Antibody responses to meningococcal (groups A, C, Y and W135) polysaccharide diphtheria toxoid conjugate vaccine in children who previously received meningococcal C conjugate vaccine

Vaccine 24 (2006) 2544–2549

Antibody responses to meningococcal (groups A, C, Y and W135) polysaccharide diphtheria toxoid conjugate vaccine in children who previously received meningococcal C conjugate vaccine Haitham El Bashir a,∗ , Paul T. Heath b , Thomas Papa c , Jens U Ruggeberg b , Nik Johnson b , Ruchi Sinha b , Gail Balfour b , Robert Booy a a

Research Centre for Child Health, St. Bartholomew’s and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK b St. George’s Vaccine Institute, St. George’s Hospital Medical School, London, UK c Clinical Department, sanofi pasteur Inc., Swiftwater, PA, USA Received 4 October 2005; received in revised form 9 December 2005; accepted 10 December 2005 Available online 27 December 2005

Abstract A randomised, modified, double-blind trial was conducted in children 2 to <5 years of age to evaluate immunogenicity and reactogenicity of a meningococcal (serogroups A, C, Y, W135) diphtheria toxoid conjugate vaccine (MCV-4) in healthy children previously vaccinated with a monovalent meningococcal C conjugate vaccine. Participants received one dose of either MCV-4 or Haemophilus influenzae type b vaccine (Hib vaccine, control group). Serum bactericidal antibodies (SBA) were determined in sera obtained before and approximately 28 days following vaccination. MCV-4 was highly immunogenic for serogroups A, C, Y and W135, the response to serogroup C being consistent with a booster response in participants primed with monovalent C conjugate vaccine. No major between-group differences in solicited local and systemic reactions or adverse events (AEs). © 2005 Elsevier Ltd. All rights reserved. Keywords: Neisseria meningitidis; Serogroup C; Meningococcal disease; Conjugate vaccine

1. Introduction Neisseria meningitidis causes morbidity and mortality worldwide. The organism inhabits the human nasopharynx, leading to carrier status in most cases, but can invade to cause septicaemia or meningitis [1]. Despite appropriate treatment, overall mortality in patients ranges from 9 to 12%, and can be as high as 40% among those who develop septicaemia [2]. N. meningitidis is classified into serogroups based on differences in the polysaccharide capsule. While the prevalence of serogroups causing invasive disease varies, almost ∗ Correspondence to: Child Development Centre, St. Ann’s Hospital, St. Ann’s Road, London N15 3TH, UK. Tel.: +44 208 442 6604; fax: +44 208 442 6116. E-mail address: [email protected] (H.E. Bashir).

0264-410X/$ – see front matter © 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.vaccine.2005.12.018

all reported cases are caused by serogroups A, B, C, Y or W135 [1,2]. In spite of the availability of highly efficacious meningococcal polysaccharide vaccines, from the late 1980s serogroup C became increasingly important as a cause of invasive meningococcal disease in parts of Europe, North and South America [1–7]. In United Kingdom, most cases of invasive meningococcal disease are caused by serogroups B or C, with an annual incidence rate of invasive disease ranging between 2 and 6 per 100,000 [8]. Attack rates were highest among infants, teenagers and young adults. No suitable vaccine against serogroup B is currently available, but a mass immunisation campaign with novel meningococcal C conjugate vaccines, targeting all persons up to 21 years of age, was implemented in the UK in 1999 [9]. Conjugation of meningococcal polysaccharide to a carrier protein produces a T-cell dependent antigen, which elicits

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protective antibody responses in infants and young children [10]. Sustained protection in young children (but not infants) resulted from better persistence of antibodies and immune memory [10]. Infants probably require boosting in the second year of life, to achieve long term benefit. Further benefits observed with monovalent C conjugate vaccines include a reduction in meningococcal carriage rates, and evidence of herd immunity [11,12]. The comprehensive immunisation campaign with meningococcal C conjugate vaccines in the UK has led to a major reduction of cases due to serogroup C [10,13]. Changing epidemiology, however, may indicate a need for additional serogroup coverage. In 2000 and 2001, an outbreak of serogroup W135 disease originated at the Hajj in Saudi Arabia, and spread to the UK and other countries [14,15]. In the United States, disease caused by serogroup Y increased in the 1990s to become equally predominant with serogroups B and C [16]. In children aged 2–10 years, the quadrivalent meningococcal conjugate vaccine, MenactraTM (MCV-4, sanofi pasteur Inc., Swiftwater, PA, USA), has a reactogenicity and safety profile similar to that of meningococcal polysaccharide vaccine, while eliciting significantly higher and more persistent serum bactericidal antibody (SBA) responses against meningococcal serogroups A, C, Y and W135 [17]. In children below 2 years of age, the vaccine had an acceptable safety profile and the majority of children had measurable serum bactericidal antibody titres [18]. We anticipate that MCV-4 may be used to provide broader serogroup coverage in populations currently immunised against serogroup C only. Therefore, we evaluated the antibody responses for serogroups A, C, Y and W135 to a single dose of MCV-4 in children between 2 and 5 years of age primed with meningococcal C conjugate vaccine at least 1 year previously.

dose of monovalent meningococcal C conjugate vaccine at least 1 year previously. Children were excluded if they fell into any of the following groups; serious chronic disease, history of documented invasive meningococcal disease, known or suspected impairment of immunologic function, enrolment in another clinical trial, acute medical illness with or without fever within the last 72 h, any vaccination in the 28day period prior to enrolment or scheduled during enrolment, any recognised contraindication to vaccination, or any condition requiring the use of immune globulin or other blood products within 3 months, injected or oral corticosteroids, or other immunomodulatory therapy within the 6 weeks prior to enrolment.

2. Materials and methods

2.3. Safety

2.1. Sites and participants

Children were monitored for 30 min after each injection for immediate hypersensitivity reactions. Parents were supplied with standard thermometers, rulers and diary cards to record highest axillary temperature for each day and the presence and severity of any solicited local and systemic reactions for 7 days following vaccination. During the entire trial period, all adverse events (AEs) irrespective of association with the vaccine or not, were identified and recorded. Safety information was collected by personnel blinded to the study groups.

Between August 2003 and February 2004, parents of children 2–5 years of age registered with the Spitalfield practice in east London or who resided in the Wandsworth, Merton and Sutton or Croydon Primary Care Trusts in southwest London were contacted. This age range was selected because children born after April 1999 were recommended by the Department of Health (UK) to receive a booster dose of Hib conjugate vaccine), which was to serve as the control vaccine [19]. The trial was approved by the East London, and Wandsworth, Merton and Sutton and Croydon Research Ethics Committees. Written informed consent was obtained before the trial from the parent or guardian of each subject. Eligible children were at least 2 years and less than 5 years of age at the time of vaccination, in good health as determined by medical history and physical examination with an axillary temperature <37.5 ◦ C, and had received at least one

2.2. Design We conducted a phase II, randomised, modified, doubleblind trial to evaluate antibody responses to MenactraTM (MCV-4) a meningococcal diphtheria toxoid conjugate vaccine against serogroups A, C, Y, and W135, in children who had received a monovalent meningococcal C conjugate vaccine at least 1 year previously. Each participant who met the eligibility criteria was randomised via a computer-generated schedule to receive either MCV-4 or the control (Hib) vaccine. Participants in the MCV-4 group received a dose of Hib vaccine at the conclusion of the study in accordance with the UK Hib vaccine catch-up campaign [19]. Sera were prepared from blood samples (5 mL) drawn immediately prior to vaccination (day 0), and at least 28 days and not more than 35 days post-vaccination for assessment of immune responses. Serum bactericidal antibody titres to meningococcal serogroups A, C, Y and W135 were measured with a standard assay using baby rabbit complement [20], and were expressed as the reciprocal of the highest serum dilution yielding ≥50% bactericidal killing.

2.4. Vaccines MCV-4 (MenactraTM , sanofi pasteur Inc., Swiftwater, PA, USA) is prepared from the same capsular polysaccharide material used in the licensed polysaccharide vaccine, Menomune® -A/C/Y/W135. One dose contains 4 ␮g of each serogroup A, C, Y and W135 polysaccharide covalently

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Fig. 1. Trial profile for per-protocol analysis.

linked to approximately 48 ␮g of diphtheria toxoid protein. MCV-4 is supplied as a clear to slightly turbid liquid in 0.5 mL of sterile, pyrogen-free, phosphate buffered physiologic saline, with no preservative, and prepared in single dose pre-filled syringes. The control vaccine was the licensed Hib conjugate vaccine (Hiberix® GlaxoSmithKline, Rixensart, Belgium). Each dose contains 10 ␮g of purified polyribosylribitol-phosphate (PRP) capsular Hib polysaccharide covalently bound to approximately 30 ␮g of tetanus toxoid as a lyophilised powder, reconstituted in 0.5 mL sterile saline (0.9%) for administration. Both vaccines were administered intramuscularly into the deltoid muscle of the arm of choice. 2.5. Statistics Immune responses were expressed as geometric mean titres (GMTs) of SBA with 95% confidence intervals (CIs) for the four meningococcal serogroups. SBA GMTs at days 0 and 28 and 95% CIs were calculated as log base 2 assuming that they followed a log normal distribution. The proportion of participants with SBA of 128 were calculated, with 95% CIs. The statistical analysis was performed with SAS software

version 8.2. The intent to treat population for immunogenicity consisted of all participants who received one injection of either MCV-4 or Hib conjugate vaccine, and had at least one valid serology result.

3. Results A total of 103 children were enrolled between 13 August 2003 and 11 March 2004; 52 received MCV-4 and 51 received Hib. Of these, 97 (94.2%) completed the safety and 80 (77.7%) completed the immunogenicity part of the study according to protocol (Fig. 1). Both groups were similar in age, sex and race distribution (Table 1). 3.1. Immunogenicity Table 2 shows the SBA GMTs at baseline and on day 28 after vaccination and the geometric mean fold rises. Baseline SBA levels for meningococcal serogroups A, C, Y, and W135 before vaccination, and proportions of subjects with detectable SBA (titre ≥8) were similar in both groups

H.E. Bashir et al. / Vaccine 24 (2006) 2544–2549 Table 1 Participant demographics (all participants) Demographic characteristics

MCV-4 [n (%)] N = 52

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Table 4 Overall participant safety profile (safety population) Hib [n (%)] N = 51

Sex Male Female

24 (46.2) 28 (53.8)

29 (56.9) 22 (43.1)

Age (months) Mean Range

37.0 25–55

37.6 24–57

Race [n (%)] Caucasian Black Asian Hispanic Other

22 (42.3) 4 (7.7) 22 (42.3) 1 (1.9) 3 (5.8)

26 (51.0) 3 (5.8) 21 (41.2) 0 (0) 1 (2.0)

Types of adverse events

Immediate reactions (within 30 min) Solicited local reaction (days 0–7) Solicited systemic reactions (days 0–7) Unsolicited adverse events (days 0–28) Serious adverse events (days 0–28)

MCV-4

Hib

n/Na

%

n/Na

%

0/52 27/51 35/52 29/51 1/52

0.0 52.9 67.3 56.9 1.9

0/50 24/49 25/49 31/47 0/50

0.0 49.0 51.0 66.0 0.0

a

n: number of participants reporting at least one event in this category, N: total number of participants who submitted safety information at each time point.

exception of one subject who had a titre of 1:64 for serogroup Y (Table 3). 3.2. Safety

(Table 3). There was little or no increase in SBA titres between baseline and day 28 in the control group. In the MCV-4 group GMTs against all four serogroups were significantly higher than at baseline and compared with the control group at day 28, indicating a robust immune response to the vaccine: SBA GMTs against all four serogroups ranged from 4032 for serogroup Y to 12,535 for serogroup C. The geometric mean fold rise in SBA ranged from 16.5 for serogroup Y to 160 in serogroup W135. All subjects given MCV-4 achieved SBA titres ≥128 at day 28 against all four serogroups, with the

Overall safety results are summarised in Table 4. No immediate reactions were observed within 30 min after vaccination. There were no significant between-group differences in solicited local (p = 0.84) or systemic (p = 0.71) reactions. Redness and pain were the most commonly reported solicited local reactions, whereas irritability was the most common systemic reaction. The majority of local and systemic reactions were classified as mild and resolved by day 3. During days 0–28, unsolicited AEs were reported in 56.9% (29/51)

Table 2 SBA geometric mean titres at baseline and day 28, and geometric mean fold rise in SBA titres from baseline to day 28 Serogroup A

Parameter GMT GM fold rise

C

GMT GM fold rise

Y

GMT GM fold rise

W135

GMT GM fold rise

Timing

MCV-4 N = 44 (95% CI)

Hib N = 36 (95% CI)

Day 0 Day 28 Days 0–28

136 (69.4, 268) 11404 (7384, 17614) 70.3 (34.5, 144)

99.7 (47.7, 208) 199 (93.1, 427) 1.6 (1.0, 2.8)

Day 0 Day 28 Days 0–28

76.1 (36.6, 158) 12535 (8408, 18688) 136 (61.7, 301)

26.9 (12.5, 58) 22.6 (10.5, 48.8) 0.6 (0.4, 0.8)

Day 0 Day 28 Days 0–28

237 (133, 421) 4032 (2399, 6776) 16.5 (8.6, 32)

266 (151, 469) 299 (156, 573) 1.1 (0.8, 1.5)

Day 0 Day 28 Days 0–28

26.1 (13.3, 51.1) 5978 (3853, 9276) 160 (84.8, 300)

24.4 (11.8, 50.8) 32 (16.3, 62.7) 0.9 (0.6, 1.5)

Table 3 Numbers and percentages of participants with SBA antibody titres ≥8 on days 0 and 28, and ≥128 on day 28 in the two study groups Serogroup

Vaccine group

N

n (%) SBA titre ≥8

n (%) SBA titre ≥128

Day 0

Day 28

Day 28

A

MCV-4 Hib Control

44 36

33 (75) 26 (72)

44 (100) 28 (78)

44 (100) 28 (78)

C

MCV-4 Hib Control

44 36

32 (73) 16 (44)

44 (100) 16 (44)

44 (100) 11 (31)

Y

MCV-4 Hib Control

44 36

42 (95) 33 (92)

44 (100) 32 (89)

43 (98) 30 (83)

W135

MCV-4 Hib Control

44 36

21 (48) 17 (47)

44 (100) 21 (58)

44 (100) 13 (36)

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of MCV-4 recipients and 66.0% (31/47) of the control group given Hib vaccine. The most frequent reported unsolicited AE was upper respiratory tract infection, in 31.4% (16/51) of the MCV-4 group and 46.8% (22/47) of the control group. In the MCV-4 group, 84.1% (37/44) of the unsolicited AEs were reported as unrelated to the vaccine, 15.9% (7/44) as possibly related and none as probably or definitely related. In the control group, 94.1% (48/51) of unsolicited AEs were reported as unrelated to the vaccine, 3.9% (2/51) as possibly related and 2% (1/51) as probably or definitely related. One event reported as definitely related to the vaccine was an injection site haematoma in the control group, which was classified as mild and non-serious. The only reported serious AE was a febrile convulsion, which occurred one day after vaccination with MCV-4 in a child with a previous medical history of febrile convulsions. The subject, who had a respiratory tract infection at the time of vaccination, recovered at home without sequelae.

4. Discussion We observed that the quadrivalent meningococcal diphtheria conjugate vaccine, MCV-4, was both immunogenic and well tolerated in children aged from 2 up to 5 years who had been vaccinated with monovalent C conjugate vaccine at least 1 year previously. It is noteworthy that 32 of the 80 enrolled children with immunogenicity data (40%) did not have bactericidal antibody titres higher than 8 to serogroup C prior to study vaccination. This finding is consistent with the recent observation in the UK that 63% of 4-year olds had undetectable SBA to serogroup C within 2 years of a single dose of meningococcal C conjugate vaccine [21]. There is no generally agreed serologic correlate of protection for SBA titres assayed using baby rabbit complement, but the UK experience has shown that SBA titres <8 correlate with susceptibility to invasive meningococcal disease due to serogroup C, while titres ≥128 correlate with protection [22,23]. In our study, 100% of the group vaccinated with MCV-4 had SBA titres ≥128 to serogroup C, compared with only 31% of the children who received Hib conjugate vaccine. Our study has the limitation of being performed in the context of current universal meningococcal C vaccination of UK infants and children, so it was not possible to compare the serogroup C response in these Men C-primed subjects with age-matched vaccine-na¨ıve subjects. In the study conducted in US children aged 2–10 years with no prior meningococcal vaccination, 81% (95% CI: 78, 100) had an SBA titre ≥128 after one dose of MCV-4 [17]. The superior response observed in UK children was despite the higher mean age of the US children and the known age-dependence of the response to this vaccine [24]. This lends support to the 136fold increase in SBA to serogroup C elicited by MCV-4 being indicative of a booster response. Of the additional serogroups covered by the quadrivalent vaccine, at baseline 26.2, 6.2 and 52.5% of children, respec-

tively, had pre-vaccination titres <8 to serogroups A, Y and W135. In the US 2–10-year olds approximately 43, 14 and 62% had SBA <8 against serogroups A, Y and W135, respectively using the same assay [17]. High antibody levels for serogroups A and Y were possibly due to acquired immunity through natural acquisition or naturally occurring crossreacting antigens [25,26]. However, we would not expect that over 90% of the UK children had SBA ≥8 to serogroup Y due to natural exposure, for while cases of serogroup Y meningococcal disease are becoming increasingly prevalent in the US [1], such cases have remained rare in the UK. The higher rate of W135 baseline activity in UK children may reflect the higher proportion of Asian Muslim subjects in this population (>40%) compared with the US study (<1%). W135 outbreaks in London have been specifically associated with pilgrims returning from the Hajj [14,15,27]. We observed that vaccination with MCV-4 resulted in robust rises in SBA antibodies, with all but one recipient achieving an SBA titre ≥128 to serogroups A, Y and W135. The increment in GMT was lowest for serogroup Y. This might be explained by the higher levels of pre-existing antibody for this serogroup as compared with the others. Despite this, all vaccinees achieved post-vaccination titres to Y of ≥8. The safety profile in this study was favourable for both administered vaccines. The proportions of children with solicited and unsolicited adverse events or reactions were similar among children who received the routine licensed Hib vaccine or MCV-4. For both groups of children, the majority of solicited injection site reactions were mild and resolved within 3 days. Irritability and drowsiness were the most common systemic complaints. One MCV-4 recipient, who had a history of febrile convulsions, experienced a febrile convulsion within 24 h of immunisation, which was the only reported severe AE. This was not reported previously in studies using the same vaccine [18,28]. A study using N. meningitidis (A + C) diphtheria conjugate vaccine in infants reported one seizure episode 32 days after dose 2 of the vaccine, however it was considered not to be vaccine-related. None occurred during the 72 h post-vaccination period [29]. Unsolicited AEs were primarily common medical complaints considered unrelated to vaccination, notably upper respiratory tract infections. The success of the current UK meningococcal C conjugate vaccination programme could be undermined by changes in the epidemiology of meningococcal disease. In addition, as individual immunity induced by previous group C conjugate meningococcal vaccination may wane [10], booster dosing may provide an opportunity to introduce the added protection that multivalent vaccines, such as MCV-4, could offer.

Acknowledgements We are grateful to all the children and their parents who volunteered to participate in this study. sanofi pasteur manufactured and supplied the study vaccine, and procured the

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control commercial Hib vaccine. The respective departments of sanofi pasteur performed all serological analyses in a blinded manner before breaking of the study code, and the subsequent statistical analyses and preparation of the study report, which was corroborated and confirmed independently by the investigators. Financial disclosure: The study was funded by a research grant from sanofi pasteur Inc., Swiftwater, PA, USA. Professor Booy and Dr. Heath have received support from sanofi pasteur (formerly Aventis Pasteur) to conduct studies and attend scientific meetings.

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