Enhanced memory B-cell immune responses after a second acellular pertussis booster vaccination in children 9 years of age

Vaccine 30 (2011) 51–58

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Enhanced memory B-cell immune responses after a second acellular pertussis booster vaccination in children 9 years of age Lotte H. Hendrikx a,b,∗ , Mariet K. Felderhof b , Kemal Öztürk a , Lia G.H. de Rond a , Marlies A. van Houten b , Elisabeth A.M. Sanders c , Guy A.M. Berbers a , Anne-Marie Buisman a a

Centre for Infectious Disease and Control (Cib), National Institute for Public Health and the Environment, Bilthoven, The Netherlands Pediatric Department, Spaarne Hospital Hoofddorp, The Netherlands c Department of Pediatric Immunology and Infectious Diseases, University Medical Center Utrecht, The Netherlands b

a r t i c l e

i n f o

Article history: Received 3 May 2011 Accepted 19 October 2011 Available online 4 November 2011 Keywords: Pertussis Booster vaccination Children Memory B-cell immune response

a b s t r a c t Whooping cough has made its comeback and the incidence of pertussis in countries with widespread pertussis vaccination is most prominent in individuals above 9 years of age. To control the burden of infection, several countries already introduced acellular pertussis (aP) booster vaccination in adolescents and/or adults. However, antibody levels wane rapidly after vaccination even at older age. In this longitudinal study we investigated the effect of a second aP booster on the pertussis-specific memory B-cell immunity in children 9 years of age that have previously been vaccinated according to the national immunization program. Longitudinal blood samples were taken before, one month and one year after the booster. Purified B-cells were polyclonally stimulated and frequencies of memory B-cells were identified by ELISPOT-assays specific for various pertussis antigens. In addition, IgG levels and avidity indices were measured with fluorescent bead-based multiplex immunoassays. Starting with low pertussis-specific antibody and memory B-cell levels, a typical booster response was measured at one month after vaccination with increased antibody and memory B-cell responses. Although these responses declined slightly after one year, they substantially exceeded pre-booster levels and the avidity indices of the anti-pertussis antibodies remained high. Furthermore, high numbers of pertussisspecific memory B-cells at one-month post-booster correlate quite reliably with the corresponding high antibody response at one-year follow-up. In conclusion, booster vaccination in children 9 years of age induced an enhanced pertussis-specific memory immune response that sustained at least for one year. Therefore, this study supports the introduction of booster vaccination in older age groups. © 2011 Elsevier Ltd. All rights reserved.

1. Introduction Since the comeback of whooping cough in the 1990s in countries that had implemented widespread pertussis immunization programs [1–3], pertussis vaccination strategies are a topic of scientific debate. Nowadays, in developed countries acellular pertussis (aP) vaccines are administered at infant age and as preschool booster. Consequently, the peak incidence of whooping cough has shifted to adolescents and adults [4,5]. Although the vast majority of these older age groups suffer from relatively mild symptoms, they are the main source of infection for the young, not fully vaccinated infants [6] who are at risk for the pertussisassociated life-threatening complications. Recently, during a large

∗ Corresponding author at: RIVM, LIS, Postbak 22, Antonie van Leeuwenhoeklaan 9, 3720 BA, Bilthoven, The Netherlands. Tel.: +31 30 2743944; fax: +31 30 274418. E-mail addresses: [email protected], [email protected] (L.H. Hendrikx). 0264-410X/$ – see front matter © 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.vaccine.2011.10.048

pertussis-outbreak in California, USA, 10 unvaccinated infants died from the pertussis disease [7]. To control the burden of whooping cough, an aP booster vaccination in adolescents and adults has already been introduced in some countries (USA, Canada, Austria, France, Germany, Luxembourg, Finland, Italy and Sweden (www.euvac.net), but vaccine uptake is generally low. In The Netherlands, aP vaccines are administered as a preschool booster at 4 years of age in children since 2001. Furthermore, from 2005 onwards an aP vaccine has replaced the Dutch whole-cell pertussis (wP) vaccine at 2, 3, 4 and 11 months of age. These five aP vaccinations have improved protection against whooping cough in young children in The Netherlands [8]. However, nowadays a shift in the epidemiology of pertussis is observed with peak disease incidences in children 9–10 years of age who all had received the Dutch wP vaccine in their first year of life and the aP booster at 4 years of age [6]. Since serum antibody levels rapidly wane after both wP and aP vaccination [9–11], cellular immunity might play an important role in protection against whooping cough. Information about the

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capacity of pertussis vaccines to elicit memory B-cell immunity is scarce. Insight in the pertussis-specific memory B-cell pool will improve the understanding of the immunological mechanisms of protection against pertussis provided by vaccination around adolescence. The aim of this study is to longitudinally investigate the effect of a second aP booster vaccination in children 9 years of age on the pertussis-specific memory B-cell immunity at one month and one year after the booster. 2. Subjects and methods 2.1. Study population A cohort of 83 children of 9 years of age was included in this longitudinal interventional study (ISRCTN64117538). Paired blood samples (15 ml) were taken just before (n = 83), 1 month (n = 81) and 1 year (n = 79) after the second aP booster vaccination. All children were healthy and had no prolonged coughing periods as symptom of infection with Bordetella pertussis within the year before sampling as measured by a parental questionnaire (data not shown). Another group of children 9 years of age (n = 65) who participated in 2007 in a cross-sectional observational study (ISRCTN65428640) was included for comparison of pre-booster anti-pertussis IgG-responses. In 2007 one blood sample (15 ml) was taken from each child. Both studies were conducted according to the Declaration of Helsinki, Good Clinical Practice Guidelines with the approval of the relevant ethics review committee. Written informed consent was obtained from both parents/legal representatives before the start of the studies. 2.2. Vaccines After vaccination with DTwP-IPV-Hib (NVI, Bilthoven, The Netherlands) at 2, 3, 4 and 11 months of age (wP primed), the children had received ACV-SBTM that contained 25 ␮g pertussis toxin (PT), 25 ␮g filamentous heamagglutinin (FHA) and 8 ␮g pertactin (Prn), in addition to the DTP-IPV vaccine (NVI, Bilthoven, The Netherlands) as a preschool booster vaccination at the age of 4 according to the Dutch national immunization program. In this study, Boostrix-IPVTM (GlaxoSmithKline Biologicals S.A., Rixensart, Belgium) was administered as a second aP booster at 9 years of age and replaced the DT-IPV (NVI, Bilthoven, The Netherlands) routinely administered at age 9. Boostrix-IPVTM contained 8 ␮g PT, 8 ␮g FHA and 2.5 ␮g Prn for the pertussis antigens. 2.3. Serological assays For measurement of plasma IgG levels directed against the 3 B. pertussis vaccine antigens PT, FHA (both from Kaketsuken, Kumamoto, Japan), and Prn (P.69 pertactin expressed and purified from an Escherichia coli construct as previously described [12]) together with combined fimbriae type 2 and 3 (Fim2/3 from Aventis Pasteur, Lyon, France), adenylate cyclase toxin (ACT, kindly provided by Peter Sebo from the Institute of Microbiology, Prague, Czech Republic) and tetanus toxine (Tt from Sigma–Aldrich, St. Louis, MO) the fluorescent bead-based multiplex immunoassay (MIA) as previously described was used [13,14]. In-house reference and control sera were included on each plate. The in-house reference serum was calibrated for PT and FHA against the FDAhuman pertussis antiserum lot 3, for Prn against lot 4, for the Fim 2/3 against lot 3 that was arbitrarily set at 100 EU/ml and for ACT against the 1st international standard that was arbitrarily set at 10 U/ml.

2.4. Avidity assay The avidity of PT- and Prn- antibodies was measured in plasmas from a subgroup (n = 40) of the children with the MIA as previously described [13]. In short, IgG levels were diluted to a final concentration of 0.2 EU/ml for IgG-PT and 0.05 EU/ml for IgG-Prn. The avidity MIA was performed with ammonium thiocyanate (NH4 SCN) (1.0 M for PT-antibodies and 1.5 M for Prn-antibodies) and the avidity index (AI) was expressed as a percentage of the remaining IgG levels in the presence of ammonium thiocyanate in comparison with the IgG levels after addition of PBS in which the avidity was set at 100%. The avidity percentages were classified as low (AI < 80%) and high (AI > 80%) 2.5. B-cell isolation, stimulation and ELISPOT-assays In 20 blood samples of randomly selected children we performed pertussis- and tetanus toxoïd (Td, Netherlands Vaccine Institute, Bilthoven, The Netherlands) antigen specific enzymelinked immunospot (ELISPOT) assays as previously described in detail [15,16]. In short, PBMCs were isolated from 4 ml vacutainer cell preparation tubes and stored at −135 ◦ C and plasmas were frozen at −20 ◦ C until further testing. On average 9.3% B-cells were present in the total PBMC pool, which were purified with an anti-CD19 positive selection cocktail. After polyclonal stimulation with CpG, IL-2, IL-10 and IL-15 for 5 days at 37 ◦ C and 5% CO2 the memory B-cell population increased about 6-fold and on average 19.0 ± 8.7% of this population produced IgG antibodies. In the ELISPOT-assays, the following antigens were coated in 50 ␮l PBS containing 30 ␮g/ml PT, 20 ␮g/ml FHA, 80 ␮g/ml Prn, 10 ␮g/ml Fim2/3, 20 ␮g/ml ACT or 7LF/ml Td. Numbers of antigen-specific memory B-cells were counted per 105 B-cells. A value of 0.1 was assigned to the lower limit of determination of the number of memory B-cells. Frequencies of antigen-specific memory B-cells were calculated per total IgG-producing B-cells. 2.6. Statistical methods Results were expressed in average or geometric mean (GM) values with a 95% confidence interval (CI). The paired t-test was used to compare the results between the defined groups. To analyze the correlation between variables Spearman correlations (rs ) and linear regression analysis were used. P < 0.05 was considered significantly different. Since no internationally accepted protective antibody levels for pertussis antigens exist, a positive antibody response directed against PT-antibodies was defined here as a post-vaccination level of ≥20 EU/ml (arbitrarily protective [17]) in children in whom at least a 4-fold increase in antibody levels from pre-vaccination levels was measured. 3. Results 3.1. Antibody responses In 65 and 83 children of 9 years of age recruited in 2007 and 2009, respectively, similar low geometric mean concentrations (GMCs) of anti-pertussis IgG levels were measured before the booster (Table 1). An IgG-PT level ≥62.5 EU/ml is suggestive for natural infection with B. pertussis [18] and was observed in 6.2% of the children in 2007 and 10.8% of the children in 2009. In general, IgG levels to the 3 pertussis- and Tt-vaccine antigens were low before the booster but significantly increased one month after the booster (Table 1). At one month post-booster 75% of the children showed a 4-fold rise in anti-PT antibody response. In the

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Table 1 Geometric mean concentrations (GMCs) and 95% confidence intervals (CIs) of the IgG levels to the pertussis antigens (expressed in EU/ml) and to Tt (IU/ml) in the group of children 9 years of age studied in 2007 (n = 64) and the group of children from 2009 also 9 years of age just before (n = 83), one month (n = 81) and one year (n = 79) after they had received the aP booster vaccination. N

PT

FHA

GMC

95% CI

Pre-booster 8.9 2007 65 2009 83 8.5 1 month post-booster 81 131.5a 2009 1 year post-booster 2010 79 27.6a a

GMC

6.4–12.3 6.2–11.7

Prn 95% CI

Fim2/3

GMC

95% CI

GMC

ACT 95% CI

GMC

Tt 95% CI

GMC

31.9 41.1

25.1–40.6 31.9–53.0

16.6 13.2

12.4–22.1 9.8–17.6

3.1 2.7

2.4–4.1 2.1–3.4

– 2.84

– 2.15–3.76

0.46 0.82

105.9–163.3

356.5a

304.0–418.0

383.4a

301.6–487.4

4.0a

2.9–5.3

2.75

2.04–3.70

12.21

21.3–35.6

127.1a

110.8–145.8

95.3a

70.7–128.5

3.4

2.6–4.6

2.54

1.96–3.29

1.22

95% CI 0.37–0.57 0.67–1.01 10.11–14.74 0.88–1.68

Significant difference between given time point and pre-booster IgG levels (2009).

13 samples showing a less than 4-fold increase in anti-PT IgG-level, high pre-booster levels were observed. Reverse cumulative distribution curves illustrate the course of the IgG levels for each pertussis vaccine antigen before and after the booster (Fig. 1). After one year all IgG levels had decreased again, however they significantly exceeded those before the booster. Importantly, the percentage of children with IgGPT levels ≥20 EU/ml increased from 27% before to 57% one year after the booster. Despite a small decrease during the follow-up,

the percentage of children with high antibody responses to FHA and Prn after one year still amply exceeded that of the prebooster levels. As expected, similar anti-Fim2/3 and anti-ACT antibody levels were found at all time points, since these antigens are not included in the aP booster vaccine. The GMCs for the pertussis- and Tt-specific IgG levels as presented in Table 1 for the complete group of children were comparable with those in the subset of children (n = 20) in which cellular assays were performed.

A. PT

B. FHA

100

pre + 1month + 1year

100

80

80

70

70

60 50 40

60 50 40

30

30

20

20

10

10

0

pre + 1month + 1year

90

% subjects

% subjects

90

0

1

10

100

1000

10000

antibody concentration (EU/ml)

1

10

100

1000

10000

antibody concentration (EU/ml)

C. Prn 100

pre + 1month + 1year

90 80

% subjects

70 60 50 40 30 20 10 0 1

10

100

1000

10000

antibody concentration (EU/ml) Fig. 1. Reverse cumulative distribution curves of the IgG levels against PT (A), FHA (B) and Prn (C) measured pre-booster (red), one month (green) and one year (blue) after booster vaccination. The vertical line in A indicates the arbitrary level of protection for IgG-PT (20 EU/ml). The x-axis is logarithmic. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of the article.)

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Table 2 Geometric mean avidity indices (GMAIs) and 95% CIs of PT- and Prn-antibodies in percentages for a subset of children (n = 40) just before, one month and one year after the booster at 9 years of age. 9 years cohort

Pre-booster 1 month post-booster 1 year post-booster a

PT

Prn

N

GMAI

95% CI

N

GMAI

40 40 40

65.5 91.6a 91.9a

55.4–77.5 88.9–94.4 85.7–98.6

40 40 40

77.9 85.5a 88.9a

95% CI 71.3–85.0 81.2–90.0 86.2–91.6

Significant difference between given time point and pre-booster AI.

3.2. PT- and Prn-antibody specific avidity indices In all children a significant increase in the avidity index to both PT- and Prn-specific antibodies was measured one month postbooster compared to pre-booster values (Table 2). Remarkably, at one-year follow-up, avidity indices to these antibodies remained at the same high level as one month after the booster. A low pre-booster avidity profile for PT-antibodies together with low anti-PT levels (<20 EU/ml) were observed in more than half of the children (53%). In contrast, high anti-Prn levels (>20 EU/ml) combined with a high Prn-specific avidity profile was already found before the booster vaccination in the majority (75%) of the children. After one month, in all children a high antibody level and a high avidity profile to PT and Prn was measured in respectively 85% and 75% of them. After one year, 93% and 95% of the children still showed a high antibody level and avidity index to PT and Prn, respectively. 3.3. Memory B-cell responses In general, the number of the pertussis vaccine- and the Tdspecific memory B-cell responses had significantly increased one month after the booster and decreased after one year (Fig. 2). Importantly, the Prn- and Td-specific memory B-cell responses at

one year remained significantly higher compared to pre-booster responses. The responses for PT- and FHA showed a similar pattern, but failed to reach significant differences. As expected, the number of Fim2/3- and ACT-specific memory B-cell responses did not change before and after the booster. Frequencies of the antigen-specific memory B-cells in relation with the plasma IgG-levels are shown in Fig. 3. Remarkably, the same pattern is noticed for memory B-cell frequencies and the antibody responses specific for all vaccine antigens. An increase of both responses was observed one month after the booster, followed by a smaller decrease after one year that still exceeded the pre-booster responses. 3.4. Memory B-cell responses predict antibody levels Importantly, the number of PT- and Prn-specific memory B-cells at one month post-booster significantly correlated with the corresponding IgG level at one year (Fig. 4A–C). Due to high B-cell and antibody-responses in the majority of the children, this correlation failed to reach significance for FHA. Moreover, a correlation was found between the pre-booster number of memory B-cells and the antibody response at 1-month post-booster which was significant for PT, but not for FHA and Prn (Fig. 4D–F).

Fig. 2. Longitudinal numbers of PT-, FHA-, Prn- and Td-specific memory B-cells per 105 B-cells (y-axis logarithmic scale) for each child before, one month and one year after the booster (x-axis).

L.H. Hendrikx et al. / Vaccine 30 (2011) 51–58

A.

B.

C.

D.

E.

F.

55

Fig. 3. Correlation between the geometric mean frequencies of the memory B-cells (in histograms with a linear left y-axis) indicated as percentages of the total IgG-producing memory B-cell pool and the GMCs (indicated as circles with a connecting line with a logarithmic right y-axis) of specific antibodies to PT (A), FHA (B), Prn (C), Fim2/3 (D), ACT (E) and tetanus (F).

4. Discussion A second aP booster vaccination in Dutch wP primed children 9 years of age induces an enhanced memory B-cell immune response specific for the B. pertussis vaccine antigens. Notwithstanding a small decline after one year, most importantly, both B-cell and humoral responses substantially exceeded pre-booster levels at one-year follow-up and the persistent high avidity of the PT- and Prn-antibodies reflects the increased memory B-cell pool that may be sustained hopefully for a longer time. Furthermore, high numbers of pertussis-specific memory B-cells at one month after the booster correlate quite reliably with the corresponding high antibody response still found after one year. This underlines the importance of an adequate induction of memory B-cell immunity. Recently, we identified significantly higher pertussis-specific memory B-cell and IgG responses in aP primed children 4 years of age compared to Dutch wP primed children of the same age, indicating that the Dutch wP vaccine is less immunogenic than the aP vaccine [13,41]. Memory B-cell immune responses to PT and FHA in children 9 years of age in this study are comparable with those in aP primed children that were measured in a previous study at 4 years of age [41]. This is remarkable since the aP vaccine used as a second booster vaccination in the present study contained a much lower pertussis-antigen dose as compared to the high-dose aP vaccine that was administered 5 times in the aP primed children that were studied at 4 years of age. Only for Prn both memory B-cell and IgG responses excelled in aP primed children at 4 years of age, indicating that Prn is a highly immunogenic component in aP vaccines. Since the introduction of the aP vaccine has led to improved protection against whooping cough in the young children [8], the results

of this study imply an important role for an aP booster vaccination in older children and adults who had received the wP vaccine at infant age and in which pertussis is reemerging nowadays. In our study a typical vaccine-specific memory response was identified up to one year after booster vaccination for both memory B-cells and antibodies. About 0.1–0.4% of the total memory B-cells were specific for the antigens included in the aP booster vaccine, which is concurrent with percentages found after vaccination against other pathogens [19–21]. Most importantly, the high level of pertussis-specific memory B-cells observed at one month after the booster and associated with the high corresponding antibody levels and avidity indices at one-year follow-up, indicates an important role for the pertussis-specific memory B-cell pool in long-term immunity after vaccination at adolescent age. In steady state conditions, the long-lived plasma cells in the bone marrow are responsible for the production of background serum IgG levels. Antigen-specific memory B-cells circulate in the blood and after re-encountering the antigen they are able to rapidly respond, proliferate and differentiate in antibody-producing plasma cells. Afterwards, a higher number of antigen-specific memory B-cells in the blood is expected and avidity maturation of the produced antibodies occurs [22], which is supported by our findings. De Greeff et al. recently showed an incidence of whooping cough of 9% in the Dutch population above 9 years of age, based on increased IgG-PT levels >62.5 EU/ml [23], which is consistent with our findings in children 9 years of age. Despite this substantial part of children that recently contacted B. pertussis, this did not influence our findings as pre-booster pertussis-specific memory B-cell immune responses and antibody values were low in both study groups of children recruited in 2007 and 2009. Since we additionally measured low pre- and post-booster antibody and

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A.

D.

B.

E.

C.

F.

Fig. 4. Spearman correlations and linear regression lines between the one-month post-booster number of PT (A), FHA (B) and Prn (C) specific memory B-cells per 105 B-cells (y-axis, logarithmic) and the corresponding plasma IgG level at one year post-booster (x-axis, logarithmic) and the pre-booster number of PT (D), FHA (E) and Prn (F) specific memory B-cells (y-axis, logarithmic) and the corresponding IgG level at one month post-booster (x-axis, logarithmic).

memory B-cell responses to the non-vaccine pertussis proteins, we tentatively conclude that the results presented here in the present study were induced by the aP booster and were not significantly affected by the circulation of B. pertussis in the Dutch population. Previous studies about the effect of pertussis vaccinations on the immune response in adolescents or adults mainly focused on antibody levels. Booster responses at one month in our study are concurrent with the antibody levels found in these studies [24–30]. Moreover, we found the same pattern of post-booster antibody responses with one-year follow-up IgG levels that significantly surpassed pre-booster levels, which was also observed in other studies [9,31,32]. Hallander et al. showed a pattern of pertussisspecific antibody responses that consisted of a fast antibody decay within the first year after infant vaccination followed by a slower decrease in the 6 years thereafter [11]. If the same pattern is also applicable after booster vaccination in older children, our higher anti-PT levels might imply an improved long-term protection against whooping cough. Nevertheless, Mertsola et al. recently showed that pertussis-specific antibody levels had waned to

pre-booster levels 10 years after an adolescent booster vaccination [33]. Therefore, memory B- and T-lymphocytes are considered to play a major role in protection against whooping cough [34]. In this longitudinal study, the effect of an adolescent booster vaccination on pertussis-specific memory B-cell immunity is determined for the first time. Only a small number of studies investigated cell-mediated immune responses after pertussis vaccination in humans, which solely comprised T-cell responses [35–38]. Guiso et al. showed higher lymphoproliferative responses in aP primed children 7–9 years of age compared with wP primed children [36]. Since at present the aP vaccine is administered at infant age in most countries, it will be of great interest to investigate the influence of aP priming on memory B-cell immune responses before and after an aP booster vaccination at older age. However, questions about the effectiveness of booster vaccinations in older children and adolescents have risen as well. Transmission studies have shown that mothers and siblings (regularly < 9 years of age) are the main source of infection for the vulnerable young infant [6,39]. Recently, Rohani et al. disputed the

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epidemiological relevance and cost effectiveness of booster programs in adolescents and adults, since they found that the contact network structure is important in the epidemiology of pertussis [40]. Nevertheless, in some industrialized countries the adolescent booster vaccination has already been introduced in an attempt to challenge the resurgence of B. pertussis. In The Netherlands, the regular DT-IPV at the age of 9 can easily be replaced by a combined DTaP-IPV without jeopardizing the high vaccination coverage since this implies no extra injection. To contribute to the discussion about the optimalization of pertussis immunization policies, follow-up data beyond one year in our wP primed children 9 years of age as well as future studies in the aP primed populations are needed. In conclusion, the second aP booster vaccination in children 9 years of age enhanced pertussis-specific memory immune responses that sustain at least for one year. Since antibody levels wane in both wP and aP vaccinated populations and the incidence of whooping cough is most prominent in individuals above 9 years of age [23], this study supports the introduction of a booster vaccination in these large age cohorts.

[15]

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Acknowledgements

[22]

This study work was supported by the Dutch government. Conflict of interest: There is no conflict of interest. We would like to thank all children who participated in the BOOSTER study. In addition we would like to thank all research staff from the Spaarne hospital Hoofddorp, in special Carlinda Bresser. At the National Institute for Public Health and the Environment in Bilthoven we would like to thank Rose-minke Schure for technical assistance.

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