Comparison of the immunogenicity and reactogenicity of two commercially available hexavalent vaccines administered as a primary vaccination course at 2, 4 and 6 months of age

Vaccine 23 (2005) 3272–3279

Comparison of the immunogenicity and reactogenicity of two commercially available hexavalent vaccines administered as a primary vaccination course at 2, 4 and 6 months of age夽 I. Tichmann a , H. Preidel b , D. Grunert c , S. Habash d , R. Schult e , R. Maier f , P.K. Gildberg e , H.-C. Sengespeik a , F. Meurice g , R. S¨anger h, ∗ a

Arztpraxis M¨unchen, Germany Arztpraxis Olching, Germany c Arztpraxis N¨ ordlingen, Germany d Arztpraxis Cham, Germany e Arztpraxis Flensburg, Germany f Arztpraxis Tuttlingen, Germany GlaxoSmithKline (GSK) Biologicals, Rue de l’institut 89, Rixensart B1330, Belgium h GlaxoSmithKline GmbH & Co KG, D-80339 Munich, Germany b

g

Received 3 June 2004; received in revised form 27 December 2004; accepted 5 January 2005 Available online 26 January 2005

Abstract Infants (N = 459) were randomly assigned to receive either InfanrixTM hexa or HexavacTM vaccines at 2, 4 and 6 months of age as a primary vaccination schedule. The immunogenicity of the hepatitis B component was statistically significantly higher for InfanrixTM hexa compared to HexavacTM in terms of both seroprotection (98.6% versus 94.7%, p = 0.0302) and GMCs (905.6 versus 226.4, p < 0.0001). Significantly (p ≤ 0.0001) higher antibody levels against diphtheria and the 3 polio components were also induced by InfanrixTM hexa. The responses to tetanus, Hib and pertussis components were similar. The incidences of clinically relevant solicited symptoms, unsolicited symptoms or serious adverse events were low in both groups. © 2005 Elsevier Ltd. All rights reserved. Keywords: Combined hexavalent paediatric vaccines; Diphtheria–tetanus–pertussis–hepatitis B–polio–Haemophilus influenzae type b vaccines; Primary immunisation

1. Introduction In recent years, the availability of new vaccines has led to an increase in the number of injections required to complete recommended paediatric vaccine schedules. This trend is likely to continue. Thus, the development of combination vaccines plays a key role in facilitating the inclusion of new 夽 The results from this trial have been presented in part during the satellite symposium at the 21st ESPID meeting, Taormina, Sicily in 2003. ∗ Corresponding author. Tel.: +49 89 3 60 44 0/86 64/86 37; fax: +49 89 3 60 44 89 22. E-mail address: [email protected] (R. S¨anger).

0264-410X/$ – see front matter © 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.vaccine.2005.01.087

vaccines into paediatric immunisation programmes. The diphtheria–tetanus–pertussis (DTP) combination vaccine has been the cornerstone of infant vaccination since the 1940s and has provided the foundation for development of combination vaccines. The original whole cell pertussis vaccine component in DTP is now being increasingly replaced by the equally efficacious but less reactogenic acellular pertussis vaccines [1–7]. During the last decade, routine paediatric vaccination with conjugate Haemophilus influenzae type b (Hib) vaccines has been introduced in many countries and has proven to be highly successful in the prevention of Hib disease in young children. Hepatitis B vaccination is also increasingly being

I. Tichmann et al. / Vaccine 23 (2005) 3272–3279

incorporated into infant schedules as this seems to be the most effective means of preventing circulation of the hepatitis B virus [8–14]. Hepatitis B infection in childhood carries a high risk of progression to a chronic carrier state, which can lead to the development of fatal complications in later life [15]. As polio disease becomes rare and the risk of the oral polio vaccine (OPV) associated paralytic poliomyelitis appears relatively more significant, many industrialised countries are moving towards the use of the inactivated Salk polio vaccine (IPV), which is administered by injection [16]. The recently available Neisseria meningitidis C and Streptococcus pneumoniae conjugate vaccines are also being incorporated into infant schedules. The complicated logistics of administering all these different injections and the negative impact on vaccination compliance has prompted research into candidate multivalent vaccines that allow several different antigens to be administered in one single injection. Two such vaccines InfanrixTM hexa (GSK Biologicals) [17] and HexavacTM (Aventis Pasteur MSD) [18] have been licensed for use in paediatric schedules in Europe since 2000. Both are hexavalent vaccines containing diphtheria, tetanus, acellular pertussis, IPV, hepatitis B and Hib components. Data from non-comparative studies on the individual vaccines have indicated that there may be differences between these two vaccines with respect to the immunogenicity of one or more components [19–23]. However, until this present report, direct comparative data between these two vaccines had never been generated.

2. Methods 2.1. Study design and subjects This multi-centre, single blinded, randomised trial was conducted in 45 centres in Germany. The trial was approved by the appropriate Independent Ethics Committees and was conducted according to the Declaration of Helsinki and Good Clinical Practice. Written informed consent was

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obtained from the parents/guardians of all infants before enrolment into the study. Exclusion criteria for enrolment included evidence of previous or intercurrent diphtheria, tetanus, pertussis, hepatitis B, polio or Hib vaccination or disease and chronic administration (defined as more than 14 days) of immunosuppressants or other immune-modifying drugs from birth to the first vaccine dose or at any time during the study. Subjects were also excluded if they were participating in any other clinical trial or if they received any other vaccine during the study. 2.2. Study vaccines The composition of the two study vaccines HexavacTM (manufactured by Aventis Pasteur MSD) and InfanrixTM hexa (manufactured by GSK Biologicals) is given in Table 1. A series of three injections was administered intramuscularly in the antero-lateral thigh to each subject at 2, 4 and 6 months of age. 2.3. Serological analysis Blood samples were drawn immediately before administration of the first vaccine dose and at 1 month following administration of the third dose. Serum samples were stored at −20 to −70 ◦ C until blinded analyses conducted at GSK Biologicals’ laboratory in Rixensart, Belgium. Antibodies against diphtheria toxoid, tetanus toxoid, hepatitis B surface antigen (HBsAg), polio virus antigens, Hib polyribosyl ribitol phosphate (PRP) and pertussis antigens (pertussis toxoid (PT), Filamentous Haemagglutinin (FHA) and pertactin (PRN) were determined by standard techniques as described previously [24,25]. For all antibodies except pertussis, levels at or above the assay cut-offs were considered protective. The assay cut-offs were 0.1 IU/ml for diphtheria and tetanus, 10 mIU/ml for HBsAg, 0.15 ␮g/ml for Hib PRP and a neutralisation titre of 1:8 for polio virus types 1, 2 and 3. The minimum protective antibody level for diphtheria is generally accepted to be

Table 1 Vaccine formulation Vaccine component

Diphtheria toxoid (IU) Tetanus toxoid (IU) Pertussis toxoid (PT) (␮g) Filamentous haemagglutinin (FHA) (␮g) Pertactin (PRN) (␮g) Recombinant hepatitis B surface antigen (HBsAg) (␮g) Inactivated poliomyelitis type 1 (Ag units) Inactivated poliomyelitis type 2 (Ag units) Inactivated poliomyelitis type 3 (Ag units) Hib polysaccharide (polyribosyl ribitol phosphate) conjugated to tetanus toxoid (PRP-T)

Amount per dose (0.5 ml) InfanrixTM hexa

HexavacTM

≥30 ≥40 25 25 8 10

≥20 ≥40 25 25 – 5

40D 8D 32D 10 ␮g PRP, 20–40 ␮g T

40D 8D 32D 12 ␮g PRP, 24 ␮g T

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Table 2 Demographic characteristics Vaccine group

Number of subjects

Mean agea ± S.D. (weeks)

Gender (%female/%male)

Total cohort for safety analysis InfanrixTM hexa HexavacTM

235 224

8.7 ± 1.76 8.7 ± 1.83

41.7/58.3 46.4/53.6

ATP cohort for immunogenicity analysis InfanrixTM hexa 214 HexavacTM 207

8.7 ± 1.77 8.7 ± 1.85

41.6/58.4 46.4/53.6

a

Age at the time of the first vaccine dose.

0.01 IU/ml as determined by in vivo neutralisation assays [26]. As the cut-off of the ELISA assay used in this study was 0.1 IU/ml, samples with ELISA antibody levels below 0.1 IU/ml were retested using a VERO cell neutralising assay [27,28] with a cut-off of 0.016 IU/ml. As there are no generally accepted seroprotective antibody levels for pertussis, the criterion of vaccine response for PT, FHA and PRN components was defined as follows: a post vaccination concentration at or above the cut-off value (5 EU/ml) in initially seronegative subjects and at least maintenance of pre-vaccination antibody concentrations in subjects who were seropositive (i.e. with concentrations ≥ cut-off value) before vaccination. This definition thereby takes into consideration the half-life of decreasing maternal antibodies in initially seropositive subjects [29]. 2.4. Safety/reactogenicity The occurrence of solicited local (pain, redness and swelling at the injection site) and systemic symptoms (irritability, drowsiness, loss of appetite and fever) were recorded by parents or guardians in diary cards for a 4-day follow up period following each vaccine dose. Other unsolicited events occurring within a 31 day follow up after each vaccine dose and any serious adverse events occurring during the entire study period were also recorded. Any symptoms recorded were graded according to intensity. Clinically relevant symptoms were defined: for local pain as “crying when limb was moved/spontaneously painful”, for local redness and swelling as a diameter >20 mm, for fever as a rectal temperature >38.5 ◦ C, for irritability as “crying that could not be comforted or prevented normal everyday activities”, for loss of appetite as “not eating at all” during the day under consideration and for any other adverse event (solicited or unsolicited) as “preventing normal everyday activity”.

using the t-test and through the computation of the GMT ratio point estimate and associated 95% CI with adjustment for baseline titres. Standardised asymptotic 95% CI and two-sided Fisher exact test was used to study the difference in seroprotection and vaccine response rates between groups. The primary objective of this study was to demonstrate that the immunogenicity of the hepatitis B and/or Hib components of InfanrixTM hexa was higher than that of HexavacTM in terms of anti-HBsAg or anti-PRP antibody concentrations. Hence if one of the two-sided p-values (t-test) for the comparison of post-vaccination anti-HBsAg GMTs and anti-PRP GMTs was below 2.5% with a higher GMT observed with InfanrixTM hexa, one could conclude that the primary objective had been reached, thus preserving the overall 5% level for the study conclusion. A secondary objective was to demonstrate the non-inferiority of InfanrixTM hexa compared to HexavacTM in terms of seroprotection rates for diphtheria, tetanus and the three poliovirus types and also vaccine response rates to pertussis antigens. The criteria for non-inferiority was that the upper limit of the two-sided standardised asymptotic 95% CI for the group difference in seroprotection rates and vaccine response rates (HexavacTM minus InfanrixTM hexa) had to be below 10%. Another secondary objective of the study was to assess the reactogenicity of both vaccines. The percentage of doses (with 95% CI) followed by a report of any symptom and individual solicited symptoms within the 4-day follow-up period was calculated per group. Exploratory comparisons between groups were made for each symptom using the Fisher exact two-sided test. The incidence of unsolicited symptoms occurring within 31 days of vaccination was also computed.

3. Results 3.1. Subject population

2.5. Statistical analysis Analyses were performed using SAS (version 8.02) under Windows and StatXact (version 5.0). Seroprotection or vaccine response rates, geometric mean titres (GMT) and GMT ratios with 95% confidence intervals (CIs) were calculated per group for each antigen. Comparisons of post-vaccination GMTs between the two study groups were performed through direct comparisons on the log titres between groups

A total of 459 eligible healthy male and female infants aged 6–12 weeks were enrolled and randomly assigned to one of two groups to receive primary vaccination with either InfanrixTM hexa or HexavacTM vaccines. Of these, 442 completed the study. No subjects dropped out as a result of an adverse event. Four subjects were eliminated from the According to Protocol (ATP) safety analysis due to receipt of vaccines not specified in the protocol or missing essential

905.6 [752.3–1090.1] 226.4 [182.6–280.7] 911.0 [747.2–1110.6] 237.4 [193.0–292.0] 272.4 [216.9–342.1] 119.6 [96.8–147.8]

3.2. Immunogenicity The results of the ATP immunogenicity analysis 1 month following completion of the three dose primary vaccination course are shown in Table 3 (seroprotection or vaccine response rates and GMT levels) and Fig. 1 (antibody GMT ratio for InfanrixTM hexa/HexavacTM ). An analysis of all subjects from whom data had been collected (data not shown) indicated that no bias was introduced by focusing on the ATP population. The immunogenicity of the hepatitis B component was found to be statistically significantly higher for InfanrixTM hexa compared to HexavacTM in terms of both seroprotection (98.6% versus 94.7%, p = 0.0302) and GMTs (905.6 mIU/ml versus 226.4 mIU/ml, p < 0.0001). The primary objective of the study was therefore met. The data for the Hib component (seroprotection 94.9% versus 92.2%, GMTs 2.69 ␮g/ml versus 2.43 ␮g/ml for InfanrixTM hexa compared to HexavacTM ) did not show a significant difference. Data for the diphtheria, tetanus, polio and pertussis components of InfanrixTM hexa showed that there was no decrease in seroprotection or vaccine response rates when compared to HexavacTM . The criteria for non-inferiority were reached, as in all cases, the upper limit of the two-sided asymptotic 95% CI computed for the group difference was below 10%. For diphtheria the immune response was found to be significantly higher for InfanrixTM hexa compared to

cell neutralising assay was 98.1 [95.1–99.5]. ∗∗

∗

p < 0.05 by Fisher exact test. p ≤ 0.0001 by t-test.

302.8 [277.8–330.1] 300.3 [276.6–326.1] 65.2 [60.3–70.6] 61.5 [56.3–67.2] 2.42 [2.16–2.72] 2.53 [2.21–2.90]

GMTs [95%CI] InfanrixTM hexa (N = 214) 2.69 [2.19–3.32] 1.51 [1.33–1.72] HexavacTM (N = 207) 2.43 [1.89–3.14] 0.99 [0.84–1.16] a % seroprotection following further analysis by VERO

Anti-polio

PRN** FHA PT

Anti-pertussis Anti-T Anti-D** Anti-PRP

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data. A further 34 subjects (19 from the InfanrixTM hexa group and 15 from the HexavacTM group) were excluded from the ATP immunogenicity analysis. These exclusions were due to non-compliance with protocol criteria for vaccination (7 subjects) and blood sampling (4 subjects) schedules or because of lack of essential serological data (23 subjects) due to blood samples either missing or not analysable (insufficient volume or haemolysis). The safety analysis was performed on the total cohort only, as the difference between the ATP safety cohort and total cohort was less than 5%. Table 2 shows that the demographic characteristics of the cohorts for safety and immunogenicity analysis were comparable for the two groups.

167.4 [149.4–187.6] 2.7 [2.5–2.8]

283.7 [229.6–350.6] 132.6 [108.8–161.6]

Anti-HBs** 3** 2** 1**

98.6 [95.9–99.7] 94.7 [90.6–97.3] 99.5 [97.1–100] 99.5 [97.0–100] 98.4 [95.5–99.7] 96.4 [92.7–98.5] 99.5 [97.1–100] 99.5 [97.2–100] 99.1 [96.6–99.9] 99.0 [96.5–99.9] 98.1 [95.2–99.5] 97.0 [93.6–98.9] 100 [98.3–100] 100 [98.2–100] 100 [98.3–100] 96.1a [92.5–98.3]a 94.9 [91.0–97.4] 92.2 [87.7–95.5]

FHA PT

97.6 [94.5–99.2] 0.5 [0–2.8]

2

Seroprotection or Vaccine Response Rates (%) [95%CI] InfanrixTM hexa (N = 214) HexavacTM (N = 207)

PRN*

1

3

Anti-HBs* ≥0.10 mIU/ml Anti-polio ≥1:8 Anti-pertussis vaccine response Anti-T ≥0.1 IU/ml Anti-D* ≥0.1 IU/ml Anti-PRP ≥0.15 ␮g/ml

Table 3 Seroprotection/vaccine response rates and antibody GMT levels at 1 month following completion of the three dose primary vaccination course with InfanrixTM hexa or HexavacTM (ATP analysis)

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Fig. 1. GMT ratios InfanrixTM hexa/HexavacTM .

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Table 4 Incidence (per total number of doses) of clinically relevant solicited symptoms within 4 days following vaccination (Total Safety Cohort) Symptom Solicited local symptoms Pain Redness Swelling* Solicited systemic symptoms Drowsiness Irritability Loss of appetite Fever (rectal temperature) ∗

Definition of “clinically relevant”

InfanrixTM hexa (N = 673), % [95% CI]

HexavacTM (N = 647), % [95% CI]

Crying when limb was moved/spontaneously painful >20 mm diameter >20 mm diameter

0.9 [0.3–1.9]

1.1 [0.4–2.2]

3.9 [2.5–5.6] 6.1 [4.4–8.2]

2.2 [1.2–3.6] 3.6 [2.3–5.3]

Drowsiness preventing normal activity Crying that could not be comforted/preventing normal activity Not eating at all >38.5 ◦ C >39.0 ◦ C >39.5 ◦ C

0.9 [0.3–1.9]

1.2 [0.5–2.4]

1.9 [1.0–3.3]

1.9 [1.0–3.2]

0.6 [0.2–1.5] 4.8 [3.3–6.6] 0.9 [0.3–1.9] 0.0 [0.0–0.5]

0.5 [0.1–1.3] 2.9 [1.8–4.5] 0.5 [0.1–1.3] 0.2 [0.0–0.9]

p < 0.05 by Fisher exact test.

HexavacTM in terms of both the percentage of subjects with anti-diphtheria ELISA antibody titres ≥ 0.1 IU/ml (100% versus 96.1%, p = 0.0032) and anti-diphtheria antibody GMTs (1.51 IU/ml versus 0.99 IU/ml, p = 0.0001). Further analysis of the serum samples from the 8 subjects in the HexavacTM group with anti-diphtheria ELISA antibody titres <0.1 IU/ml however showed that 4 of these did have neutralising antibodies when tested by the VERO cell neutralising assay. Therefore, the anti-diphtheria seroprotection rate 1 month after primary immunisation with HexavacTM was 98.1%. The antibody levels against all three poliovirus components (types 1, 2 and 3) were also found to be significantly higher following vaccination with InfanrixTM hexa compared to HexavacTM (p < 0.0001). This was particularly evident for type 3 (GMT 911.0 versus 237.4). 3.3. Safety and reactogenicity The percentage of doses followed by a report of at least one symptom (local or general, solicited or unsolicited) was similar in both groups (72.8% of doses in the InfanrixTM hexa group and 69.3% of doses in the HexavacTM group). The incidences of clinically relevant solicited symptoms during the 4-day follow-up period after vaccination were low (Table 4). There were no significant differences between the two groups except for swelling (p = 0.04) which was the most frequently reported clinically relevant local symptom (6.1% of doses in InfanrixTM hexa group and 3.6% of doses in HexavacTM group). The most frequently reported clinically relevant systemic symptom in both groups was fever >38.5 ◦ C (4.8% of doses in InfanrixTM hexa group and 2.9% of doses in HexavacTM group). There was only one report of fever >39.5 ◦ C which occurred in the HexavacTM group following the third vaccine dose. Most of the fever reported in both groups occurred within the first 24 h following vaccination and the majority of cases resolved within 24 h. Antipyretic medication

within 4 days following vaccination was administered after 3.0% of the InfanrixTM hexa doses and after 2.1% of the HexavacTM doses. Antipyretics were seldom used prophylactically (after 0.1% of the InfanrixTM hexa doses and 0.3% of the HexavacTM doses). Unsolicited symptoms were reported following 24.2% of InfanrixTM hexa doses and 24.7% of HexavacTM doses, of these only 0.9% and 1.8%, respectively, were considered by the investigators to be related to vaccination. Twenty serious adverse events (SAEs) were reported (11 in the InfanrixTM hexa group and 9 in the HexavacTM group), none were considered to be causally related to vaccination.

4. Discussion This trial was designed to compare the immunogenicity of InfanrixTM hexa and HexavacTM vaccines following primary vaccination. The immunogenicity of InfanrixTM hexa was statistically significantly higher than HexavacTM with respect to hepatitis B in terms of both seroprotection and antibody titres. Significantly higher antibody levels against diphtheria and the three polio components were also induced by InfanrixTM hexa. The response induced to tetanus, Hib and pertussis components were equivalent for the two vaccines except for PRN, which is not included in the HexavacTM vaccine. The stronger immunogenicity of the hepatitis B component in InfanrixTM hexa could reflect the higher antigen content compared to HexavacTM . Differences in formulation may also play a role. The protection level in a population depends on high seroprotection rates [30–32], combined with high vaccine coverage. Given that the vaccine coverage decreases for the booster dose (in Germany the coverage for the pertussis-containing vaccine booster dose estimated through data collected in 1999 to be 70% at 24 months of age [30]), and that specifically for hepatitis B, routine boosters are no longer universally recommended, the percentage of

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seroprotected individuals after primary vaccination is of key importance. Whether the important difference between both vaccines in terms of post-primary anti-HBs antibody GMTs will result in even bigger differences prior to the booster dose will need to be evaluated. However, with respect to the anti-HBs antibody GMTs, the importance of the peak level of anti-HBs antibodies post-primary vaccination on the strength of priming the immune system and duration of protection may be of relevance [33]. Hepatitis B is one of the most widespread infectious diseases. Vaccination targeted at high risk groups has failed to control the disease, and thus integration of hepatitis B vaccine into infant immunisation schedules was proposed as a strategy by the World Health Organisation (WHO) [8,9] and is recommended by the US Advisory Committee on Immunisation Practices (ACIP) [10–12] and the American Academy of Paediatrics [13,14]. Clearly the inclusion of hepatitis B in multivalent vaccines will facilitate universal infant vaccination however, it is important that the level of protection afforded is not compromised. The future will see even more antigens being administered in early childhood. One example is the incorporation of the recently licensed 7-valent pneumococcal CRM197 conjugate vaccine (PrevenarTM ) into infant programmes. Early data from separate studies indicate that when HexavacTM was co-administered with PrevenarTM , the level of seroprotection against hepatitis B was only 87.9% [34] while following the co-administration of InfanrixTM hexa with PrevenarTM rates were at 96.4% in two separate studies [35,36]. In contrast to hepatitis B, diphtheria disease is now relatively rare in industrialised countries due to the success of routine vaccination introduced in the 1940s and 1950s. However, the resurgence of epidemic diphtheria in the newly independent states of the former Soviet Union and the chronic endemicity in some poor countries like Ha¨ıti has underlined the need for maintaining the highest possible level of protection against this disease [37–40]. InfanrixTM hexa induced significantly higher titres of antibodies against diphtheria toxoid as well as against the three polioviruses types. The short term follow up data presented in this report do not allow us to draw any conclusion as to the potential impact on long term protection of the higher diphtheria and polio virus antibody levels induced by InfanrixTM hexa. This would depend on the relative persistence of protective antibody levels up to the time of the routine booster or 4th dose vaccination and on the level of coverage for booster vaccination. In terms of pertussis, the antibody response induced by the two common components PT and FHA was similar for both InfanrixTM hexa and HexavacTM . InfanrixTM hexa also contains a third pertussis component, pertactin or PRN, which induced an antibody response in 97.6% of vaccinees. A number of studies have demonstrated the efficacy of acellular pertussis vaccines from different manufacturers. These include a study in Germany [4] and an NIH study in Italy [2] conducted on the tricomponent acellular vaccine contained in InfanrixTM hexa. None of the efficacy studies

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led to the establishment of definite serological correlates of protection for pertussis, although long-term follow-up data from Sweden suggested some correlation between low anti-PT antibody titres and susceptibility to pertussis [41]. Two independent studies have however shown that high levels of antibodies against PT, fimbriae and PRN are associated with a lower risk of pertussis infection with the strongest correlation being exhibited by PRN antibodies [42,43]. Indeed clinical data indicate that three or more component vaccines containing PRN in addition to PT and FHA are more effective than either single or two-component vaccines [7,44–46]. This is supported by animal data showing that the addition of PRN to a bicomponent vaccine had a synergistic effect on protection in an intranasal challenge model [47,48]. These observations suggest that the presence of PRN antibodies in addition to PT and FHA antibodies in InfanrixTM hexa vaccinees may confer an advantage with respect to the provision of protection against pertussis. In this study, the differences in the immunogenicity profiles of InfanrixTM hexa and HexavacTM described above suggest that InfanrixTM hexa has a greater potential to provide protection. Moreover, the observed difference between the vaccines needs careful evaluation in the context of co-administration with other antigens such as pneumococcal and meningococcal conjugate vaccines. The incidences of clinically relevant solicited symptoms, unsolicited symptoms or serious adverse events following vaccination were low in both the InfanrixTM hexa and HexavacTM groups. This confirms previous observations that both InfanrixTM hexa and HexavacTM vaccines are well tolerated when administered to infants [17,21,23,49–51]. The acceptable tolerability profile of both these multivalent vaccines together with the reduction in the number of required injections should promote compliance and thus increase vaccine coverage rates. In conclusion, this comparative study indicates that InfanrixTM hexa and HexavacTM are both well tolerated in infants. InfanrixTM hexa induces a better immune response with respect to hepatitis B, higher antibody levels against diphtheria and polio and an equal response for all other antigens after a three-dose primary immunisation course.

Acknowledgements The authors would like to thank the participating investigators—Dr. Bakowski, Dr. Baukhage, Dr. Bittmann, Dr. B¨orzs¨onyi, Dr. Burow, Dr. B¨uttner, Dr. Clapier, Dr. Collet, Dr. Dabor, Dr. Disselhoff, Dr. Erdl, Dr. Gildberg, Dr. Grunert, Dr. Haase, Dr. Habash, Dr. Holtorf, Dr. Johannsen, Dr. Kindler, Dr. Kirsten, Dr. Krause, Dr. K¨ustermann, Dr. Laakmann, Dr. Mahler, Dr. Maier, Dr. Mangeldorf-Taxis, Dr. Morandini, Dr. M¨uller, Dr. Nolte, Dr. Pankow-Culot, Dr. Pfletschinger, Dr. Potthast, Dr. Preidel, Dr. Rosemann, Dr. Scherer, Dr. Schmitz Hauss, Dr. Schult, Dr. Schumann, Dr. Sengespeik, Dr. Soemantri, Dr. Steiner, Dr. Steinhauer, Dr. Tichmann, Dr. Verheyen, Dr. Vomstein, Dr. Weidinger, Dr.

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Wolf, Dr. Zelazny—for their contribution to this study. This study was supported by a grant from GSK Biologicals Rixensart Belgium.

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