Whooping cough (pertussis) is a highly contagious respiratory disease caused primarily by the gram-negative bacterium Bordetella pertussis, rarely by Bordetella parapertussis. Pertussis occurs at all ages, but infants aged <6 months are at greatest risk for developing severe disease.1
Whole-cell pertussis vaccines (wP) were introduced in Germany in the 1960s, followed by a marked decrease in pertussis incidence.2 However, the recommendation for routine vaccination with wP vaccine was withdrawn in the Federal Republic of Germany (FRG) in 1974 due to anecdotal reports of severe adverse events. In contrast, in the German Democratic Republic (GDR) the recommendation was upheld, with an estimated coverage of over 90% (compared with estimates of 2–60% in the FRG). As a consequence, pertussis incidence differed in the 2 parts of Germany, ranging from <1 case/100,000 in the GDR to 160–180 cases/100,000 per year in the FRG in the 1980s.2
In 1991, the German Standing Committee on Vaccination (STIKO) recommended pertussis vaccination for all infants in the reunified West and East Germany (ie, FRG prior 1990 and GDR, respectively). High concentration acellular pertussis vaccines (aP) were licensed in Germany in 1995, both alone and in combination with diphtheria and tetanus toxoids (DTaP), and rapidly replaced wP vaccines, although the latter remained on the market until 2001. Furthermore, a pertussis booster was recommended from 2000 for 11- to 17-year-olds (from 2001 for 9- to 17-year-olds) either with lower concentration pertussis (ap) combined with tetanus toxoid and reduced diphtheria toxoid (Tdap) or a monovalent aP vaccine available until 2003 and from 2006 for 5- to 6-year-olds with Tdap throughout Germany.2 An overview on the evolution of pertussis vaccination recommendations in Germany since 1995 is shown in Figure 1, including those relevant to adult populations.
Despite added boosters, pertussis incidence in Germany increased markedly in the late 1990s and early 2000s, with persistent cyclical increases in the past decade.2–4 Similar trends have been reported from the United States and Canada, as well as from several European coutries.5–9 Since implementation of the pre-school booster in Germany in 2006, peak incidences shifted from younger to older children and adolescents.4 A number of recent studies suggest that waning immunity, especially among those vaccinated exclusively with aP, plays an important role in the incidence increase.8,10–15
Vaccination registries are not established in Germany, but vaccination coverage (VC) has been evaluated using aggregated datasets on the vaccination status of children at school entry examinations. Pertussis VC at school entry increased steadily from 84.3% in 2001 to 95.1% in 2011.16,17 However, limited data available for other age groups indicate markedly lower VC in adolescents and adults, with lower VC reported in Western compared with Eastern Federal states.18–21
To investigate reasons for high pertussis morbidity, we analyzed age-specific pertussis incidences, VC and vaccine effectiveness (VE) of routine and booster pertussis vaccination in the federal state of Brandenburg, East Germany. Brandenburg was selected for this investigation due to its statutory notification of pertussis cases with data transmission to the national level since 2002 and the availability of case-based data on the vaccination status of toddlers, pre-school children and adolescents.
Notified pertussis cases from Brandenburg were considered confirmed if they met clinical criteria and were either laboratory confirmed or had an epidemiological link to a laboratory-confirmed case as specified in the uniform case definitions applied to notified cases from 2002 to 200822,23 and 2009 to 201222,23:
Clinical case definition: Cough lasting >14 days (in laboratory confirmed cases, cough of any duration was accepted from 2002 to 2008) and at least one of the following symptoms: paroxysms of coughing, inspiratory whoop, posttussive vomiting without other apparent cause. In infants, cough of any duration and apnea were also sufficient.
Laboratory confirmation: A positive result with at least one of the following methods: Isolation of B. pertussis, detection of B. pertussis-specific amplification targets with polymerase chain reaction (PCR), single serum positive serology with clearly elevated IgG (2009–2012) or IgA antibodies (2002–2008) to pertussis toxin, or increase in antibody concentration in acute and convalescent serum samples.
Case-based data on month and year of birth, sex, symptoms, laboratory results and number of received pertussis vaccinations were available in our dataset.
Population cohorts: Data on pertussis VC in Brandenburg are routinely obtained annually from kindergarten as well as from obligatory school entry and school exit examinations performed by local public health authorities. The case-based anonymized vaccination status of all children presenting their vaccination card is forwarded to the Brandenburg public health authority. Datasets included the following variables: Type of examination (kindergarten-, school entry- or school exit-examination), county, month and year of examination, age at examination, sex, availability of vaccination record and number of pertussis vaccine doses received.
For VC and VE calculations, we used case (notification) and cohort data pertaining to the same birth years and ages, including all records with information on vaccination status. Case–cohorts were defined for periods and ages with available VC data as follows: (1) toddler cohort: children born 2005–2009 aged 2–3 years; (2) pre-school cohort: children born 1995–2006 aged 5–7 years and (3) adolescent cohort: children born 1995–1996 aged 15–16 years. We compared the size of our study cohorts with that of the corresponding total population cohorts based on population data for Brandenburg from the German federal statistical office to estimate the proportion included in our cohorts.24 We also compared the sex distribution in the study cohorts and the source population (for details, see Table 1). Based on this comparison, the toddler cohort comprised 49% of children born 2005–2009 in Brandenburg, the pre-school cohort 108% of children born 1995–2006, and the adolescent cohort 37% of children born 1995–1996. Percentages >100% can be explained by infant deliveries in other federal states, relocation after the birth of a child, and, most importantly, some duplicates in the pre-school dataset. These result when children are held back from school based on their school entrance examination (up to 10%), and lead to re-examination in the following year. Sex distributions were similar in the study cohorts and the total population cohorts. Comparison of further demographic or social indicators was not possible due to lack of data in the datasets.
All cases aged <18 years notified in Brandenburg meeting the case definition were used for incidence calculations based on population data for Brandenburg from the Federal Statistical Office.25
Calculation of VC and VE
We used a case–cohort design to calculate VE in the age and birth year strata described above for which VC data were available.26–28 We further stratified pre-school cohorts according to exposure to wP (see below).
We calculated VC for 0, 1, 2, 3, 4, ≥4, 5, ≥5 and ≥6 doses (Table 2). According to STIKO, 2- to 3-year-olds should have received 4 doses DTaP. Since 2006, children entering school should have received one pre-school booster (ie, 1 dose Tdap). The adolescent cohort would not have been eligible for the pre-school booster, but should have received the booster for older children recommended in 2000 (ie, also 4 doses DTaP and 1 dose Tdap; see Fig. 1.).
Since wP vaccines were available in Germany until 2001, some adolescents and pre-school children might not have received aP vaccines exclusively. The routine datasets available for this study lacked information on the types of vaccines administered. To estimate the proportion of children who may have received wP vaccines, we used data from KiGGS, a large nationwide representative health survey of 17,461 children and adolescents conducted from 2003 to 2006, in which vaccination status was documented in detail from vaccination records, as described elsewhere.18 Because the KiGGS sample was representative for Eastern federal states, but not for Brandenburg alone,29 we calculated the proportion of participating children born 1995 or later who received wP vaccine according to birth year in the Eastern federal states and used this as an estimate for Brandenburg. As the proportion of children receiving wP decreased with consecutive doses of the primary series, we based our estimate of exposure to wP only on the first dose in all participants with information on vaccine type received available. We stratified the pre-school cohort into birth years with a higher (≥10%) or lower (<10%) proportion of children exposed to wP vaccine to better estimate the effect of wP vaccines on our VE estimates.
VE was calculated using the formula (1 - relative risk) × 100.30 The relative risk and 95% confidence intervals were calculated using Poisson regression—wherever possible exact Poisson regression with robust CIs—adjusted for sex (significance level of P < 0.05). Exposure to 4 or 5 documented doses of pertussis vaccine was compared with no exposure, ie, having received 0 doses. We analyzed the data with STATA (Stata Statistical Software: Release 12. College Station, TX: StataCorp LP).
For scientific use of routine anonymized data, ethical approval is not required in Germany.
A total of 3,219 cases aged <18 years that met the pertussis case definition were notified in Brandenburg from 2002 to 2012. Of these, 2,155 were born in 1995 or later. Of these, 2,144 had specific information on clinical presentation. All had cough, 2,134 for >14 days. Apnea was reported in 5% and posttussive vomiting in 18% of cases. The type of laboratory diagnosis was reported for 1,642 cases (76%), of which 20% were diagnosed by PCR or culture and 80% by serological testing. Serial IgG testing was performed in 65% of serologically confirmed cases (n = 859). The proportion of cases confirmed by PCR increased from 0–5% in the years 2002–2006 to 32% in 2012. Of all 2,155 cases born in 1995 or later, 441 were notified as part of an outbreak.
Complete data on vaccination status were available for 1,514 cases (71%). In the population cohorts, complete data on the vaccination status from available vaccination cards was available for 45,368 toddlers (89%), 223,173 pre-school children (93%) and 10,567 adolescents (78%).
The mean annual pertussis incidence in children <18 years in Brandenburg was 80.4 cases/100,000 inhabitants from 2002 to 2012. Incidence in boys was 79.9/100,000 and in girls 87.3/100,000. From 2002, there was a steady increase in incidence to a peak of 163/100,000 children in 2006. It then dropped to 32/100,000 in 2009, rising again to 120/100,000 in 2012. Peak incidences shifted from younger children aged 5–14 years in 2004–2006 to older children aged 10–17 years in 2011–2012 (Fig. 2). In 2012, incidence in 15- to 17-year-olds was higher than in all younger age groups for the first time.
VC in Brandenburg in Cases and Cohorts
Pertussis VC is displayed in Table 2 for each of the case–cohort strata. Coverage with ≥4 doses and ≥5 doses was consistently higher in the cohorts than in the cases (Table 2). In addition, coverage was higher for ≥4 than for ≥5 doses.
As the pre-school booster was recommended from 2006 onwards (Fig. 1), it was not recommended for children born before 2000. VC for ≥5 doses in pre-schoolers born after 2000 was thus somewhat higher at 30% compared with 10% overall (Table 2).
Proportion of Infants Exposed to wP Vaccines
Of all KiGGS participants born from 1995 to 2006, 3,282 were residents of the Eastern federal states. Of these, 2,487 (76%) had data available on the type of pertussis vaccine administered as the first dose. Among KiGGS participants born 1995 to 1998 with information available on vaccine type, 30%, 15%, 7% and 3%, respectively, had received wP vaccines. The proportion diminished further in subsequent cohorts and from 2002 onwards no KiGGS participant had received wP vaccines. We therefore stratified the VE calculations for pre-school children by birth years 1995–1996 (21% wP vaccine exposure) versus 1997–2006 (1% wP vaccine exposure).
Four-dose VE was highest at 97% in 2- to 3-year-olds, followed by 88% in 5- to 7-year-olds and 82% in 15- to 16-year-olds. VE was higher in children aged 5–7 and 15–16 years who had received a booster (5th) dose, at 93% and 97%, respectively (Table 3).
When we stratified the pre-school cohort according to wP exposure, we found a lower VE for children born after1996 (ie, with negligible wP exposure) than for those born in 1995–1996, for 4 but not 5 vaccine doses (Table 3). However, the number of cases in the stratum of children born 1995–1996 was very small.
Our age-stratified case–cohort analysis to estimate pertussis VE over a time period in which wP vaccines were subsequently replaced with aP vaccines revealed 3 key findings: (1) Waning immunity within 3 to 5 years following 4 dose aP vaccination, reflected in the lower VE in pre-schoolers than toddlers; (2) lower VE in pre-school children when birth cohorts that received ≥10% wP in the primary series were excluded and (3) a higher VE in pre-school children and adolescents who had received a booster vaccination.
A high VE of 96.9% for 4 DTaP doses was observed in toddlers, who would have received the last vaccine dose very recently. According to the recommended vaccination schedule in Germany, children should receive the 4th dose of the primary vaccination series by the age of 14 months. However, analysis of health insurance claims indicates that the primary series is actually completed later than recommended.31 In Brandenburg, 78% of all 4 dose pertussis vaccinated children received their 4th dose by 24 months of age, 88% by 48 months of age (personal communication, Thorsten Rieck). Thus, our VE estimate for 2- to 3-year-olds is for a very short interval after the 4th dose. High VE estimates were also observed by Bisgard et al32 shortly after completion of a four-dose DTaP series, with VE up to 99.3%.
Although only a very small number of cases was observed in pre-schoolers born in 1995–1996, the higher observed VE of >99% in this group compared with preschoolers born later suggests that priming with wP vaccines may have led to a more prolonged disease protection, as recently suggested in a number of studies from Europe, the US and Australia, reviewed by Sheridan et al.15 Thus, the lower VE for pre-school children born after 1996 of 75.4% is likely a better estimate of the effectiveness of primary vaccination with aP vaccines in 5- to 7-year-old children in Germany, and suggests substantial waning in the 2–5 years following completion of the primary aP series. As our adolescent cohort consisted only of children born 1995–1996, ~21% of whom had received wP vaccine, it is possible that four-dose VE for exclusive exposure to aP vaccines would in fact be lower than the observed 81.7% in this older group in analogy to the results seen in the pre-school cohort.
Waning immunity following vaccination with aP vaccines has recently been described in a number of other studies from the US and Australia.8,10–12,14 Tartof et al8 showed that the risk for pertussis increased up to fourfold only 6 years after vaccination with 5 DTaP doses. Klein et al11 showed that the risk for pertussis increased by 42% in each successive year following 5 DTaP doses. Misegades et al10 showed a decrease in VE from 98.1% in the first year after the 5th dose of DTaP to 71.2% at ≥60 months thereafter. Koepke et al14 showed an almost complete loss of VE in 12- to 14-year-olds from 75% in the year they received their Tdap booster to 12% 3 to 4 years later. Sheridan et al12 similarly showed a highly significant decreasing trend with age in children 5–12 years of age for VE after primary vaccination with ap vaccines followed by an ap-booster at age 4 in Queensland, Australia. Based on these results, one would expect to see a further marked decrease in four-dose VE in our adolescents, who would have had a much longer interval since the last dose than pre-schoolers, but this was not the case—in fact, when pre-school children born in 1995–1996 were excluded from the VE estimate for pre-schoolers, four-dose VE in adolescents and in pre-schoolers was similar. Again, this suggests that the receipt of wP vaccines by a significant proportion of adolescents may have led to better persistence of protection. A further possible explanation for the relatively high observed VE in adolescents, however, may be that exposure to circulating B. pertussis in a relatively high incidence setting throughout childhood led to natural boosting. Subclinical pertussis infections, especially in children previously vaccinated, may act as a natural booster.33,34
When interpreting four-dose VE, it must be borne in mind that children in the pre-school cohort would uniformly have received their Tdap booster only a short time before their health examination according to STIKO recommendations. This likely explains why five-dose VE did not differ significantly according to birth year (Table 3)—high short-term VE would likely be expected regardless of whether priming occurred with wP vaccines or not. In fact, in a US study, Misegades et al10 observed an even higher VE in the first year after 5 doses of DTaP vaccines (98.1%) in pre-schoolers, possibly related to the higher concentration of pertussis antigens in the 5th booster dose used in the US.
In contrast to pre-schoolers, adolescents would have received their 5th dose at a range of time points starting at the age of 9 years onwards, again in accordance with STIKO recommendations—ie, up to 7 years before ascertainment of the vaccination status. Thus five-dose VE would be expected to be lower in adolescents than in pre-schoolers, but in fact the 95% confidence intervals for the VE estimates in adolescents and in both pre-school strata overlapped. However, the preschool stratum born 1995–1996 included only 2 cases, making comparison difficult (Table 3). Our observed five-dose VE in adolescents was also markedly higher than the VE observed by Misegades et al in the US 5 to <6 years (82.8%) and ≥6 years (71.2%) after 5 DTaP doses. A possible explanation for the higher than expected VE in adolescents in our study could again be due to better protection afforded by priming with wP vaccines in approximately one-fifth of our adolescent cohort, as reviewed by Sheridan et al.15 However, the higher VE than in the US studies may also partly be explained by the later (age 9 years and older) receipt of the 5th dose in Germany. Further natural boosting may also have played a role.33,34
In view of these results, the current maximum reported disease incidence in our study population in 10- to 17-year-olds is most likely due to the low uptake of the recommended booster for adolescents. In keeping with the high observed five-dose VE, the decrease in incidence in younger children and the shift of peak incidences to older children (Fig. 2) after the introduction of the pre-school booster in 2006, also described for the other 4 Eastern federal states,3 suggests that booster vaccination has a major impact on disease incidence. Thus, improved uptake of recommended boosters is urgently required, especially in view of markedly lower booster VC reported in the Western than Eastern federal states.17,18
Our study has some important limitations. First, there is some uncertainty surrounding our VC estimates. Data on vaccination status was missing in 30% of cases. If these were less likely to be vaccinated, our VC estimate in cases may be an overestimate, which would lead to underestimation of VE. We may have underestimated VC for the last dose of the primary series in toddlers or the booster vaccinations in the pre-school and adolescent cohorts, because parents are given recommendations to complete outstanding vaccinations identified in the obligatory health examinations. Underestimation of VC in the cohorts would lead to underestimation of VE. On the other hand, evidence from school-based ascertainment of MMR vaccination status during an outbreak investigation suggests that VC is lower in children who do not provide vaccination cards.35 As not all children participating in the health examinations could present their vaccination cards, this would lead to overestimation of VC and thereby VE, particularly in the toddler and adolescent cohorts, in whom the proportion of children not presenting their vaccination card was highest. Despite these uncertainties, our estimates are based on ascertainment of vaccination records of a very large number of children, and present the best assessment of VC currently possible.
In addition, pertussis diagnosis has important limitations. It has been shown previously that some commercial ELISAs used for serological pertussis diagnostics in Germany lack specificity.36 As false-positive cases would be more likely to be vaccinated than true cases, use of tests with low specificity would lead to underestimation of VE. However, slightly over half the serologically confirmed cases were confirmed with an increase in IgG-antibodies, much less likely to be false positive, and the majority of cases had a cough duration of >14 days. The use of more specific PCR testing for pertussis increased during the study period, which may have led to a reduction of false-positive cases in more recent years.
In addition, it is also likely that mild cases were underrepresented in our study population, because pertussis is frequently not clinically suspected by physicians, as reflected in much higher incidence estimates based on serological surveys than passive surveillance.37 Underascertainment may be particularly likely in vaccinated children, which would lead to overestimation of VE. As discussed by Cherry,34 more rigorous case definitions were associated with higher VE in original vaccine trials for aP vaccines.38–41 Thus, underascertainment of mild cases in our passive surveillance system may partly explain the relatively high VE observed in our study, but also in other observational studies,10,32 at least for short intervals after vaccination with aP vaccines.
A further limitation was the lack of information on vaccine type in our datasets, which meant we had to estimate exposure to wP vaccines. However, we believe the KiGGS dataset provided us with a robust estimate. In addition, our analysis is based on a relatively small number of pertussis cases in some of the analyzed strata (Table 3). Thus, repeating this analysis in the future, when more cases have accrued, would be worthwhile. In April 2013, statutory notification of pertussis was introduced throughout Germany; therefore, more robust data on regional differences in incidence will become available and more comprehensive studies to investigate pertussis VE will be feasible if VC data are collected in other states in the future.
A further constraint was that vaccination dates were not available in the cohorts. Thus, possible differences between cases and cohorts in time since last vaccination cannot be ruled out (or adjusted for in the analyses). However, the narrow age bands within the case–cohort strata make substantial differences unlikely. For the adolescent cohort, VC data were obtained only for youths leaving school after grades 9–10; but not from students intending to complete high school. However, data from KiGGS did not show a significant influence of social or migrant status on pertussis vaccination status.18
We conclude that adolescents and pre-school children benefitted from booster vaccination, particularly those without exposure to wP vaccines in their primary vaccination series. A combination of waning immunity and low booster VC likely explains the high pertussis incidence in school children and adolescents in Brandenburg. Our results suggest that measures to increase coverage for the recommended pertussis booster vaccine doses in Germany would lead to a substantial decrease in pertussis incidence, particularly in older children and adolescents. Examination of vaccination cards in schools followed by recommendations to close identified vaccination gaps either by consulting the pediatrician or family doctor or by providing an immediate on-site vaccination opportunity in schools has improved VC in various regions in Germany.42–45 Further resources for such public health initiatives should be made available. In addition, measures to increase participation of 12- to 14-year-olds in the adolescent health check-up (J1) could lead to higher vaccination uptake.46 More detailed and nationwide monitoring of vaccination status including information on vaccine brands might permit more comprehensive analysis of VE in the future.
The authors thank the staff of local and state health departments in Brandenburg for collecting the data that were the basis for our analysis. The authors thank Karin Lüdecke for entering and transmitting the dataset. Further we thank the PAE/EPIET coordinators for their help with the project and the manuscript.
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