Whooping cough is reemerging worldwide despite widespread adaptations of vaccination schemes. Since the early 1990s, whole cell pertussis (wP) vaccines have been replaced by acellular pertussis (aP) vaccines.1–3 In 2005, the Dutch wP combination vaccine used in the primary vaccination series for infants at age 2, 3, 4 and 11 months was replaced by an aP combination vaccine. Three years later, children who have been primed with aP vaccines in infancy received a fifth aP combination vaccine at 4 years of age. Since then, an increase in adverse events (AEs) shortly after the administration of the diphtheria, tetanus, acellular pertussis and inactivated polio (DTaP-IPV) preschool booster vaccine was observed. Significantly more pronounced local and systemic AEs were reported in aP-primed children compared with wP-primed children.4
The underlying immunologic mechanisms for these heightened AEs in aP-primed children are not well understood. Previous studies revealed higher numbers of pertussis-specific T-helper 2 (Th2) cells indicative for Th2 skewing in aP-primed children compared with wP-primed children.5,6 Profound Th2 skewing after aP vaccination was also shown in the baboon model when compared with wP vaccination.7 Besides pertussis-specific T-cell differences, significantly higher levels of pertussis-specific IgG, IgG4 and IgE antibodies were described in aP-primed children compared with wP-primed children.6,8,9 In general, IgG4, IgE and Th2 responses are associated with allergic inflammatory diseases such as asthma and atopic dermatitis.10,11
Pre-existing high tetanus-specific Th2 cytokine responses have been correlated with increased risk of local AEs12 and pertussis toxin (PT)-specific IgE antibodies before and after DTaP booster vaccination were significantly higher in children with AEs compared with children without them.13 The differences in AEs between aP and wP priming suggest that the occurrence of AEs in aP-primed children could be related to pertussis-specific humoral and cellular immune responses. Few studies have reported on immune responses in children with AEs after a DTaP booster vaccination at preschool age. We therefore performed a study in 4 years old children with and without a pronounced local AE. Blood samples were collected shortly after a fifth DTaP-IPV vaccination to investigate a possible association between immune responses and AEs. Vaccine antigen-specific humoral and cellular immune responses were compared between the 2 groups.
MATERIALS AND METHODS
Study Population and Design
AEs are requested to be reported to the Dutch Pharmacovigilance Centre (Lareb). Parents of 4 years old children who spontaneously reported local swelling and/or erythema of ≥5 cm at the injection site within 48 hours after the booster vaccination were invited to participate in the study by Lareb (case group). If parents were willing to participate, the study nurse made an appointment for a home visit 10 days (±3 days) after the booster vaccination. A blood sample (8 mL) and a questionnaire including a few questions regarding atopic background of the children were collected. Parents of 4-year-olds without pronounced AEs (<1 cm) were invited to participate by an information letter (control group). The same study procedures after the booster vaccination applied for the control group. All children were vaccinated according to the Dutch national immunization program. Children were excluded in case of other vaccinations within a month before DTaP-IPV booster vaccination and in case of comorbidity or fever ≥38°C at the day of blood sampling.
This phase IV case-control study was approved by the Medical research Ethics Committees United (MEC-U, Nieuwegein, The Netherlands). Written informed consent from both parents and/or legal representatives was obtained.
At 4 years of age, children received a pediatric combination vaccine (DTaP-IPV), that is, Infanrix-IPV [GlaxoSmithKline Biologicals (GSK), Rixensart, Belgium]. In infancy, children had received 4 pediatric DTaP-IPV combination vaccines at 2, 3, 4 and 11 months of age [Infanrix-IPV+Hib, Infanrix-hexa (both GSK, Rixensart, Belgium) or Pediacel (Sanofi Pasteur, Lille, France)].
Peripheral blood was collected in vacutainer cell preparation tubes containing sodium citrate (BD Biosciences, San Diego, CA) and peripheral blood mononuclear cells (PBMCs) were isolated within 18 hours, washed, counted and stored at −135°C as described earlier14 and plasmas were stored at −20°C.
Plasma IgG antibody concentrations against diphtheria toxoid, tetanus toxin, and the 3 pertussis vaccine antigens namely PT, filamentous hemagglutinin (FHA) and pertactin (Prn) (DTaP antigens) were determined using the fluorescent bead–based multiplex immunoassay (MIA) as described.15,16 The in-house pertussis reference sample was calibrated to the World Health Organization International Standard (Pertussis Antiserum 1st international standard, 06/140, national institute for biologic standards and control, Potters Bar, UK) to express IgG concentrations in international units per milliliter. As a control, plasma IgG antibody levels against mumps, measles and rubella (MMR) were quantified using MIA as described.17
The 4 IgG subclasses against DTaP vaccine antigens were measured as reported.9 Blanc mean fluorescent intensity (MFI) values were subtracted from all samples. Individual IgG-subclass levels were first expressed as MFI values, and subsequently, each IgG subclass was expressed as a percentage of the sum of MFI of all 4 IgG subclasses together. Samples without a detectable response were given a value of 1 MFI.
DTaP antigen-specific IgE was determined according to the IgG MIA described above, by using mouse anti-human IgE-PE (eBioscience, San Diego, CA) as secondary antibody and expressed as MFI. For quantification of total IgE, Bio-Plex Pro Human IgE Isotyping Assay (Bio-Rad Laboratories, Redmond, WA) was used according to manufacturers’ instructions.
PBMCs were stimulated according to Schure et al.6 In short, 3.0 × 105 viable cells per well were cultured in AIM-V (adoptive immunotherapy medium-V) medium (Gibco Invitrogen, Grand Island, NY) containing 5% heat-inactivated human AB serum (Harlan Laboratories, Leicestershire, United Kingdom) and stimulated with 2 µg/mL heat-inactivated PT or FHA (Kaketsuken, Kumamoto, Japan), 4 µg/mL recombinant Prn (kindly donated by Wyeth, Collegeville, PA),18 6.67 Lf/mL tetanus toxoid [Netherlands Vaccine Institute (NVI), Bilthoven, The Netherlands], 10 Lf/mL diphtheria toxoid (NVI, Bilthoven, The Netherlands), or 4.4 µg/mL lectin (LC) (Pokeweed mitogen, Sigma-Aldrich, MO) as a positive control. Nonstimulated cells served as negative controls. Cells were incubated for 5 days at 37°C with 5% CO2 in 96-well round-bottom culture plates, supernatants were collected and stored at −80°C until cytokine analysis.
Cytokines interleukin (IL)-10, IL-13, IL-17 and interferon-gamma (IFN-γ) were quantified with MIA as described.19,20 Cytokine concentration of nonstimulated cells were subtracted from all samples. Values below the detection limit were set at half of the lowest quantifiable concentration for each cytokine.
Geometric mean concentrations (GMCs) and corresponding 95% confidence intervals (CIs) of vaccine antigen-specific antibody and cytokine responses were calculated. Percentages of IgG subclasses were described as mean with standard deviations. Normal distribution of GMCs and mean percentages of log transformed data was checked before analysis. Differences between case and control groups were tested with Mann-Whitney U test. Differences in the ratio of IFN-γ/IL-13 within the groups were tested with Wilcoxon signed rank test. GMCs and corresponding 95% CIs were calculated using GraphPad Prism 6 (GraphPad Software, La Jolla, CA), and statistical analysis was performed using SPSS statistics 22 (IBM, Armonk, NY). A P value of ≤0.05 was considered statistically significant. Because of changes in the immunization program regarding vaccine manufacturer, participants have been divided in subgroups based on primary vaccines for subanalysis (Table 1).
A linear mixed model analysis was performed to explore possible differences between the 2 study groups regarding the response to all vaccine antigens together per participant. This model consists of 3 parts. First, the response variable, which are the IgG4 MFI values, IFN-γ or IL-13 cytokine concentrations. Second, the so-called fixed effect variables (the explanatory variables), here a variable indicating whether a participant belongs to the case or control group (our variable of interest), and a variable indicating one of the 5 DTaP vaccine antigens, because vaccine responses will differ between the antigens. Third, the so-called random effect variable, here the participant ID, which is included in the model as a random intercept.
Between March 2012 and September 2013, 63 children were enrolled in the study. During the inclusion period, 290 eligible children with pronounced local AEs were reported to Lareb and were invited to participate, of which 10% accepted to join the study. From 60 children, that is, 30 cases and 30 controls, sufficient plasma was available and from 59 enough PBMCs. Of the cases, 16 children showed inflammation of the whole upper limb and adjacent body parts (extensive limb swelling), and 14 children had injection site inflammation with at least 2 inflammation symptoms (swelling, redness, heat and/or pain) (an example of an AE was available in Fig. S1, Supplemental Digital Content 1, http://links.lww.com/INF/C715). There were no differences in mean age and gender between the 2 groups (Table 1). A small but significant difference existed in the sampling window between the case and the control groups (mean days 10.4 ± 2.0 vs. 9.0 ± 1.8, respectively). Therefore, children were also divided into subgroups excluding those sampled at day 13 (7 children in the case group, none in the controls), which resulted in a similar sampling window between these subgroups. Because subgroup analysis excluding children sampled at day 13 resulted in similar findings, humoral and cellular immune responses were described for the entire study population.
Humoral Immune Responses
The GMC of nonantigen-specific total IgE (Fig. S2, Supplemental Digital Content 2, http://links.lww.com/INF/C716) of the case group (284.2 ng/mL, 95% CI 138.2-584.4) was significantly higher than that of the controls (109.8 ng/mL, 95% CI 50.6-238.4; P = 0.029). Antigen-specific IgE levels were also determined but were below the detection limit for the majority of children (data not shown).
Overall, the GMCs of DTaP antigen-specific IgG responses upon the preschool booster vaccination tended to be higher in the case group compared with the controls, reaching significance only for diphtheria-specific IgG (P = 0.01) (Fig. 1 and Table 2). As a control, IgG antibodies to the MMR vaccine antigens, which all children had received at 14 months of age, were measured. No differences in MMR-IgG GMCs between the case and control groups were observed (Table 2 and Fig. S3, Supplemental Digital Content 3, http://links.lww.com/INF/C717).
Subsequently, IgG-subclass responses showed that DTaP antigen-specific IgG2 and IgG4 MFI values were significantly higher in the case group compared with the controls. In concordance with total vaccine antigen-specific IgG, IgG1 MFI values were only significantly different between the 2 groups for diphtheria (Table 3). No differences in IgG3 MFI values were found between the groups. Notably, within the case group and the controls, the antigen-specific MFI values for the IgG subclasses varied considerably between the individuals. In line with results of a previous study, the sum of the MFI values of the IgG subclasses correlated well with the MFI values of antigen-specific total IgG.9
The predominant IgG subclass for all 5 vaccine antigens in both groups was IgG1, with mean values ranging from 86.2% in the case group to 95.4% in the controls (Fig. 2A and Table 3). After IgG1, IgG4 contributed most to the IgG levels, up to 13%. IgG2 and IgG3 hardly contributed to the antigen-specific IgG levels, respectively ranging from 0.5% to 4.7% and 0.2% to 1.2%. The contribution of IgG1 to total IgG was significantly lower in the case group compared with the controls for the pertussis antigens PT, FHA and Prn and for tetanus (Table 3). In particular, the relative contribution of IgG4 specific for FHA, Prn and tetanus was significantly higher in the case group compared with the controls. Also, most of the IgG2 contributions were significantly higher in the case group, but these percentages were (very) low (Table 3). Next to the overall antibody values, several children in both groups showed high proportions of antigen-specific IgG4, varying from around 20% up to even 72% (Fig. 2B). More specific, 17 of 30 children (57%) in the case group and 7 of 29 (23%) in the controls showed a proportion of IgG4 of ≥10% for 1 or more antigen. Interestingly, 3 children in the case group and 2 in the control group showed ≥10% IgG4 antibodies for all 5 vaccine antigens. Overall, children with extensive limb swelling tended to show higher humoral responses than children with injection site inflammation, reaching significance for PT- and Prn-specific IgG4.
The response to all 5 vaccine antigens together was analyzed with a linear mixed model for IgG4 MFI values. Comparing the case and the control groups, the combined IgG4 response to the 5 DTaP antigens resulted in a GMC ratio of 4.06 (95% CI: 1.84–8.86; P < 0.001). This corroborates the difference in IgG4 response between the 2 groups even further.
Because a difference was observed between the case and the control groups in vaccines during the primary series, a subanalysis was performed including just the participants primed with Pediacel vaccines (Table 1). Overall, the subanalysis resulted in similar differences in humoral immune responses between the case and the control group compared with the analysis of the entire study population, although for some parameters significance was lost because of low numbers in these subgroups (data not shown).
Cellular Vaccine Antigen-specific Cytokine Responses
T-helper cytokines IFN-γ (Th1), IL-13 (Th2), IL-17 (Th17) and IL-10 (T-regulatory) were evaluated after antigen stimulation. IFN-γ was higher in the case group compared with the controls for FHA, Prn and diphtheria, although not significant (Fig. S4, Supplemental Digital Content 4, http://links.lww.com/INF/C718). Furthermore, no difference was found between the 2 groups for the combined results of the DTaP antigens using the linear mixed model. IL-13 values specific for Prn, diphtheria and tetanus, as well as Prn-specific IL-10 values, were significantly higher in the case group compared with the controls. Antigen-specific IL-17 responses were not significantly different between the 2 groups.
Variation between individuals within the groups proved high for all different cytokine concentrations, up to a 1000-fold. While some children did not have detectable antigen-specific IFN-γ or IL-13 responses, high values of them were produced by PBMCs stimulated with LC, indicating that all children were able to induce Th1 and Th2 responses. Furthermore, all children showed IL-10 and IL-17 responses to at least one of the antigens. After LC stimulation, no significant differences between the 2 groups were observed for any of the cytokines supporting that differences between groups were antigen specific (Fig. S4, Supplemental Digital Content 4, http://links.lww.com/INF/C718).
Comparing IFN-γ and IL-13 concentrations within the 2 groups, IFN-γ was significantly lower than IL-13 for all 5 DTaP vaccine antigens (all P < 0.01). This resulted in IFN-γ/IL-13 ratios <1 for all antigens in both groups, which is indicative for Th2 skewing (Fig. 3). This low IFN-γ/IL-13 ratio was most pronounced for diphtheria (ratio of 0.06 for the case group and 0.04 for the controls) but without differences between the 2 groups. In contrast, aspecific LC stimulation induced significantly more IFN-γ than IL-13 (with IFN-γ/IL-13 ratio of 13.5 for the case group and 12.1 for the controls), showing that the Th2 skewing was specific for the antigens in the preschool DTaP booster vaccination. Similar results were found in the subgroups based on vaccination background showing significance just for tetanus-specific IL-13.
This study showed elevated immune responses to the DTaP vaccine antigens in children with a pronounced local AE within 48 hours upon a fifth DTaP-IPV vaccination at 4 years of age compared with children without an AE (controls), though with high individual variation. Children with AEs showed significantly higher values of total IgE, diphtheria-specific IgG, IgG4 for all DTaP antigens and IL-13 for Prn, diphtheria and tetanus. Th2 skewing was observed for all DTaP vaccine antigens in both groups.
Two previous studies found no differences in total antigen-specific IgG responses between children with and without AEs after vaccination.12,21 In contrast to our study, only tetanus-specific IgG was analyzed12 or the allocation of subgroups was based on AEs after the primary vaccinations rather than the occurrence of AEs after the booster vaccination.21 However, the significantly higher diphtheria IgG concentrations in our study were in agreement with results of Edelman et al.13 This similarity was remarkable since their study was conducted in 2 years old children sampled 1 month after their fourth DTaP vaccination.
The most remarkable finding in our study was the high values of all vaccine antigen-specific IgG4 responses in the case group. In general, protein antigens predominantly elicit an IgG1-subclass response, with less IgG3 and IgG4 and rarely IgG2.22–24 Surprisingly, we found high proportions of DTaP antigen-specific IgG4, with a prevalence of even 11% tetanus-specific IgG4 antibodies in the case group. This is in contrast to previous studies, where a very low prevalence of tetanus-specific IgG4 was reported.23,25 With regard to pertussis-specific IgG-subclass responses, so far only 3 studies were conducted in aP-primed children.9,26,27 The results of these studies were consistent with our study showing higher IgG4 concentrations after repeated exposure to vaccine antigens.23,25 IgG4 responses are associated with chronic antigenic stimulations,28 suggesting that the high amounts of purified antigens in the DTaP vaccines given within a relatively short period (at 2, 3, 4 and 11 months of age) initiate this response. Interestingly, a sixth DTaP booster vaccination in pre-adolescents also results in at least similar high IgG4 production (van der Lee et al, manuscript in preparation). Because class switching to IgG4 is dependent on the Th2 cytokines IL-4 and IL-13, similar to IgE class switching, IgG4 is often associated with Th2-skewed responses.22 IgG4 antibodies are suggested to have anti-inflammatory properties as the appearance of IgG4 seems to be related to symptom reduction in allergic patients.22,29 This might suggest that an AE following DTaP vaccination is associated with higher total IgE and IL-13 concentrations and that IgG4 may not contribute to clinically observed AEs in these children. The determination of IgG4 responses could be relatively easily implemented in more vaccine immunogenicity studies to be able to evaluate Th2 skewing of vaccine responses.
Studies investigating atopic diseases have reported significantly lower Th1/Th2 ratios in supernatants of LC-stimulated PBMCs in atopic children compared with nonatopic children.11 In contrast, we observed a high Th1/Th2 ratio in both groups upon LC stimulation suggesting that the higher IgE values 10 days post vaccination may be related to vaccine antigens and not to the already established Th2 skewing in the case group. However, it is also reported that plasma Th2 cytokine values in 4–6 years old aP-primed children were higher before and 35 days after aP-booster vaccination in atopic children compared with nonatopic children, all without AEs.30 We did not find more atopic children in our case group based on questionnaires, but the numbers of children in our groups were small. However, the higher total IgE values in children with an AE suggests a more atopic background. Atopic children could be at increased risk for AEs after a fifth DTaP vaccination but this needs to be further studied.10,11,28,31 Interestingly, swelling of the injection site is also seen after repeated administration of influenza vaccines in children and adults.32
Recently, Scheifele et al33 reported a doubled incidence of erythema at the injection site in children with detectable diphtheria-specific cell-mediated immunity before a DTaP booster vaccination, compared with children without diphtheria-specific cell-mediated immunity. This suggests that pre-existing high concentrations of vaccine antigen-specific Th2 cells and the Th2-skewed immune response to DTaP vaccination influence the susceptibility to local AEs post booster vaccination. We found significantly higher values of the Th2 cytokine IL-13 for Prn, diphtheria and tetanus in the case group, which is in line with others showing this just for tetanus.12 The high Th2 responses to the vaccine antigens in aP-primed children might be due to the absence of bacterial components in the aP combination vaccines, which were present in wP vaccines. The lack of these components could be the cause of a more Th2-skewed response, not just specific for the pertussis antigens but also for the diphtheria and tetanus antigens.34,35 Our findings of Th2 skewing were vaccine antigen specific since aspecific stimulation with LC induced Th1-dominated responses as expected, and the IFN-γ/IL-13 ratio below 1 was only found for the vaccine antigens. Although human studies are scarce, we and others previously reported mixed Th1/Th2 profiles in aP-primed children, with a tendency to Th2 skewing.5,36
Immune responses in relation to AEs have been studied for one or some of the DTaP vaccine antigens, mostly 1 month postbooster vaccination in 4–6-year-olds.12,33 A strength of our study was the ability to investigate a broad range of vaccine antigen-specific humoral and cellular immune responses in relation to AEs already 10 days after the 4 years old DTaP booster vaccination, when immune responses are already at its peak.6,8,37 This short time interval between vaccination and sampling enabled us to establish differences between groups that would otherwise have remained unobserved. Although there was a significant difference in sampling window between the 2 groups, a subanalysis was performed excluding children sampled on day 13, which resulted in a similar sampling window between the 2 groups. Moreover, results of the subanalysis regarding differences in immune responses between the 2 groups were comparable with the analysis performed on all children. Furthermore, de Voer et al38 demonstrated that meningococcal serogroup C–specific IgG concentrations were similar 10 and 17 days after meningococcal serogroup C conjugate booster vaccination, indicating that variation in sampling interval from 10 to 13 days post vaccination may not be critical as the IgG values seem not to increase any further.
One of the limitations of this study was that prevaccination samples were not included. However, the occurrence of pronounced AEs is too low and does not allow the enrolment of many children for longitudinal sampling and also resulted in small group numbers in this study. Despite the small groups, we do see interesting differences between children with and without pronounced AEs. Another limitation is the different priming with 3 aP combination vaccines. However, we reanalyzed all findings in subgroups with participants only vaccinated with Infanrix or Pediacel combinations. Although numbers were low and the power limited, similar differences as described were observed in these subgroups. This indicates that the differences observed between the case and the control groups in humoral immune responses after the preschool booster vaccination were most likely not driven by a difference in priming vaccines.
As a control, MMR antibody concentrations, induced after MMR vaccination at 14 months of age, were determined to explore if the antibody values for non-DTaP vaccine antigens between both groups were similar. From a population-based serosurveillance study performed in 2006/2007, it was clear that the decay of MMR antibody values was only minimal between 14 months and 4 years. We found no differences in MMR antibody values between the 2 groups indicating that other vaccines induced comparable immune responses in both groups.39
In summary, it was previously suggested that the AEs after the DTaP preschool booster vaccination were most likely due to the repeated administration of the aP vaccine antigens, because the increase in AEs was mainly seen after introduction of aP combination vaccines in the primary vaccination schedule. We now demonstrated high immune responses in children with pronounced AEs not only to the pertussis vaccine antigens but also to diphtheria and tetanus, and Th2 skewing for all antigens in all participants. The variation in the individual immune responses of children with an AE indicates that these events are associated with an accumulation of high Th2-skewed responses in combination with an additional biologic factor. This needs to be evaluated in further studies. On the long run, new DTaP vaccines that would elicit a more Th1-skewed response might reduce the risk of these rare local, but pronounced, reactions.
We thank all children and their parents who participated in this study and Dr. W. de Jager (Multiplex Core Facility, Laboratory of Translational Immunology, University Medical Center Utrecht, The Netherlands) for cytokine measurements, Dr. J. van de Kassteele for statistical support and P. Oomen (RIVM) for recruitment support.
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pronounced adverse events; acellular pertussis booster vaccination; immune response; children; T-helper 2 skewing
Supplemental Digital Content
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