodies against pertussis toxin in a single serum sample for diagnosis of infection with Bordetella pertussis.
      ;
      • van der Lee S
      • Stoof SP
      • van Ravenhorst MB
      • van Gageldonk PGM
      • van der Maas NAT
      • Sanders EAM
      • et al.
      Enhanced Bordetella pertussis acquisition rate in adolescents during the 2012 epidemic in the Netherlands and evidence for prolonged antibody persistence after infection.
      ). Recent infections during the previous 12 months were used as the primary outcome, and recent infections during the previous 6 months as the secondary outcome. Anti-Pt IgG concentrations induced by the booster vaccination at ∼4 y of age can increase up to 9 y of age (Figure 1A) and thus interfere with analyses aimed at determining recent infections. To ensure that increased concentrations are due to a recent infection and not falsely induced by a missed vaccination, children younger than 9 y were excluded from the analyses. This cut-off was set at 9 y because the booster vaccine at ∼4 y is administered as part of a school-based program, and the timing of its administration may fluctuate.
      Figure 1
      Figure 1Individual anti-Pt IgG concentrations (IU/mL) and weighted age-specific prevalence of a recent infection and GMCs. Panel A shows vaccine-induced responses of anti-Pt in children who received at least one pertussis-containing vaccine. The generalized additive model spline with eight knots indicates waning of anti-Pt IgG; a cut-off for the arbitrary age when children may be yet susceptible to B. pertussis infection was placed at 9 y (lowest concentration of anti-Pt IgG in this graph). Panel B shows the prevalence of recent infection in four categories: twice, no recent infection (< 5 IU/mL or 5 to < 50 IU/mL), in the last 6–12 months (50 to < 100 IU/mL), and in the previous 6 months (≥ 100 IU/mL). It also shows GMCs with corresponding 95% CIs.
      Participants were assigned sampling weights to match the population distribution on each island, taking into account age, sex, and country of birth (and neighborhood for residents of Bonaire). Weighted age-specific prevalences with corresponding 95% confidence intervals (CI) were estimated. To increase power, participants from St Eustatius and Saba were combined into a Windward Islands category, which was justified by their close proximity and comparable overall characteristics. Absolute anti-Pt IgG concentrations were log-transformed and expressed in GMCs with corresponding 95% CIs.

       Risk factors for a recent infection

      Univariable logistic regression was used to identify potential risk factors for a recent infection in the previous 12 months (anti-Pt IgG ≥ 50 IU/mL) among participants aged 9 y and older. Participants with missing data for ethnic background (n = 13) or household size (n = 7), and those who had been vaccinated in the previous 5 years (n = 4) were excluded from the analyses (total remaining, n =1484). The following variables were investigated: island of residence, sex, age group, maternal education level, household size, number of ‘yesterday's contacts’ (i.e. on the day before completing the questionnaire), and ethnic background as defined by origin, including the Dutch Caribbean territories — CN (Bonaire, Saba, and St Eustatius), Aruba, Curaçao, and St Maarten, plus Suriname, a former Dutch colony on the northeastern coast of South America. The median number of yesterday's contacts was calculated for each age group separately, and participants were subsequently categorized as equal/higher or lower than the median.
      Variables with a p-value of < 0.10 in the univariable analyses were selected for multivariable logistic regression, along with a priori controlling for age group and island of residence, following the sample design. Individual variables contributing to the risk of infection were identified by performing stepwise backward selection. A p-value < 0.05 was considered significant. Odds ratios (ORs), corresponding 95% CIs, and p-values of variables in univariable analyses and multivariable analyses were provided. Sensitivity analyses were performed to explore recent infections in the previous 6 months (anti-Pt IgG ≥ 100 IU/mL) as the dependent variable (Appendix 2).

      Results

       Study sample and demographics

      Our study included 1900 participants, of whom 1829 individuals or their guardians provided a questionnaire and blood sample. Most of them resided on Bonaire (1129, 61.7%), followed by St Eustatius (477, 26.1%), and Saba (223, 12.2%) (Table 1). Participants’ ages ranged from 3 m to 90 y, and 824 (45.1%) were male. Most participants originated from the Dutch Caribbean territories or Suriname (1312, 72.2%), followed by Latin America or other non-Western countries (281, 15.5%), and European Netherlands or other Western countries (223, 12.2%). The majority of children under 9 y (265 of 321; 82.5%) had been vaccinated against pertussis at least four times; 38 (11.8%) had received up to three doses, and 18 (5.6%) were most likely unvaccinated. Six participants had been vaccinated against pertussis at 9 y or older — four of these during the previous 5 years.
      Table 1Sociodemographic characteristics and vaccination histories of participants with a blood sample in the Health Study Caribbean Netherlands, by island
      Sociodemographic characteristics and vaccination historyBonaire, n (%)n = 1129 (61.7)St Eustatius, n (%)n = 477 (26.1)Saba, n (%)n = 223 (12.2)Total, n (%)n = 1829
      Sex
      Male506 (44.8)221 (46.3)97 (43.5)824 (45.1)
      Female623 (55.2)256 (53.7)126 (56.5)1005 (54.9)
      Age group, years
      0–8197 (17.4)87 (18.2)37 (16.6)321 (17.6)
      9–17255 (22.6)127 (26.6)37 (16.6)419 (22.9)
      18–29103 (9.1)49 (10.3)23 (10.3)175 (9.6)
      30–44136 (12.0)68 (14.3)34 (15.2)238 (13.0)
      45–59163 (14.4)65 (13.6)35 (15.7)263 (14.4)
      60–90275 (24.4)81 (17.0)57 (25.6)413 (22.6)
      Ethnic background
      Missing data: 13 for ethnic background
      Dutch Caribbean territories
      Dutch Caribbean territories include Bonaire, St Eustatius, and Saba (CN), plus Aruba, Curaçao, and St Maarten. Of the participants with an ethnic background in European Netherlands or other Western countries, 147 (66%) were Dutch. Of those with an ethnic background in Latin America and other non-Western countries, 261 (93%) were born in Latin America.
      or Suriname
      803 (71.2)383 (82.0)126 (57.0)1312 (72.2)
      European Netherlands or other Western countries143 (12.7)30 (6.4)50 (22.6)223 (12.3)
      Latin America or other non-Western countries182 (16.1)54 (11.6)45 (20.4)281 (15.5)
      (Maternal) education level
      Maternal educational level was used for participants aged 0–11 y; active education was used for participants aged 12–25 y, and highest accomplished educational level was used for participants aged > 25 y. Low = no education, primary school, pre-vocational education (VMBO), lower vocational education (LBO/MBO-1), and lower general secondary education (MAVO/VMBO). Middle = intermediate/secondary vocational education (MBO-2-4), higher/senior vocational education (HAVO), and pre-university education (VWO/Gymnasium). High = higher professional education (HBO), university BSc, university MSc, and doctorate
      High172 (15.2)68 (14.3)87 (39.0)327 (17.9)
      Middle298 (26.4)125 (26.2)45 (20.2)468 (25.6)
      Low571 (50.6)232 (48.6)80 (35.9)883 (48.3)
      Unknown88 (7.8)52 (10.9)11 (4.9)151 (8.2)
      Monthly gross income
      High (≥ $3001)197 (17.4)91 (19.1)60 (26.9)348 (19.0)
      Middle ($1501–3000)328 (29.1)88 (18.5)60 (26.9)476 (26.0)
      Low (< $1500)329 (29.1)133 (27.8)56 (25.1518 (28.3)
      Does not want to answer106 (9.4)73 (15.3)23 (10.3)202 (11.1)
      Unknown169 (15.0)92 (19.3)24 (10.8)285 (15.6)
      Number of contacts yesterday
      Higher than or equal to the median per age group
      Overall median number of contacts yesterday was 8.
      532 (47.1)163 (34.2)62 (27.8)757 (41.4)
      Lower than the median per age group520 (46.1)204 (42.8)132 (59.2)856 (46.8)
      Unknown77 (6.8)110 (23.1)29 (13.0)216 (11.8)
      Household size, persons
      Single-person household139 (12.3)51 (10.7)31 (13.9)221 (12.1)
      2–5864 (76.5)350 (73.4)176 (78.9)1390 (76.0)
      ≥ 6119 (10.5)72 (15.1)13 (5.8)204 (11.2)
      Unknown7 (0.6)4 (0.8)3 (1.3)14 (0.8)
      Vaccination history against pertussis
      94.4% of children under 9 y received at least one vaccination against pertussis.
      ≥ 4 doses422 (37.4)226 (47.4)75 (33.6)723 (39.5)
      1–3 doses68 (6.0)35 (7.3)10 (4.5)113 (6.2)
      (Partly) participated in national immunization program (self-reported)498 (44.1)151 (31.7)107 (48.0)756 (41.3)
      Unvaccinated141 (12.5)65 (13.6)31 (13.9)237 (13.0)
      a Dutch Caribbean territories include Bonaire, St Eustatius, and Saba (CN), plus Aruba, Curaçao, and St Maarten. Of the participants with an ethnic background in European Netherlands or other Western countries, 147 (66%) were Dutch. Of those with an ethnic background in Latin America and other non-Western countries, 261 (93%) were born in Latin America.
      b Maternal educational level was used for participants aged 0–11 y; active education was used for participants aged 12–25 y, and highest accomplished educational level was used for participants aged > 25 y. Low = no education, primary school, pre-vocational education (VMBO), lower vocational education (LBO/MBO-1), and lower general secondary education (MAVO/VMBO). Middle = intermediate/secondary vocational education (MBO-2-4), higher/senior vocational education (HAVO), and pre-university education (VWO/Gymnasium). High = higher professional education (HBO), university BSc, university MSc, and doctorate
      c Overall median number of contacts yesterday was 8.
      d 94.4% of children under 9 y received at least one vaccination against pertussis.
      low asterisk Missing data: 13 for ethnic background

       Age-specific GMC and prevalence of increased anti-Pt IgG concentration

      Among children who had received at least one vaccination, anti-Pt IgG had waned to the lowest concentrations by age 9 y (Figure 1A). Overall weighted prevalence of a recent infection in the previous 12 months and GMCs among age groups < 9 y generally followed the vaccination schedule (Appendix 1). Peak GMCs were found within the ages directly after the primary vaccination series, i.e. between 0 and 1 y. After antibodies had waned, GMCs increased significantly again in the ages after booster vaccination, i.e. ∼4 y of age (12.9 IU/mL at 3 y vs 39.0 IU/mL at 4–6 y. GMC decreased significantly in those aged 7–8 y (8.3 IU/mL, 95% CI 5.8–11.8), well below the cut-off for recent infection at 50 IU/mL.
      The overall weighted prevalence of recent infections in the previous 12 months in the ≥ 9y CN population was 8.2% (95% CI 6.6–10.1). This was highest on Bonaire (8.6%, 95% CI 6.6–10.9), followed by St Eustatius (7.4%, 95% CI 4.7–11.0), and Saba (5.7%, 95% CI 2.9–10.0). Participants aged 12–17 y and 18–29 y had the highest prevalence of recent infections in the previous 12 months, i.e. 16.1% (95% CI 11.5–22.6) and 16.7% (95% CI 10.4–24.9), respectively (Figure 1B). The lowest prevalence was in age group 30–44 y, with 4.8% (95% CI 2.4–8.6). Corresponding GMCs of anti-Pt IgG for the 12–17 y and 18–29 y age groups were 8.9 IU/mL (95% CI 7.2–10.9) and 8.5 IU/mL (95% CI 6.2–11.5), respectively. The GMC for the 12–17 y age group was significantly higher than for the 30–44 y age group (5.8 IU/mL, 95% CI 4.8–7.0) (Figure 1B). Subsequently, GMCs of anti-Pt IgG gradually increased in age groups ≥ 45 y, but not significantly. Among those aged 9–17 y, the frequency of recent infections in the previous 12 months differed across the islands of CN, with 14.9% (95% CI 10.6–20.2) on Bonaire vs 5.5% (95% CI 2.7–10.0) on the Windward Islands (Figure 2A). In the 60–90 y age group, the frequency was higher on the Windward Islands (13.1%, 95% CI 7.5-20.6) than on Bonaire (6.4%, 95% CI 3.8–9.9), but not significantly.
      Figure 2
      Figure 2Weighted age-specific prevalence of a recent infection in the previous 12 months (anti-Pt IgG concentration ≥ 50 IU/mL; panel A) or in the previous 6 months (anti-Pt IgG concentration ≥ 100 IU/mL; panel B), stratified for island of residence, with 95% CIs. *The Windward Islands include St Eustatius and Saba. **Number of participants per age group and island of residence.

       Risk factors for a recent infection

      Among the 1484 participants aged ≥ 9 y in CN, 134 had been infected in the previous 12 months. In both univariable and multivariable analyses, age group and ethnic background were significant risk factors for a recent infection (Table 2). The odds were higher in participants aged 9–17 y and 18–29 y compared with those aged 30–44 y, with adjusted ORs of 2.5 (95% CI 1.3–5.2) and 2.8 (95% CI 1.4–6.0), respectively). Participants originating from the European Netherlands or other Western countries had lower odds for recent infection compared with those originating from the Dutch Caribbean territories or Suriname (adjusted OR 0.4, 95% CI 0.2–0.8). In sensitivity analyses exploring the outcomes of recent infections in the previous 6 months (anti-Pt IgG ≥ 100–IU/mL, n = 53), significantly associated risk factors included island of residence (adjusted OR for Bonaire vs Windward Islands 3.6, 95% CI 1.8–8.2) and ethnic background (adjusted OR for Latin America or other non-Western countries vs Dutch Caribbean territories or Suriname 0.3, 95% CI 0.1–0.9) (Appendix 2). ORs for different age groups were in line with the main analysis, but not significantly.
      Table 2Risk factor analysis for a recent infection in the previous 12 months (anti-Pt ≥ 50 IU/mL) among participants aged 9 years and older in the Caribbean Netherlands population
      Potential risk factor for infectionn (%)n = 1484
      Missing data: 13 for ethnic background, seven for household size, four for vaccinated against pertussis in the past 5 years.
      n (%) anti-Pt ≥ 50 IU/mL

      n = 134 (9.0)
      Univariable crude OR (95% CI)p-valueMultivariable adjusted OR (95% CI)p-value
      Island0.3640.522
      Bonaire922 (62.1)89 (9.7)1.2 (0.8–1.9)1.3 (0.8–2.0)
      St Eustatius378 (25.5)31 (8.2)Ref.Ref.
      Saba184 (12.4)14 (7.6)0.9 (0.5–1.8)1.1 (0.6–2.2)
      Sex0.955
      Male645 (43.5)58 (9.0)Ref.
      Female839 (56.5)76 (9.1)1.0 (0.7–1.5)
      Age group, years<0.0001<0.001
      9–11124 (8.4)8 (6.9)1.3 (0.5–3.2)1.1 (0.4–2.7)
      12–17289 (19.5)40 (13.8)3.0 (1.6–6.1)2.5 (1.3–5.2)
      18–29171 (11.5)25 (14.6)3.2 (1.6–6.7)2.8 (1.4–6.0)
      30–44234 (15.8)12 (5.1)Ref.Ref.
      45–59257 (17.3)11 (4.3)0.8 (0.4–1.9)0.8 (0.4–1.9)
      60–90409 (27.6)38 (9.3)1.9 (1.0–3.9)1.8 (0.9–3.6)
      Ethnic background
      Missing data: 13 for ethnic background, seven for household size, four for vaccinated against pertussis in the past 5 years.
      <0.00010.016
      Dutch Caribbean territories or Suriname1016 (68.5)

      109 (10.7)Ref.Ref.
      European Netherlands or other Western countries199 (13.4)

      8 (4.0)0.4 (0.2–0.7)0.4 (0.2–0.8)
      Latin America or other non-Western countries269 (18.1)

      17 (6.3)0.6 (0.3–0.9)0.6 (0.4–1.0)
      (Maternal) education level0.318
      High257 (17.3)22 (8.6)Ref.
      Middle353 (23.8)32 (9.1)1.1 (0.6–1.9)
      Low754 (50.8)73 (9.7)1.2 (0.7–1.9)
      Unknown120 (8.1)7 (5.8)0.7 (0.3–1.5)
      Number of contacts yesterday0.677
      Higher than or equal to the median per age group
      Overall median number of contacts yesterday was 8.
      626 (42.2)61 (9.7)1.0 (0.5–1.5)
      Lower than median per age group686 (46.2)55 (9.3)Ref.
      Unknown172 (11.6)18 (10.5)1.2 (0.7–2.1)
      Household size, persons
      Missing data: 13 for ethnic background, seven for household size, four for vaccinated against pertussis in the past 5 years.
      0.450
      Single-person household218 (14.7)16 (7.3)Ref.
      2–51112 (74.9)103 (9.3)1.3 (0.8–2.3)
      ≥ 6154 (10.4)15 (9.7)1.4 (0.7–2.9)
      a Overall median number of contacts yesterday was 8.
      low asterisk Missing data: 13 for ethnic background, seven for household size, four for vaccinated against pertussis in the past 5 years.

      Discussion

      This was the first seroepidemiological study to investigate recent B. pertussis infections in the general population of CN, comprising the islands of Bonaire, St Eustatius, and Saba. Overall, an estimated 8.2% of CN residents aged ≥ 9 y were recently infected in the previous 12 months. The highest rates were seen in adolescents aged 12–17 y and young adults aged 18–29 y. These results emphasize that B. pertussis is circulating in the general CN population and that circulation is vastly underestimated using reporting systems for clinical pertussis cases. Furthermore, participants who reside on Bonaire and participants originating from the Dutch Caribbean territories or Suriname were most likely to be recently infected with B. pertussis.
      The highest frequency of recent infections with B. pertussis in the previous 12 months was seen in the 12–17 y and 18–29 y age groups, with estimates of 16.1% and 16.7%, respectively. Such high percentages suggest that, despite vaccination, adolescents and young adults are susceptible to contracting pertussis. Their vaccine-induced immunity may have waned, because the fifth dose of a pertussis vaccine (the 4-year booster dose for CN) provides protection for approximately 5 years (
      • McGirr A
      • Fisman DN.
      Duration of pertussis immunity after DTaP immunization: a meta-analysis.
      ;
      • van der Lee S
      • Sanders EAM
      • Berbers GAM
      • Buisman AM.
      Whole-cell or acellular pertussis vaccination in infancy determines IgG subclass profiles to DTaP booster vaccination.
      ). Once infected, adolescents may readily transmit B. pertussis due to clustering in secondary schools (
      • De Serres G
      • Shadmani R
      • Duval B
      • Boulianne N
      • Dery P
      • Douville Fradet M
      • et al.
      Morbidity of pertussis in adolescents and adults.
      ;
      • Wu Y
      • Zhu B
      • Gao Y
      • Shi Z
      • Wang J
      • Wang H
      • et al.
      Clustered cases of Bordetella pertussis infection cause high levels of IgG antibodies against pertussis toxin in adolescents in Gaobeidian city.
      ). The source of infection for adolescents probably lies in fellow schoolmates, from whom it can be passed on to vulnerable individuals, such as unvaccinated infants. Additionally, GMCs of anti-Pt IgG seemed to increase gradually from the age of 45 y to 90 y. The source of exposure in these age groups may lie in those aged 12–29 y, since 35% of those aged 45–59 y in this study reported living in a household with at least one person aged 12-29 y. Moreover, repeated exposure to B. pertussis at older ages may cause longer duration of memory against Pt, which may also explain rises in GMCs in those aged ≥ 45 y (
      • Barkoff AM
      • Grondahl-Yli-Hannuksela K
      • Vuononvirta J
      • Mertsola J
      • Kallonen T
      • He Q.
      Differences in avidity of IgG antibodies to pertussis toxin after acellular pertussis booster vaccination and natural infection.
      ). The high frequency of recent B. pertussis infections among participants originating from the Dutch Caribbean territories or Suriname is not well understood. We hypothesize that such differences based on ethnic background could be related to travel behavior, tourism, and work on the islands of CN, which would contribute to B. pertussis circulation. Additionally, residents of CN may have families in the Netherlands or other European countries, where B. pertussis is also known to circulate in the population. Further data on this topic are lacking and remain implicated for future research.
      A global interpretation of recent B. pertussis infections based on serology has been provided in a review that assessed many population-based studies in countries with different vaccination programs (
      • Barkoff AM
      • Grondahl-Yli-Hannuksela K
      • He Q.
      Seroprevalence studies of pertussis: what have we learned from different immunized populations.
      ). The authors concluded that the number of pertussis cases was underestimated in many countries, which is in line with our results. They also confirmed that the frequency of a recent infection with B. pertussis depended on age, with peak anti-Pt IgG concentrations in adolescents and young adults in studies from Finland, France, the Netherlands, East Germany, Denmark, the USA, and The Gambia (
      • Baughman AL
      • Bisgard KM
      • Edwards KM
      • Guris D
      • Decker MD
      • Holland K
      • et al.
      Establishment of diagnostic cutoff points for levels of serum antibodies to pertussis toxin, filamentous hemagglutinin, and fimbriae in adolescents and adults in the United States.
      ;
      • Cattaneo LA
      • Reed GW
      • Haase DH
      • Wills MJ
      • Edwards KM.
      The seroepidemiology of Bordetella pertussis infections: a study of persons ages 1–65 years.
      ;
      • de Melker HE
      • Versteegh FG
      • Schellekens JF
      • Teunis PF
      • Kretzschmar M.
      The incidence of Bordetella pertussis infections estimated in the population from a combination of serological surveys.
      ;
      • Launay O
      • Toneatti C
      • Bernede C
      • Njamkepo E
      • Petitprez K
      • Leblond A
      • et al.
      Antibodies to tetanus, diphtheria and pertussis among healthy adults vaccinated according to the French vaccination recommendations.
      ;
      • Pebody RG
      • Gay NJ
      • Giammanco A
      • Baron S
      • Schellekens J
      • Tischer A
      • et al.
      The seroepidemiology of Bordetella pertussis infection in Western Europe.
      ;
      • Ronn PF
      • Dalby T
      • Simonsen J
      • Jorgensen CS
      • Linneberg A
      • Krogfelt KA.
      Seroepidemiology of pertussis in a cross-sectional study of an adult general population in Denmark.
      ;
      • Scott S
      • van der Sande M
      • Faye-Joof T
      • Mendy M
      • Sanneh B
      • Barry Jallow F
      • et al.
      Seroprevalence of pertussis in the Gambia: evidence for continued circulation of bordetella pertussis despite high vaccination rates.
      ;
      • Strebel P
      • Nordin J
      • Edwards K
      • Hunt J
      • Besser J
      • Burns S
      • et al.
      Population-based incidence of pertussis among adolescents and adults, Minnesota, 1995–1996.
      ). To our knowledge, only one population-based serosurveillance study has been performed in Latin America. This study was also included in the above-mentioned review. In the Mexican population in 2010, the highest proportion of recent infections (based on anti-Pt IgG ≥ 44 IU/mL) was seen in those aged 50–59 y (
      • Conde-Glez C
      • Lazcano-Ponce E
      • Rojas R
      • DeAntonio R
      • Romano-Mazzotti L
      • Cervantes Y
      • et al.
      Seroprevalence of Bordetella pertussis in the Mexican population: a cross-sectional study.
      ). In contrast with our study, the authors reported no increased risk for a recent infection in adolescents and young adults. This dissimilarity may reflect the fact that Mexican and CN children were vaccinated according to a different vaccination schedule. Moreover, the Mexican study was conducted before a large pertussis epidemic in 2012, which could have led to lower anti-Pt IgG concentrations in younger age groups.
      In the European Netherlands, a nationwide serosurveillance study was conducted simultaneously with our study, and in a similar way (manuscript submitted for publication). Consistent with our results, the authors found an increased risk of a recent infection among adolescents and people living in larger households. Although the frequency of recent infections in large households was slightly higher in our study, its association with CN could not be confirmed. Future seroepidemiological research in other Latin American countries may provide more insight into the risk factors for a B. pertussis infection.
      On Bonaire, the frequency of B. pertussis infections in the previous 6 months was significantly higher than on the Windward Islands, but frequencies did not differ among the islands in the previous 12 months. This finding indicates that Bonaire participants might have been infected shortly before the current study began; it also emphasizes the lack of insight into B. pertussis circulation. Given the frequency of recent infections, we would expect higher numbers of clinical cases to be reported (

      Schurink-van 't Klooster TM, de Melker HE. The national immunization programme in the Netherlands 2018–2019. 2020b.

      ). Enhanced disease surveillance could provide better insight into numbers of pertussis cases, particularly for individuals who are vulnerable to severe disease. As young infants are at risk of severe complications (and unvaccinated neonates were among Bonaire's reported infections), many countries now focus on maternal immunization to prevent transmission of B. pertussis to young infants. Maternal vaccination protects newborns in the first months of life by conferring passive immunity through transplacental antibody transfer. The Netherlands, Saba, and the Latin American countries Argentina, Brazil, Chile, Colombia, Mexico, and Panama have already introduced this strategy in their national immunization programs (

      Mack A. Latin American pertussis workshop: summary of proceedings; 2019. Available from: https://www.sabin.org/sites/sabin.org/files/latin_american_pertussis_meeting_report_english_final.pdf. [Accessed July 16, 2021]

      ). As CN generally follows the developments in the Dutch immunization program, Bonaire and St Eustatius are expected to follow the Netherlands and Saba in adopting this strategy in the near future.
      Our study presented some limitations. Firstly, 45.1% of our study population were males, compared with 51.5% in the CN general population, while people originating from the Dutch Caribbean territories or Suriname were 72.2% of the study population, compared with 59.4% in the general population (

      Statistics-Netherlands-CBS. Caribbean Netherlands; population, gender, age and country of birth; 2017. Available from: https://opendata.cbs.nl/statline/#/CBS/nl/dataset/84712NED/table?ts=1612802577435. [Accessed February 8, 2021]

      ). These dissimilarities are expected to have had little impact on the generalizability of our findings, because we used participants’ sampling weights to correct for selective participation. Secondly, the absolute number of participants with a recent infection was low. Although a relatively large proportion of the population was sampled (7.5%), the low number of recent infections made it challenging to detect small differences, and additional risk factors could have been missed. Lastly, although cut-offs for anti-Pt IgG are often used in seroepidemiological studies, some cases may still have sufficient anti-Pt IgG concentrations to be classified as recently infected, as waning sometimes manifests more slowly. Therefore, the actual number of recent infections may have been overestimated, and the recentness of infection must be interpreted with caution (
      • van der Lee S
      • Stoof SP
      • van Ravenhorst MB
      • van Gageldonk PGM
      • van der Maas NAT
      • Sanders EAM
      • et al.
      Enhanced Bordetella pertussis acquisition rate in adolescents during the 2012 epidemic in the Netherlands and evidence for prolonged antibody persistence after infection.
      ).

      Conclusion

      This seroepidemiological study confirmed that the circulation of B. pertussis in the general population of CN is vastly underestimated using its pertussis reporting systems. Transmission to vulnerable individuals seems likely and should be taken into account in optimizing the vaccination program. Seroepidemiological data should be updated regularly in order to understand the circulation of B. pertussis (
      • Cutts FT
      • Hanson M.
      Seroepidemiology: an underused tool for designing and monitoring vaccination programmes in low- and middle-income countries.
      ). Likewise, monitoring of pertussis epidemiology in CN can be improved by making mild cases more recognizable to the public and the medical community.

      Contributions

      EV, HdM and FvdK designed the study. EV prepared, executed, and coordinated the study on the islands. AJ, SB, and KH contributed to study preparations, logistics, and acquisition of data on the islands, and JvV contributed to logistics in the Netherlands. JK performed the laboratory analyses. EV processed the data. MI performed the epidemiological analyses and interpreted the results under the supervision of EV. MI wrote the manuscript. EV, GdH, HdM, and NvdM critically revised subsequent versions. All authors approved the final version. MI had full access to all study data and takes responsibility for the integrity of the data and the accuracy of the data analysis.

      Funding source

      This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

      Ethical approval

      The study was organized in accordance with the Declaration of Helsinki. Permission to conduct this study was obtained from the North Holland Medical Ethics Review Committee (registered under no. M015-022). Informed consent was provided by each participant or his/her guardian.

      Conflicts of interest

      The authors have no conflicts of interest to declare.

      Appendix. Supplementary materials

      References

        • Althouse BM
        • Scarpino SV.
        Asymptomatic transmission and the resurgence of Bordetella pertussis.
        BMC Med. 2015; 13: 146
        • Amirthalingam G
        • Andrews N
        • Campbell H
        • Ribeiro S
        • Kara E
        • Donegan K
        • et al.
        Effectiveness of maternal pertussis vaccination in England: an observational study.
        Lancet. 2014; 384: 1521-1528
        • Barkoff AM
        • Grondahl-Yli-Hannuksela K
        • He Q.
        Seroprevalence studies of pertussis: what have we learned from different immunized populations.
        Pathog Dis. 2015; 73
        • Barkoff AM
        • Grondahl-Yli-Hannuksela K
        • Vuononvirta J
        • Mertsola J
        • Kallonen T
        • He Q.
        Differences in avidity of IgG antibodies to pertussis toxin after acellular pertussis booster vaccination and natural infection.
        Vaccine. 2012; 30: 6897-6902
        • Baughman AL
        • Bisgard KM
        • Edwards KM
        • Guris D
        • Decker MD
        • Holland K
        • et al.
        Establishment of diagnostic cutoff points for levels of serum antibodies to pertussis toxin, filamentous hemagglutinin, and fimbriae in adolescents and adults in the United States.
        Clin Diagn Lab Immunol. 2004; 11: 1045-1053
        • Berbers GA
        • van de Wetering MS
        • van Gageldonk PG
        • Schellekens JF
        • Versteegh FG
        • Teunis PF.
        A novel method for evaluating natural and vaccine induced serological responses to Bordetella pertussis antigens.
        Vaccine. 2013; 31: 3732-3738
        • Cattaneo LA
        • Reed GW
        • Haase DH
        • Wills MJ
        • Edwards KM.
        The seroepidemiology of Bordetella pertussis infections: a study of persons ages 1–65 years.
        J Infect Dis. 1996; 173: 1256-1259
        • Conde-Glez C
        • Lazcano-Ponce E
        • Rojas R
        • DeAntonio R
        • Romano-Mazzotti L
        • Cervantes Y
        • et al.
        Seroprevalence of Bordetella pertussis in the Mexican population: a cross-sectional study.
        Epidemiol Infect. 2014; 142: 706-713
        • Cutts FT
        • Hanson M.
        Seroepidemiology: an underused tool for designing and monitoring vaccination programmes in low- and middle-income countries.
        Trop Med Int Health. 2016; 21: 1086-1098
        • de Greeff SC
        • de Melker HE
        • van Gageldonk PG
        • Schellekens JF
        • van der Klis FR
        • Mollema L
        • et al.
        Seroprevalence of pertussis in the Netherlands: evidence for increased circulation of Bordetella pertussis.
        PLoS One. 2010; 5: e14183
        • de Melker HE
        • Schellekens JF
        • Neppelenbroek SE
        • Mooi FR
        • Rumke HC
        • Conyn-van Spaendonck MA.
        Reemergence of pertussis in the highly vaccinated population of the Netherlands: observations on surveillance data.
        Emerg Infect Dis. 2000; 6: 348-357
        • de Melker HE
        • Versteegh FG
        • Conyn-Van Spaendonck MA
        • Elvers LH
        • Berbers GA
        • van Der Zee A
        • et al.
        Specificity and sensitivity of high levels of immunoglobulin G antibodies against pertussis toxin in a single serum sample for diagnosis of infection with Bordetella pertussis.
        J Clin Microbiol. 2000; 38: 800-806
        • de Melker HE
        • Versteegh FG
        • Schellekens JF
        • Teunis PF
        • Kretzschmar M.
        The incidence of Bordetella pertussis infections estimated in the population from a combination of serological surveys.
        J Infect. 2006; 53: 106-113
        • De Serres G
        • Shadmani R
        • Duval B
        • Boulianne N
        • Dery P
        • Douville Fradet M
        • et al.
        Morbidity of pertussis in adolescents and adults.
        J Infect Dis. 2000; 182: 174-179
        • Edwards K
        • Freeman DM.
        Adolescent and adult pertussis: disease burden and prevention.
        Curr Opin Pediatr. 2006; 18: 77-80
        • Folaranmi T
        • Pinell-McNamara V
        • Griffith M
        • Hao Y
        • Coronado F
        • Briere EC.
        Systematic review and meta-analysis of pertussis epidemiology in Latin America and the Caribbean: 1980–2015.
        Rev Panam Salud Publica. 2017; 41: e102
        • Hannon WH.
        Blood collection on filter paper for newborn screening programs.
        Approved Standard. 6th ed. Clinical and Laboratory Standards Institute, Wayne, PA, USA2013
        • Kandeil W
        • Atanasov P
        • Avramioti D
        • Fu J
        • Demarteau N
        • Li X.
        The burden of pertussis in older adults: what is the role of vaccination? A systematic literature review.
        Expert Rev Vaccines. 2019; 18: 439-455
        • Launay O
        • Toneatti C
        • Bernede C
        • Njamkepo E
        • Petitprez K
        • Leblond A
        • et al.
        Antibodies to tetanus, diphtheria and pertussis among healthy adults vaccinated according to the French vaccination recommendations.
        Hum Vaccin. 2009; 5: 341-346
      1. Mack A. Latin American pertussis workshop: summary of proceedings; 2019. Available from: https://www.sabin.org/sites/sabin.org/files/latin_american_pertussis_meeting_report_english_final.pdf. [Accessed July 16, 2021]

        • McGirr A
        • Fisman DN.
        Duration of pertussis immunity after DTaP immunization: a meta-analysis.
        Pediatrics. 2015; 135: 331-343
        • Mei JV
        • Alexander JR
        • Adam BW
        • Hannon WH.
        Use of filter paper for the collection and analysis of human whole blood specimens.
        J Nutr. 2001; 131: 1631S-1636S
        • Pebody RG
        • Gay NJ
        • Giammanco A
        • Baron S
        • Schellekens J
        • Tischer A
        • et al.
        The seroepidemiology of Bordetella pertussis infection in Western Europe.
        Epidemiol Infect. 2005; 133: 159-171
      2. RIVM. Vaccination schedule Bonaire, Saba and St. Eustatius [in Dutch: Vaccinatieschema Bonaire, Saba en St. Eustatius]; 2018. Available from: https://rijksvaccinatieprogramma.nl/vaccinaties/vaccinatieschema. [Accessed October 29, 2020]

        • Ronn PF
        • Dalby T
        • Simonsen J
        • Jorgensen CS
        • Linneberg A
        • Krogfelt KA.
        Seroepidemiology of pertussis in a cross-sectional study of an adult general population in Denmark.
        Epidemiol Infect. 2014; 142: 729-737
        • Rothstein E
        • Edwards K.
        Health burden of pertussis in adolescents and adults.
        Pediatr Infect Dis J. 2005; 24: S44-S47
      3. Schurink-van 't Klooster TM, de Melker HE. The national immunisation programme in the Netherlands — surveillance and developments in 2019–2020. 2020a.

      4. Schurink-van 't Klooster TM, de Melker HE. The national immunization programme in the Netherlands 2018–2019. 2020b.

        • Scott S
        • van der Sande M
        • Faye-Joof T
        • Mendy M
        • Sanneh B
        • Barry Jallow F
        • et al.
        Seroprevalence of pertussis in the Gambia: evidence for continued circulation of bordetella pertussis despite high vaccination rates.
        Pediatr Infect Dis J. 2015; 34: 333-338
      5. Statistics-Netherlands-CBS. Caribbean Netherlands; population, gender, age and country of birth; 2017. Available from: https://opendata.cbs.nl/statline/#/CBS/nl/dataset/84712NED/table?ts=1612802577435. [Accessed February 8, 2021]

        • Strebel P
        • Nordin J
        • Edwards K
        • Hunt J
        • Besser J
        • Burns S
        • et al.
        Population-based incidence of pertussis among adolescents and adults, Minnesota, 1995–1996.
        J Infect Dis. 2001; 183: 1353-1359
        • van der Lee S
        • Sanders EAM
        • Berbers GAM
        • Buisman AM.
        Whole-cell or acellular pertussis vaccination in infancy determines IgG subclass profiles to DTaP booster vaccination.
        Vaccine. 2018; 36: 220-226
        • van der Lee S
        • Stoof SP
        • van Ravenhorst MB
        • van Gageldonk PGM
        • van der Maas NAT
        • Sanders EAM
        • et al.
        Enhanced Bordetella pertussis acquisition rate in adolescents during the 2012 epidemic in the Netherlands and evidence for prolonged antibody persistence after infection.
        Euro Surveill. 2017; 22
        • van der Maas NA
        • van Aerde K
        • Bont LJ
        • Bekker MN
        • Rots N
        • de Melker HE.
        [Infection prevention in newborns through maternal vaccination: current insights and developments.].
        Ned Tijdschr Geneeskd. 2016; 160: D411
        • van Gageldonk PG
        • van Schaijk FG
        • van der Klis FR
        • Berbers GA.
        Development and validation of a multiplex immunoassay for the simultaneous determination of serum antibodies to Bordetella pertussis, diphtheria and tetanus.
        J Immunol Methods. 2008; 335: 79-89
        • Van Lier EA
        • Geraedts JLE
        • Oomen PJ
        • Giesbers H
        • van Vliet JA
        • Drijfhout IH
        • Zonnenberg-Hoff IF
        • de Melker HE
        Vaccination coverage and annual report national immunisation programme Netherlands 2017 [in Dutch: Vaccinatiegraad en Jaarverslag Rijksvaccinatieprogramma Nederland 2017]. National Institute for Public Health and the Environment, Bilthoven, the Netherlands2018
        • Vegelin AL
        • van Vught AJ
        • Wolfs TF
        • Kimpen JL
        • Geelen SP.
        [Pertussis in young infants].
        Ned Tijdschr Geneeskd. 1998; 142: 2657-2660
        • Verberk JDM
        • Vos RA
        • Mollema L
        • van Vliet J
        • van Weert JWM
        • de Melker HE
        • et al.
        Third national biobank for population-based seroprevalence studies in the Netherlands, including the Caribbean Netherlands.
        BMC Infect Dis. 2019; 19: 470
        • Winter K
        • Nickell S
        • Powell M
        • Harriman K.
        Effectiveness of prenatal versus postpartum tetanus, diphtheria, and acellular pertussis vaccination in preventing infant pertussis.
        Clin Infect Dis. 2017; 64: 3-8
        • Wu Y
        • Zhu B
        • Gao Y
        • Shi Z
        • Wang J
        • Wang H
        • et al.
        Clustered cases of Bordetella pertussis infection cause high levels of IgG antibodies against pertussis toxin in adolescents in Gaobeidian city.
        China. Epidemiol Infect. 2014; 142: 738-743