low dose diphtheria vaccines given as a booster to UK teenagers

Vaccine 23 (2005) 3829–3835

Immunogenicity and reactogenicity of combined acellular pertussis/tetanus/low dose diphtheria vaccines given as a booster to UK teenagers Jo Southern a,∗ , Nick Andrews a , Moya Burrage b , Elizabeth Miller a a

Immunisation Department, Communicable Disease Surveillance Centre, Health Protection Agency, 61 Colindale Avenue, Colindale, London, UK b Immunoassay Laboratory, Health Protection Agency, Porton, Salisbury, UK Received 21 September 2004; received in revised form 21 January 2005; accepted 1 February 2005 Available online 30 March 2005

Abstract Sustained high incidence of pertussis, particularly amongst unvaccinated infants, is of concern. Inclusion of pertussis vaccination with tetanus and low dose diphtheria (Td) teenage boosters may protect individuals through reproductive years, and prevent transmission to offspring. UK teenagers who had previously received only a three-dose primary course of whole cell pertussis vaccination in infancy and who were due to receive a Td booster (n = 323) were randomised to four groups: Td, TdaP, TdaP-inactivated polio vaccine (IPV) (Aventis Pasteur), TdaP (GlaxoSmithKline). There were significant pre- to post-vaccination GMC and GMFR increase for vaccine-contained pertussis antigens (p < 0.001) in recipients of aP-containing vaccine. All groups demonstrated significant increases pre- to 4 weeks post-vaccination in diphtheria (D)/tetanus (T) geometric mean concentrations (GMCs) and fold rises (GMFRs) (p < 0.001). Groups all achieved similar D and T post-vaccination GMCs. Local reactogenicity was generally similar between groups and was not associated with pre-booster diphtheria/tetanus antibody levels. A minority of vaccinees reported systemic symptoms with similar proportions between groups for each symptom assessed. This study demonstrated that addition of aP and/or IPV to Td vaccine did not materially alter reactogenicity or immunogenicity of Td components, and induced immune responses to pertussis antigens in teenagers who had received no pertussis vaccine since infancy. © 2005 Elsevier Ltd. All rights reserved. Keywords: TdaP; Vaccination; Booster

1. Introduction The role of whooping cough in adults in maintaining endemic transmission of Bordetella pertussis in populations with well-implemented infant vaccination programmes has been increasingly recognised in recent years [1]. Not only is pertussis an important cause of persistent cough in adults [2–4] but it may also be a source of infection for young infants in whom pertussis is a severe and potentially life threatening infection. A recent study in the US of infants with reported pertussis, over 70% had been infected by their mother or other family member, the majority of whom were aged 20 years or more [5]. Another study in UK infants admitted to paediatric ∗

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0264-410X/$ – see front matter © 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.vaccine.2005.02.030

intensive care with acute respiratory tract infection, apnoea and bradycardia showed that 20% had laboratory evidence of pertussis of whom half were infected from an adult family member [6]. Though pertussis vaccination of infants has significantly reduced disease incidence in children, vaccination does not provide long-term protection [7,8] and most developed countries now give one or more booster dose after completion of the primary infant course. In the UK, a combined diphtheria, tetanus, acellular pertussis (DTaP) booster was added to the primary infant 2/3/4 month schedule in 2001 to be given at 3–4 years of age prior to school entry. However, countries already giving a pertussis vaccine booster at this age have seen rising numbers of cases in teenage years, so a second booster in adolescence may be indicated in the UK in the future, combined with the existing tetanus/low dose diphtheria/(Td)

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vaccine already given at this age. Use of wP vaccines would not be acceptable due to the high incidence of side effects such as local reactions and pyrexia [9]. Studies in adults with several aP vaccines have demonstrated immunogenicity and low reactogenicity when given either as a monovalent pertussis or combined with Td [10–13]. In anticipation of the need to boost immunity to pertussis in young UK adults, a phase II trial with candidate TdaP vaccines in adolescents was conducted. A vaccine with inactivated polio vaccine (IPV) in place of oral polio vaccine (OPV) was included in anticipation of a change in the near future to IPV. Data on antibody responses and reactogenicity of the vaccines are reported.

2. Methods 2.1. Study design This was a randomised, single blind phase II/III reactogenicity and immunogenicity study; (subjects were not informed of which vaccine they received). Prior to enrolment subjects were screened for eligibility: inclusion criteria were informed written consent from student and parent/guardian; aged 13–17 years with evidence of receipt of ≥4 doses of DT-containing vaccine (three in infancy and a booster) with ≥8 years since the last dose. Exclusions were: contraindications to diphtheria, tetanus, pertussis or poliomyelitis vaccines [14]; language difficulty sufficient to preclude adequate comprehension of the study; current participation in any other trial; possibility of pregnancy. 2.2. Sample size Immunogenicity was the primary endpoint in determining sample size. Eighty subjects per group was sufficient to detect ∼2-fold differences in geometric mean titres (GMTs) between groups assuming 80% power, 2 sided 5% significance, standard deviation within a group of 0.5 log10 titres with correction for multiple comparisons. Within any group

the 95% confidence interval for GMT was ∼±30% of the GMT. Analyses of reactogenicity data were possible by comparing between groups. Eighty subjects per group had 80% power at a 5% significance level to detect large differences in reaction rates between groups such as true rates of 20% versus 50%, allowing for multiple comparisons within groups. 2.3. Treatment schedule Subjects were assigned to a treatment group according to a computerised block-randomisation in order of inclusion. A single dose, 0.5 ml, of one of four vaccines was administered intramuscularly in the deltoid muscle of the non-dominant arm. The vaccines studied were GlaxoSimithKline (GSK), Aventis Pasteur TdaP or TdaP-IPV (all three unlicensed products given under clinical trial exemption (CTX) certificates) and Aventis Pasteur Td (licensed product, control group). The composition of these vaccines is detailed in Table 1. Re-randomisation was conducted for remaining study numbers after late inclusion of the GSK vaccine due to issues of vaccine availability. 2.4. Serology Blood samples were taken prior to and 4–6 weeks postvaccination. The First International Standard for anti-tetanus IgG human (26/488) and diphtheria antitoxin human serum (91/534) (National Institute for Biological Standards and Control (NIBSC), UK) were used as references for tetanus and diphtheria antibodies, respectively, with results expressed as International Units (IU) per ml. Pertussis serum (human) (preparation 89/530 NIBSC) was used as in-house reference for pertussis antibody assay. Enzyme-linked immunosorbent assays (ELISAs) were employed for measuring IgG to detoxified pertussis toxin (PT), filamentous haemagglutinin (FHA), pertactin (PRN) and fimbriae (FIMS) as previously described [15]. Results

Table 1 Composition of vaccines used in this study; subjects randomised 1:1:1:1 on order of inclusion in the study by a block randomised procedure Pertussis components

Tda (Aventis Pasteur) TdaPb (GlaxoSmithKline) TdaPb (Aventis Pasteur) TdaP-IPVb (Aventis Pasteur)

a b

PT (mcg)

FHA (mcg)

PRN (mcg)

FIM (mcg)

Nil 8 2.5 2.5

Nil 8 5 5

Nil 2.5 3 3

Nil Nil 5 5

Given under its licensed indication. Given under a clinical trial exemption (CTX) certificate.

AL3+ (mg)

2-Phenoxyethanol

Diphtheria

Tetanus

Polio

Nil 0.5 0.33 0.33

Nil 2.5 mg 0.60% 0.60%

≥4 IU ≥2 IU/2.5 Lf ≥2 IU/2 Lf ≥2 IU/2 Lf

≥40 IU ≥20 IU/5 Lf ≥20 IU/5 Lf ≥20 IU/5 Lf

Nil Nil Nil Type 1 – 40 D antigen units Type 2 – 8 D antigen units Type 3 – 32 D antigen units

J. Southern et al. / Vaccine 23 (2005) 3829–3835

are expressed as GMTs against reference 89/530 as in previous reports [9,15,16]. The PT, mixed FIMS 2&3, FHA, tetanus and diphtheria antigens were obtained from Porton, UK, PRN antigen from Medeva, UK. 2.5. Reactogenicity data Subjects completed 10-day post-vaccination health diaries, documenting oral temperature, local reactions and systemic symptoms. Serious adverse events (death, non-elective hospitalisation, life threatening event, any event leading to sequelae) were ascertained on interview 4–6 weeks post-vaccination, or by notification from general practitioners or subjects/family members. 2.6. Data Analysis Randomisation was validated using chi-squared and ANOVA tests to compare demographics of subjects between groups. These data were also compared for those who did or did not return a diary.

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Geometric means with 95% confidence intervals (CIs) were calculated using log-transformed data for the diphtheria, tetanus and pertussis antigens. The geometric means were compared between groups using t-tests and from pre- to post-vaccination using paired t-tests. The effect of age, sex and pre-vaccination antibody log-titre on the post-vaccination log-titre was assessed using multiple-linear regression. Proportions of subjects reporting local reactions were compared between groups using a chi-squared test or Fisher’s Exact test as appropriate for the whole diary period, and for days 1–3 (inclusive) as a measure of acute effects. Effects of age, sex and pre-existing diphtheria and tetanus antibody levels on local reactions were assessed using logistic regression. When comparing the groups it was important to use regression to adjust for pre-existing diphtheria antibodies because time since vaccination with a CRM-containing meningococcal C conjugate vaccination administered in a national catch-up campaign [17] differed between groups due to late inclusion of the GSK TdaP vaccine (Table 2); CRM is a naturally-occurring non-toxigenic mutant of diphtheria toxin that induces an antibody response similar to that of diphtheria toxoid vaccine [18].

Table 2 Geometric mean titres (GMTs) and geometric mean fold rises (GMFRs) to pertussis antigens [pertussis toxin (PT), filamentous haemagglutinin (FHA), pertactin (PRN) and fimbriae types 2&3 (FIMS)] pre to post booster, and diphtheria (d) and tetanus (T) serum IgG geometric mean concentrations (GMCs) (95% CI) in adolescents measured in standard ELISA units after booster with Td and TdaP-containing vaccines Td (control)

TdaP (GSK)

TdaP (Aventis Pasteur)

TdaP-IPV (Aventis Pasteur)

Number of subjects recruited Paired samples obtained (%) Mean age at booster (range) in years Mean interval MCC to booster (range) in years [n with MCC vaccination recorded] Sex ratio (M:F)

79 71 (89.9) 14.93 (13.7–17.3) 0.85 (0.3–1.8) [76]

79 68 (86.1) 14.95 (13.8–17.9) 1.39 (0.4–1.8) [74]

83 74 (89.2) 14.78 (14.7–14.7) 0.92 (0.3–2.6) [78]

82 75 (91.5) 15.02 (13.1–17.4) 0.93 (0.4–1.7) [76]

1.13 (42:37)

0.72 (33:46)

1.37 (48:35)

0.82 (37:45)

PT

Pre-booster GMT Post-booster GMT GMFR

995 (699, 1416) 984 (701, 1382) 0.99 (0.93, 1.04)

1077 (756, 1536) 8792 (6689, 11556) 8.16 (6.30, 10.57)

857 (633, 1160) 2998 (2288, 3925) 3.51 (2.90, 4.23)

848 (632, 1138) 3812 (2947, 4931) 4.50 (3.61, 5.61)

FHA

Pre-booster GMT Post-booster GMT GMFR

2858 (2214, 3691) 2882 (2246, 3699) 1.00 (0.97, 1.05)

2659 (2042, 3462) 36367 (30736, 43029) 13.68 (10.16, 18.41)

2450 (1930, 3111) 17360 (14058, 21439) 7.08 (5.40, 9.30)

2299 (1845, 2865) 12597 (10509, 15100) 5.48 (4.48, 6.69)

PRN

Pre-booster GMT Post-booster GMT GMFR

2524 (1819, 3502) 2534 (1840, 3491) 1.00 (0.96, 1.05)

2782 (1942, 3984) 81177 (61344, 107424) 29.18 (21.46, 39.67)

1859 (1384, 2497) 36406 (27778, 47715) 19.44 (13.40, 28.21)

1735 (1264, 2381) 66438 (52843, 83531) 38.33 (28.05, 52.37)

FIMS

Pre-booster GMT Post-booster GMT GMFR

4082 (2634, 6328) 4224 (2752, 6484) 1.03 (0.98, 1.09)

3654 (2489, 5364) 4355 (3087, 6144) 1.19 (1.10, 1.29)

3630 (2635, 5001) 58225 (44204, 76694) 16.03 (10.25, 25.06)

3558 (2455, 5157) 45704 (34466, 60608) 12.84 (8.87, 18.58)

Diphtheria

Pre-booster GMC Pre-booster number (%) with <0.1 IU/ml Post-booster GMC

4.03 (2.85, 5.68) 3 (4.3)

1.78 (1.26, 2.51) 0 (0)

3.85 (2.80, 5.29) 1 (1.4)

3.95 (2.80, 5.57) 2 (2.5)

6.60 (5.36, 8.11)

4.43 (3.69, 5.32)

7.64 (6.35, 9.18)

6.71 (5.40, 8.35)

Pre-booster GMC Pre-booster number (%) with <0.1 IU/ml Post-booster GMC

0.43 (0.32, 0.59) 10 (14.7)

0.30 (0.24, 0.39) 5 (7.1)

0.37 (0.28, 0.50) 5 (7.1)

0.402 (0.31, 0.52) 7 (8.9)

21.86 (17.57, 27.19)

22.24 (17.65, 28.03)

27.98 (22.66, 34.53)

18.20 (15.37, 21.56)

Tetanus

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Table 3 Local reactions and oral temperatures reported in subject-completed 10 day health diaries following booster vaccination with tetanus (T) and low dose diphtheria (d) vaccines, combined with acellular pertussis (aP) and inactivated polio vaccine (IPV)

Number of subjects recruited Number of diaries returned (% of N recruited)

Td (control)

TdaP (GSK)

TdaP (Aventis Pasteur)

TdaP-IPV (Aventis Pasteur)

p

79 72 (91)

79 68 (86)

83 74 (89)

82 76 (93)

0.55

Redness

Number ≥2.5 cm (%) Number ≥5.0 cm (%)

10 (13.9) 2 (2.8)

7 (10.1) 5 (7.2)

15 (20.3) 8 (10.8)

19 (25.0) 16 (21.1)

0.09 0.003a

Swelling

Number ≥2.5 cm (%) Number ≥5.0 cm (%)

10 (13.9) 5 (6.9)

11 (16.2) 5 (7.4)

18 (24.3) 11 (14.9)

15 (19.7) 11 (14.5)

0.39 0.24

Pain/tenderness

Number no pain (%) Number ≥3 days pain (%) Number ≥5 days pain (%)

13 (18.1) 45 (62.5) 16 (22.2)

10 (14.7) 40 (58.0) 15 (21.7)

15 (20.3) 45 (60.8) 16 (21.6)

9 (11.8) 39 (51.3) 9 (11.8)

0.56 0.52 0.30

Oral temp

Number >38 ◦ C (%)

4 (5.6)

2 (2.9)

5 (6.8)

3 (4.0)

0.69

a

TdaP GSK vs. Td, p = 0.265; TdaP Aventis vs. Td, p = 0.098; TdaP-IPV vs. Td, p = 0.001.

3. Results In total, 323 subjects were recruited; 290 (90%) returned diaries and 288 (89.2%) provided paired serology samples. Proportions with paired samples ranged from 86–92% between groups (p = 0.74) (Table 2). Proportions returning diaries ranged from 87–93% between groups (p = 0.55) (Table 3). Overall the mean age at vaccination was 15.02 years (range 13.08–17.86 years) and the sex ratio was 0.98 (160M:163F); the age and sex distribution did not differ significantly between vaccine (p = 0.10 and p = 0.16, respectively). Comparison of those returning a diary or not showed they were similar by age at vaccination (p = 0.36) and sex (p = 0.90). 3.1. Serology 3.1.1. Pertussis antigens Pre-booster GMTs were similar between groups for all pertussis antigens (Table 2). The three groups that received aP showed significant increases from pre-to-post booster GMTs to PT, FHA and PRN (all p < 0.001). Compared to the control group, these groups had significantly higher post-booster GMTs for these antigens and significantly greater geometric mean fold rises (GMFRs) (all p < 0.001) (Table 2). The GMFR was significantly higher for the GSK group compared to the Aventis groups for PT and FHA (all p < 0.001) (Table 2). For PRN the GMFR in the Aventis TdaP-IPV group was significantly higher than the Aventis TdaP group (p = 0.007) but was similar to the GSK group (p = 0.23). Only Aventis vaccines contained FIM, therefore as expected neither the control nor GSK groups showed responses. However, both Aventis groups had significant increases in FIM GMTs and GMFRs pre-to-post booster (all p < 0.001), which were similar between the groups (p = 0.23 and p = 0.45, respectively).

3.1.2. Diphtheria and tetanus There were no significant differences in tetanus GMCs between groups pre or post booster (all p > 0.1) and each group demonstrated significant increases in GMC pre-to-post booster (all p < 0.001) (Table 2). The proportion of subjects with tetanus IgG < 0.1 IU ml was similar between groups prebooster (p = 0.38) (Table 2) and all subjects had achieved post-booster titres ≥0.1 IU/ml. The MCC vaccine used in this age group contained CRM protein conjugate which has previously been shown to boost diphtheria levels. The late inclusion of the GSK group in the study meant that the time since MCC-CRM was longer, and hence that, consistent with waning of diphtheria IgG over time, the GSK group had a lower diphtheria GMC pre-booster than the other groups (Table 2), (p < 0.001). However, the proportion of subjects with diphtheria IgG < 0.1 IU/ml was similar between groups pre-booster (p = 0.31) (Table 2) and all subjects achieved post-booster titres ≥0.1 IU/ml. Post-booster there was a significant difference between groups in diphtheria titres (p = 0.001) with the lower titres in the GSK group persisting. However, this difference between groups in post-booster titres disappeared (p = 0.15) when the pre-booster level was adjusted for in the regression analysis. The GSK group had an adjusted titre within 5% of that in the control group. There were no differences in post-vaccination diphtheria or tetanus levels by age or sex (all p > 0.1). 3.2. Local reactions A minority of subjects reported redness and swelling, however the majority noted some pain (Table 3). 3.2.1. Association with pre-existing antibody Pre-booster antibody levels for diphtheria and tetanus were assessed (Table 2) and were not associated with any measures of local reactions: redness or swelling ≥2.5 or ≥5.0 cm, or pain ≥3 or ≥5 days (p ≥ 0.1). Age and sex

J. Southern et al. / Vaccine 23 (2005) 3829–3835

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Table 4 Systemic symptom episodes reported in subject-completed diaries within 3 or 10 days following booster vaccination with tetanus (T) and low dose diphtheria (d) vaccines, combined with acellular pertussis (aP) and inactivated polio vaccine (IPV), according to a randomisation procedure Td

Number of diaries returned (% of N recruited)

TdaP (GSK)

TdaP (Aventis Pasteur)

TdaP-IPV (Aventis Pasteur)

p

N

(%)

N

(%)

N

(%)

N

(%)

72

(91)

68

(86)

74

(89)

76

(93)

0.55

Dizziness/feeling faint

Days 1–10 (inc) Days 1–3 (inc)

7 6

(9.7) (8.3)

3 2

(4.4) (2.9)

3 3

(4.1) (4.1)

8 6

(11.8) (7.9)

0.29 0.42

Fatigue/malaise/drowsy

Days 1-10 (inc) Days 1–3 (inc)

5 4

(6.9) (5.6)

9 6

(13.2) (8.8)

12 10

(16.2) (13.5)

10 9

(13.5) (11.8)

0.39 0.38

Gastrointestinal problem – diarrhoea, constipation

Days 1–10 (inc)

1

(1.4)

2

(2.9)

4

(5.4)

3

(3.9)

0.63

Days 1–3 (inc)

1

(1.4)

1

(1.5)

2

(2.7)

1

(1.3)

0.94

Headache

Days 1–10 (inc) 20 Days 1–3 (inc) 14

(27.8) 24 (19.4) 13

(35.3) (19.1)

23 20

(31.1) (27.0)

29 25

(38.2) (33.8)

0.56 0.16

Nausea/vomiting

Days 1–10 (inc) Days 1–3 (inc)

(6.9) (5.6)

(6.9) (4.4)

9 4

(12.2) (5.4)

4 4

(5.3) (5.4)

0.48 1.00

URTI symptoms

Days 1–10 (inc) 10 Days 1–3 (inc) 6

(16.7) (5.9)

11 6

(14.9) (8.1)

18 10

(23.7) (13.2)

0.39 0.51

5 4

5 3

(13.9) 12 (8.3) 4

NB: for this analysis, each subject could contribute only once for each symptom, but could contribute to more than one symptom.

were only significantly associated with pain ≥5 days; 14/146 (28%) females had pain ≥5 days compared with 15/144 (10%) of males (p < 0.001). Those with pain ≥5 days were younger on average by 2.4 months (p = 0.03).

3.2.2. Redness Proportions reporting ≥2.5 cm redness were similar between groups (p = 0.09). Compared to the control group, proportions reporting ≥5.0 cm redness were similar for GSK

Fig. 1. (a) Reports of URTI symptom episodes from subject-completed 10 day health diaries, by vaccine. (b) Reports of headache post-vaccination from subject-completed 10 day diaries, by vaccine.

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(p = 0.27) and Aventis TdaP (p = 0.10) but were higher for TdaP-IPV (p = 0.001) (Table 3). Local erythema was maximal on the second day after vaccination for all vaccines. 3.2.3. Swelling Proportions reporting swelling of ≥2.5 and ≥5.0 cm were similar between the groups (p = 0.39 and p = 0.24, respectively) (Table 3). One swelling ≥15.0 cm was noted in each Aventis group. 3.2.4. Pain Pain was reported by the majority of subjects (Table 3). Groups were similar for proportions reporting no pain (p = 0.56), ≥3 days pain (p = 0.52) or ≥5 days pain (p = 0.30). 3.3. Systemic symptoms Systemic symptoms were reported by a minority of subjects including headache, nausea/vomiting, fatigue/malaise, gastrointestinal problems (diarrhoea/constipation) and upper respiratory tract infections (URTIs); the frequency of such symptoms within 3 or 10 days post-vaccination and with was similar between vaccine groups (Table 4). There was a clear temporal association between headache and vaccination (Fig. 1a) but URTIs were reported at a similar rate throughout the 10-day post-vaccination period (Fig. 1b). There was no association between headache and local redness ≥2.5 cm (p = 0.12) or ≥5.0 cm (p = 0.269) in the first 3 days after vaccination. The proportions reporting temperatures ≥38 ◦ C were similar between the groups (p = 0.75) (Table 3) and were mainly reported in those with URTI symptoms. No serious adverse events were reported.

4. Discussion This study showed that replacement of the Td booster vaccine currently given to UK adolescents with a combined TdaP or TdaP-IPV vaccine would not materially increase the frequency of local or systemic post-vaccination symptoms, nor compromise the diphtheria and tetanus responses. Our findings are consistent with those of others who have compared in teenagers and adults the immunogenicity and reactogenicity of a Td and TdaP vaccine [19], or a Td-IPV and TdaP-IPV vaccine [20]. Despite the long interval since primary immunisation and the lack of subsequent pertussis vaccine boosters, the study population demonstrated significant IgG antibody responses to the acellular components in the TdaP vaccines. Although there are no established serological correlates of protection for pertussis, it seems reasonable to assume that the booster responses induced by TdaP vaccines will be associated with better protection against pertussis. In our adolescent population IgG antibody levels to PT, FHA, PRN and FIMS prior to boosting were all significantly higher than we have found in

younger children in the same study area 1–3 years after completion of primary immunisation with DTPw [16]. This suggests boosting of humoral immunity through natural exposure to B. pertussis and is consistent with a population-based seroepidemiological study in the UK [21]. Efficacy studies in the UK suggest that protection from DTwP vaccines given in infancy and without a subsequent booster wanes markedly during the school age years [22,23]. The recent addition of an acellular pertussis booster to the UK schedule to be given at school entry should address this problem but the duration of protection is not known. The rise in cases in young adults in countries that already give a pre-school booster [24] suggests that addition of pertussis antigens to vaccines administered in adolescence could be indicated in the future. The study showed differences between TdaP vaccines in the magnitude of booster responses for some antigens. The higher IgG response to PT for the GSK group compared to the Aventis Pasteur groups may reflect the >3-fold higher PT content of the GSK vaccine (Table 1). When used for infant immunisation, aP vaccines from these manufacturers (which contain higher amounts of pertussis antigen than the vaccines used in this trial) demonstrated good efficacy with some evidence of better protection with the Aventis Pasteur vaccine, possibly due to the inclusion of fimbrial antigens [25]. Comparison of the Aventis Pasteur groups revealed responses to all antigens were generally similar, indicating that the addition of IPV did not materially affect immunogenicity of the other antigens. This study provided an opportunity to study the effect of high pre-vaccination diphtheria IgG levels on local reactions as many adolescents in this study had recently received a MCC vaccine containing CRM197 . It has been postulated that the local erythema and swelling that commonly develops shortly after a toxoid vaccination is the result of an Arthus reaction [26] which occurs when antigen–antibody complexes are formed in the presence of high antibody levels and deposited in the walls of blood vessels where they initiate a local inflammatory response. As expected, the pre-booster diphtheria antibody levels were high in all groups reflecting the known boosting effect of MCC-CRM [18] but there was no association between pre-booster titres and the magnitude of the local reaction. Similarly there was no correlation between pre-booster tetanus IgG levels and local reactogenicity; although no tetanus booster had been given for at least 8 years, around 90% of subjects still had levels ≥0.1 IU/ml. The local erythema and swelling observed in our study do not therefore appear to be manifestations of an Arthus-type reaction. In conclusion, the TdaP and TdaP-IPV vaccines administered in this study were immunogenic, and well tolerated in UK teenagers, when compared with the currently used Td vaccine. Replacement of Td by a TdaP or TdaP-IPV vaccine for adolescents could provide additional protection against pertussis, now recognised as a common cause of prolonged cough in young adults. However, data are required on the clinical efficacy of a booster given at this age and on the

J. Southern et al. / Vaccine 23 (2005) 3829–3835

duration of protection, a critical factor if unvaccinated young infants are to be protected from acquiring pertussis from an adult family member [6].

Acknowledgements We thank the study nurses in Hertfordshire for the patient recruitment and follow-up, and Joan Vurdien and Teresa Gibbs for their help with study administration. We also thank Dr. David Salisbury Department of Health, London, for his help in funding this study (Grant number 1632/1905/63214) and Aventis Pasteur MSD for supporting the follow up of the TdPa/IPV group. We thank the reviewers for their helpful comments.

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