Persistence of the immune response at 5 years of age following infant immunisation with investigational quadrivalent MenACWY conjugate vaccine formulations

Vaccine 30 (2012) 2831–2838

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Persistence of the immune response at 5 years of age following infant immunisation with investigational quadrivalent MenACWY conjugate vaccine formulations夽 Ameneh Khatami a,∗ , Matthew D. Snape a , Elizabeth Davis a , Helen Layton a , Tessa John a , Ly-Mee Yu b , Peter M. Dull c , Christopher J. Gill c , Tatjana Odrjlin c , Simon Dobson d , Scott A. Halperin e , Joanne M. Langley e , Shelly A. McNeil e , Andrew J. Pollard a a

Oxford Vaccine Group, Department of Paediatrics, University of Oxford, UK Centre for Statistics in Medicine, Oxford, UK c Novartis Vaccines and Diagnostics, Cambridge, MA, USA d British Columbia Children’s Hospital, University of British Columbia, Canada e Department of Pediatrics, Dalhousie University, Canada b

a r t i c l e

i n f o

Article history: Received 23 August 2011 Received in revised form 14 January 2012 Accepted 20 February 2012 Available online 3 March 2012 Keywords: Meningococcal Quadrivalent conjugate vaccine Immune response Persistence Childhood

a b s t r a c t Background and aims: Serogroup A, C, W-135 and Y meningococcal (MenACWY) conjugate vaccines are recommended for routine adolescent immunisation in the United States and Canada. We evaluated the persistence of bactericidal antibodies through early childhood, following infant immunisation with varying schedules of MenACWY-CRM197 vaccine. Methods: UK and Canadian infants were immunised with 2–3 doses of MenACWY-CRM197 or 2 doses of serogroup C meningococcal (MenC) conjugate vaccine, and either MenACWY-CRM197 , 1/5 dose of MenACWY polysaccharide vaccine or no booster at 12 months. Control groups recruited at 60 months had received country-specific infant doses of MenC conjugate vaccine. hSBA titres were measured in participants at 40 and 60 months of age. Results: 382 children were enrolled in 12 groups (22–40 per group). By age 60 months, 3–11% of children primed and boosted with MenACWY-CRM197 had hSBA titres ≥ 1:8 against serogroup A, 14–45% against serogroup C, 57–85% against serogroup W-135 and 42–71% against serogroup Y. Children primed with MenC and boosted with MenACWY-CRM197 had similar results, except for serogroup C (59%). In age-matched controls administered MenC vaccine at 2, 3, and 4 months (UK), 2 and 12 months or 12 months only (Canada), percentages with hSBA titres ≥ 1:8 were 0–3%, 29–53%, 34–36% and 10–29% against serogroups A, C, W-135 and Y respectively. Conclusions: Serogroup-specific bactericidal antibody wane following infant immunisation with MenACWY-CRM197 , most markedly against serogroup A. Best persistence against serogroup C is observed with MenC conjugate vaccine priming and MenACWY-CRM197 at 12 months, compared to schedules using only MenACWY-CRM197 , with the potential for providing broader protection compared to monovalent MenC vaccines alone. © 2012 Elsevier Ltd. All rights reserved.

1. Introduction Over 90% of invasive meningococcal disease is caused by 5 serogroups: A, B, C, Y and W-135 [1], the proportion caused by each serogroup varying geographically, with serogroups B and C predominating in Europe, serogroups A, C and W-135 most common in Asia and Africa and serogroups B, C and Y predominating in the

夽 Clinicaltrials.gov registration number: NCT00601731. ∗ Corresponding author. Tel.: +44 1865857420. E-mail address: [email protected] (A. Khatami). 0264-410X/$ – see front matter © 2012 Elsevier Ltd. All rights reserved. doi:10.1016/j.vaccine.2012.02.046

Americas [2]. Highest rates of invasive meningococcal disease occur in children aged 6–24 months, with an additional smaller peak in adolescents [1]. Case fatality of invasive disease is around 10% in treated cases [3] and up to 20% of survivors suffer from life-long sequelae [4]. Polysaccharide vaccines containing serogroups A, C, W-135 and Y (MenACWY) have been available since the 1980s [5]. However, these vaccines have limited value because polysaccharides are Tcell-independent antigens, and thus are poorly immunogenic in children under 2 years of age and do not induce immunologic memory at any age [6,7]. Large-scale vaccination against serogroup C meningococcal (MenC) disease using conjugate vaccines was highly

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Table 1 Vaccines received in each vaccine group. Country

UK

Canada

Group

Age at vaccination (months)

UK2,3,4,12+ UK2,4,12+ UK2,4C/12+ UK2,4,12− UKControl Ca2,4,6+ Ca2,4,6+/12PS Ca2,4,12+ Ca2,4+/12PS Ca2,4,12− Ca2,4−/12PS CaControl

2, 3, 4 and 12 2, 4 and 12 2, 4 and 12 2, 4 and 12 2, 3, 4 2, 4 and 6 2, 4, 6 and 12 2, 4 and 12 2, 4 and 12 2, 4 and 12 2, 4 and 12 2 and 12 or 12 only

Vaccine received Primary

12 months of age

MenACWY+ MenACWY+ MenC MenACWY− MenC* MenACWY+ MenACWY+ MenACWY+ MenACWY+ MenACWY− MenACWY− MenC* or nil

MenACWY+ MenACWY+ MenACWY+ MenACWY− – – MenPS (1/5 dose) MenACWY+ MenPS (1/5 dose) MenACWY− MenPS (1/5 dose) MenC*

MenACWY+: Quadrivalent MenACWY-CRM197 conjugate vaccine with adjuvant. MenACWY−: Quadrivalent MenACWY-CRM197 conjugate vaccine without adjuvant. MenPS: 1/5 dilution of quadrivalent MenACWY polysaccharide vaccine (Menomune; Aventis Pasteur Inc., Swiftwater, PA). MenC: Monovalent MenC-CRM197 conjugate vaccine (Menjugate; Novartis Vaccines and Diagnostics, Siena, Italy). MenC*: MenC conjugate vaccine according to country-specific schedules.

successful in the UK [8], and in January 2005, a MenACWY conjugate vaccine using a diphtheria toxoid carrier protein was licensed (currently for 9 month to 55-year-olds) in the United States (US) on the basis of immunologic non-inferiority to the polysaccharide vaccine [9]. More recently a quadrivalent meningococcal vaccine conjugated to a CRM197 carrier protein (MenACWY-CRM197 ) was licensed for individuals over the age of 11 in Europe [10] and Canada [11], and from 2 years of age in several countries, including the US [12]. The vaccine has been shown to be immunogenic [13–17] and submission for licensure for children less than 2 years has been made [18]. In this study, we evaluated the persistence of serum bactericidal activity with human complement (hSBA) against meningococcal serogroups A, C, W-135 and Y in children at 40 and 60 months of age, following infant immunisation with two different formulations of the MenACWY-CRM197 conjugate vaccine. 2. Methods A follow-on study was undertaken 2–4 years after completion of a phase II, multi-centre, open-label study evaluating infant MenACWY immunisation schedules as outlined in Table 1 [14,15]. In the original trial, two formulations of the vaccine were studied; one with an aluminium phosphate adjuvant (MenACWY+), and one without (MenACWY−), the latter formulation being licensed. The study was conducted in one UK site (Oxford) and two Canadian sites (Halifax and Vancouver). Ethical approval was obtained from the Oxfordshire Research Ethics Committee B and from the Research Ethics Board, IWK Health Centre, in Halifax and the Clinical Research Ethics Board, University of British Colombia, in Vancouver. Parents of 274 UK children and 263 Canadian children who completed the original infant study [14,15] (NCT00262002) were invited to enrol their child in this follow-on study. Healthy children whose parents gave informed consent had blood samples taken at 40 and 60 months of age. Exclusion criteria for enrolment included: known immune deficiency, receipt of systemic immunosuppressant or immune stimulant medication or blood products, epilepsy, Guillain-Barré syndrome, any progressive neurological disease, any serious acute, chronic or progressive medical condition, any contraindication to vaccination, and recent household contact with culture proven meningococcal disease. In addition, healthy children matched for age and country, immunised against MenC according to country-specific schedules, were recruited by invitation letter and enrolled with parental

consent into control groups for the 60-month visit only. Additional exclusion criteria for control children included receipt of any nonroutine childhood immunisations, except for influenza, varicella, pneumococcal, hepatitis A, hepatitis B or BCG vaccines. In the UK recommended pre-school vaccines (measles, mumps and rubella; MMR, and diphtheria, tetanus, acellular pertussis and inactivated polio; DTaP/IPV) were given to all follow-on children by their primary care physician at around 3.5 years of age. In Canada, if not already received, MMR and DTaP/IPV were given at the 60month visit. All follow-on and control participants were offered one (optional) dose of MenACWY− at 60 months of age, after the blood draw. Functional bactericidal antibody titres against each vaccine serogroup were measured using human complement (hSBA) at Novartis Vaccines and Diagnostics laboratory in Marburg, Germany, as previously reported [15]. The primary objective was to evaluate the percentage of participants with hSBA ≥ 1:8 for meningococcal serogroups A, C, W-135 and Y at 40 and 60 months of age following vaccination with MenACWY− at 2, 4 and 12 months of age. This schedule was selected as being similar to the current UK MenC schedule (primary vaccines at 3 and 4 months, and a booster dose Hib-MenC-TT [combined Haemophilus influenzae type b and MenC conjugate vaccine] at 12 months). Canadian and UK groups receiving this schedule were not combined for analysis as different concomitant routine immunisations were received in infancy. Secondary objectives included comparisons between each of the vaccination schedules, and with control groups, in terms of percentages of participants with hSBA ≥ 1:8, and hSBA geometric mean titres (GMTs) for each vaccine serogroup, at both time-points. All analyses were descriptive and 95% confidence intervals (CIs) were calculated around each point estimate. Due to small sample sizes significance testing could not be performed. GMTs were calculated by exponentiating (base 10) the least square means of logarithmically transformed titres, with titres below the limit of detection set to half that limit. 95% CIs for GMTs were obtained from a two-way Analysis of Variance (ANOVA) with factors for vaccine group and centre. For percentages of participants with hSBA ≥ 1:8 (or hSBA ≥ 1:4) 95% Clopper–Pearson CIs were calculated. Sample sizes of follow-on study groups were dictated by the number of participants from the original study and it was calculated that for 50 follow-on participants the confidence interval around a ‘true’ response rate of 50% would be 35–64%. The number of control children recruited equalled the largest group of followon children for each country. Immunogenicity data were evaluated

A. Khatami et al. / Vaccine 30 (2012) 2831–2838

in the modified intention-to-treat (MITT) population that included all participants who provided at least one evaluable blood sample. Serious adverse events (SAEs) and medically significant adverse events (AEs; events that resulted in a physician visit, excluding pre-planned follow-ups or visits for common acute childhood infections), were recorded between 40 and 60 months of age for follow-on participants and for 6 months after receipt of study vaccine at 60 months of age for all participants. 3. Results Numbers of children enrolled, and vaccines received in each group, are given in Tables 1 and 2. Of the 537 children who completed the infant study, 283 (53%) children were enrolled in the follow-on study at 40 months of age and 263 (49%) participated at the 60 month visit. Demographic and baseline characteristics were mostly similar between groups. In the UK population 92–100% of participants were Caucasian and in the Canadian population the proportion was 68–87%, with 4–17% being of Asian ethnicity. The mean age of participants was 40–43 months at the 40 month visit and 60–62 months at the 60 month visit. The gender distribution varied slightly across groups at the different time-points, however overall the percentage of male participants was 49%. Control participants enrolled at the 60 month visit were mostly Caucasian (95% in the UK population, 73% in the Canadian population) and had a mean age of about 62 months. 3.1. Immunogenicity results Exclusion of participants from the MITT population at each time-point was due to lack of blood sample being drawn. Percentages of participants (and 95% CI) with hSBA titres ≥ 1:8 in each of the groups for each serogroup are outlined in Tables 3 (UK) and 4 (Canada). Results from the 13-month blood test for the children enrolled in this follow-on study are included for comparison. For children who received MenACWY− at 2, 4 and 12 months of age, percentages of participants with hSBA titres ≥ 1:8 at 40 and 60 months of age were 3–8%, 33–45%, 58–84% and 42–64% for serogroups A, C, W-135 and Y respectively. hSBA GMTs against serogroups W-135 and Y for recipients of MenACWY− or MenACWY+ at 2, 4 and 12 months of age were relatively sustained compared with those of serogroup A. In Canada only, hSBA GMTs tended to be higher against serogroups C, Y and W135 with the non-adjuvanted than the adjuvanted vaccine. Without significance testing these differences may be due to random variation. Within the UK population (Fig. 1), no obvious differences were noted at 40 and 60 months of age between groups given 2 or 3 priming doses of MenACWY+, despite higher GMTs against all serogroups one month after the booster dose. In the original study hSBA GMTs against serogroups A, W-135 and Y were lower following the 12 month dose of MenACWY+ in children primed with 2 doses of monovalent MenC-CRM197 at 2 and 4 months, compared with those primed and boosted with either MenACWY+ or MenACWY−. By 60 months of age these differences were no longer evident, however priming with the monovalent vaccine resulted in consistently higher hSBA titres against serogroup C. For Canadian children primed with MenACWY+, by 60 months of age serogroup-specific hSBA GMTs were similar across groups, regardless of whether or not they had received a booster dose of vaccine at 12 months of age (Fig. 2). Similarly there was little difference in hSBA persistence between those receiving MenACWY+ or a 1/5 dose of the plain polysaccharide vaccine at 12 months of age. Those primed with MenACWY− and receiving either MenACWY− or the reduced dose polysaccharide vaccine at 12 months had

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higher serogroup W-135 and Y hSBA GMTs at 60 months of age than MenACWY+ recipients. All follow-on children had higher GMTs against serogroups W135 and Y at 60 months of age than control children, whereas serogroup A hSBA GMTs were similarly very low across all groups. However, children in the Canadian control group (who had received either 2 doses of a monovalent MenC conjugate vaccine at 2 and 12 months of age [Vancouver, British Columbia], or a single dose at 12 months of age [Halifax, Nova Scotia]) had higher GMTs against serogroup C than any of the other study groups. 3.2. Safety results 138 children from the UK and 176 from Canada were exposed to the study vaccines either in infancy, or at the 60 month visit. Of these, 137 and 173 children respectively had safety data available for analysis. In the UK groups 12–31% of participants reported medically significant AEs, compared with 8–21% for the Canadian groups. None of these events were assessed to be at least possibly related to the study vaccines. Five participants from the UK and two participants from Canada reported SAEs between the 40 and 60 month visits (pneumonia, jaw fracture and accidental overdose). Within the UK population, lower respiratory tract infection, fore-arm fracture and diagnosis of Asperger’s syndrome occurred during the 6 month follow-up after MenACWY− vaccine administration at 60 months of age. These were all assessed to be unrelated to the study vaccines. Overall slightly higher proportions of adverse events were reported by the groups receiving the adjuvanted vaccine (8–31% compared with 9–14% in groups receiving the non-adjuvanted vaccine). No participants withdrew from the study due to an adverse event. 4. Discussion This study provides the first data on the persistence of bactericidal antibodies induced by infant immunisation with the CRM197 -conjugated MenACWY vaccine. Irrespective of the immunisation schedule employed, waning of antibody was observed for all serogroups, most markedly for serogroup A. By contrast persistence of antibody against serogroup W-135 was better across most study groups compared with the other vaccine serogroups. Improved persistence of serogroup C antibody titres were observed for schedules that included doses of monovalent MenC conjugate vaccine. For all serogroups, the greatest degree of waning tended to occur in the second and third years of life, as noted elsewhere with the waning of MenC specific SBA in early childhood [19]. Evidence of waning effectiveness of conjugate MenACWY vaccines has been observed when administered in early adolescence, following the introduction of the diphtheria toxoid conjugated vaccine [20] in the US. For this reason the Advisory Committee on Immunisation Practices in the US now recommends that a booster dose of vaccine be administered at 16 years of age, following the first dose given at around 12 years [20]. The MenACYW vaccine studied here is different in composition; however these results demonstrate the importance of evaluating the persistence of immunity to meningococcal conjugate vaccines in all age groups. The incidence of MenC disease has been reduced through immunisation in many countries [21–23] and attention has since turned to the persistence of immune response following childhood immunisations in an effort to predict long-term effectiveness of routine and catch-up immunisation programmes. MenC conjugate vaccine effectiveness wanes beyond one year after infant immunisation, associated with a fall in rabbit complement SBA titres [24–26]. This

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Table 2 Number of participants enrolled in each group and number of participants included in the MITT population at each time-point. Infant study Enrolled

UK2,3,4,12+ UK2,4,12+ UK2,4C/12+ UK2,4,12− UKControl Ca2,4,6+ Ca2,4,6+/12PS Ca2,4,12+ Ca2,4+/12PS Ca2,4,12− Ca2,4−/12PS CaControl Total

90 90 45 90 – 98

Follow-on study Completed

74 81 42 77 – 45 46 44 45 42 41 537

98 90 601

Total enrolled

40 44 22 37 43 31 26 27 28 27 27 30 382

40 months

60 months

Enrolled

MITT (% of total enrolled)

MITT 40 months only

Enrolled

MITT (% of total enrolled)

36 37 19 34 0 28 23 27 28 25 26 0 283

33 (83%) 37 (84%) 17 (77%) 34 (92%) 0 28 (90%) 23 (88%) 27 (100%) 28 (100%) 25 (93%) 24 (89%) 0 278

6 8 2 6 0 3 1 2 2 3 2 0 35

4 7 3 3 43 3 3 0 0 2 1 30 99

33 (83%) 35 (80%) 18 (82%) 31 (84%) 42 (98%) 27 (87%) 25 (96%) 23 (85%) 25 (89%) 23 (85%) 24 (89%) 30 (100%) 336

Table 3 Numbers (n/N) and percentages of participants with hSBA ≥ 1:8 in each group and in age-matched controls in the UK population. Number, percentage and 95% CI of participants with hSBA ≥ 1:8 from the total number of children included in the MITT population for each group

Serogroup/age

UK MenA 13 months 40 months 60 months MenC 13 months 40 months 60 months MenW-135 13 months 40 months 60 months MenY 13 months 40 months 60 months

2,3,4,12+

2,4,12+

2,4C/12+

2,4,12−

Control

35/38 92% (79–98) 9/33 27% (13–46) 3/33 9% (2–24)

30/41 73% (57–86) 3/37 8% (2–22) 4/35 11% (3–27)

11/19 58% (33–80) 5/17 29% (10–56) 2/18 11% (1–35)

29/35 83% (66–93) 1/34 3% (0.074–15) 1/31 3% (0.082–17)

0/42 0% (0–8)

39/39100%(91–100) 13/32 41% (24–59) 11/32 34% (19–53)

39/41 95% (83–99) 17/36 47% (30–65) 11/34 32% (17–51)

18/1995%(74–100) 12/17 71% (44–90) 10/17 59% (33–82)

31/34 91% (76–98) 11/33 33% (18–52) 14/31 45% (27–64)

12/4229%(16–45)

37/37100%(91–100) 24/33 73% (54–87) 22/32 69% (50–84)

37/3897%(86–100) 25/36 69% (52–84) 29/34 85% (69–95)

13/19 68% (43–87) 12/17 71% (44–90) 14/18 78% (52–94)

30/30100%(88–100) 25/34 74% (56–87) 26/31 84% (66–95)

1542 36% (22–52)

39/39100%(91–100) 25/33 76% (58–89) 20/33 61% (42–77)

40/4198%(87–100) 22/36 61% (43–77) 24/34 71% (53–85)

14/19 74% (49–91) 13/17 76% (50–93) 12/17 71% (44–90)

35/35100%(90–100) 18/34 53% (35–70) 13/31 42% (25–61)

12/4229%(16–45)

decline in SBA titres is more rapid in children immunised at younger ages [19,27–30], than following immunisation of older children and adolescents [28,31,32] and occurs even in schedules incorporating a booster dose of vaccine in the second year of life. In the

absence of further boosters, persistence of adequate levels of bactericidal antibody likely mediate ongoing protection of individuals from invasive disease, as immunological memory may be too slow to confer protection in itself [33]. Since waning antibody is probably

Table 4 Numbers (n/N) and percentages of participants with hSBA ≥ 1:8 in each group and in age-matched controls in the Canadian population. Serogroup/Age

Canada MenA 13 months 40 months 60 months MenC 13 months 40 months 60 months MenW-135 13 months 40 months 60 months MenY 13 months 40 months 60 months

Number, percentage and 95% CI of participants with hSBA ≥ 1:8 from the total number of children included in the MITT population for each group 2,4,6+

2,4,6 +/12PS

2,4,12+

2,4 +/12PS

2,4,12-

2,4−/12PS

Control

6/30 20% (8–39) 0/28 0% (0–12) 0/27 0% (0–13)

23/26 88% (70–98) 1/23 4% (0–22) 0/25 0% (0–14)

23/25 92% (74–99) 2/27 7% (1–24) 1/23 4% (0–22)

19/27 70% (50–86) 0/28 0% (0–12) 1/25 4% (0–20)

24/26 92% (75–99) 2/25 8% (1–26) 1/23 4% (0–22)

22/27 81% (62–94) 0/24 0% (0–14) 0/24 0% (0–14)

1/303%(0.084–17)

16/3152%(33–70) 4/20 20% (6–44) 3/21 14% (3–36)

24/26 92% (75–99) 3/22 14% (3–35) 3/24 13% (3–32)

24/26 92% (75–99) 8/26 31% (14–52) 3/22 14% (3–35)

24/27 89% (71–98) 9/26 35% (17–56) 5/21 24% (8–47)

27/27100%(87–100) 9/24 38% (19–59) 6/22 27% (11–50)

24/27 89% (71–89) 11/24 46% (26–67) 11/24 46% (26–67)

16/3053%(34–72)

22/2781%(62–94) 8/28 29% (13–49) 8/26 31% (14–52)

24/26 92% (75–99) 11/23 48% (27–69) 11/25 44% (24–65)

25/25100%(86–100) 16/27 59% (39–78) 13/23 57% (34–77)

26/27 96% (81–100) 12/28 43% (24–63) 10/24 42% (22–63)

24/24100%(86–100) 18/25 72% (51–88) 17/21 81% (58–95)

27/27100%(87–100) 14/24 58% (37–78) 16/24 67% (45–84)

10/2934%(18–54)

25/3181%(63–93) 9/28 32% (16–52) 8/27 30% (14–50)

25/2696%(80–100) 6/23 26% (10–48) 6/25 24% (9–45)

26/26100%(87–100) 12/27 44% (25–65) 10/23 43% (23–66)

27/27100%(87–100) 6/28 21% (8–41) 5/23 22% (7–44)

26/26100%(87–100) 16/25 64% (43–82) 12/21 57% (34–78)

26/27 96% (81–100) 15/24 63% (41–81) 13/23 57% (34–77)

3/30 10% (2–27)

MenACWY conjugate vaccine persistence.

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Fig. 1. hSBA GMTs (and 95% CI) for each group and in age-matched controls in the UK population. Open, dark grey and light grey columns represent samples taken at 13, 40 and 60 months of age respectively.

also associated with an eventual breakdown in herd immunity, an adolescent booster dose of either a MenC or MenACWY conjugate vaccine has recently been added to the routine schedule in Canada following infant doses of MenC [34] vaccine, and consideration may be given to such a change in the UK. In this study, the persistence of MenC hSBA titres was moderate across most groups and similar to the UK control group who did not receive a booster vaccine after the first year of life. The majority of children in the UK control group had received doses of a CRM197 conjugated vaccine at 2, 3 and 4 months of age. Similarly, the 12 month booster dose of MenACWY-CRM197 does not appear to lead to better long-term persistence of MenC hSBA titres compared with children who only received 3 primary doses of the vaccine. In contrast, a greater proportion of UK participants who had received 2 doses of MenC-CRM197 at 2 and 4 months followed by a MenACWYCRM197 booster at 12 months still had MenC hSBA titres ≥ 1:8 at 40 and 60 months of age. This schedule appears to give the best protection against MenC disease while also providing cover against the other 3 serogroups. Better persistence of MenC hSBA titres was noted in the Canadian control group who had received 1 or 2 doses of a monovalent MenC conjugate vaccine in infancy including a dose at 12 months of age compared with the other study groups. However, monovalent vaccines are probably more immunogenic [14,15] than quadrivalent vaccines, and in Vancouver, children are

likely to have received 2 doses of the tetanus toxoid (TT) conjugated MenC vaccine, which has been shown to be the most immunogenic of the 3 licensed vaccines [19,35]. No clear advantage of a 3-dose versus 2-dose primary vaccination schedule prior to a 12 month booster was observed in terms of long term persistence of hSBA titres. In the UK, the primary course of MenC immunisations was reduced from 3 to 2 doses in 2006, as it was shown that there was little difference in SBA titres one month following 2 doses of vaccine compared with one month following 3 doses [36,37]. Although the vaccines studied here are different from the monovalent TT conjugate MenC vaccines in those studies, our results support the change to a reduced dose primary schedule. For both serogroups W-135 and Y, higher hSBA titres at both follow-on time-points compared with serogroups A and C reflect higher levels of bactericidal antibody at 13 months of age. Between 1998 and 2007, the estimated incidence of serogroup Y disease in infants under the age of 1 in the US was 1.5 per 100,000, compared with 3.08 per 100,000 for serogroup B and 0.53 for serogroup C [38]. In light of increases in the proportion of serogroup Y disease in the USA over the last 2 decades [39], and outbreaks of serogroup W-135 disease [22,40,41] globally after the turn of the century, the quadrivalent MenACWY-CRM197 vaccine would offer an advantage over monovalent MenC vaccines for broader protection against invasive meningococcal disease in children.

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Fig. 2. hSBA GMTs (and 95% CI) for each group and in age-matched controls in the Canadian population. Open, dark grey and light grey columns represent samples taken at 13, 40 and 60 months of age respectively.

For serogroup A, bactericidal antibody levels at 40 and 60 months of age in immunised children were similar to control children with no previous exposure to MenA containing vaccines. This is in contrast to the relatively good persistence of serogroup A bactericidal antibody levels following immunisation of pre-school aged children and adolescents with a quadrivalent MenACWY diphtheria toxoid conjugate vaccine [42,43]. The differences in results may reflect the younger age of the children immunised in our study, or the different composition of the vaccines used. Furthermore, in industrialised countries, immunity against serogroup A is less important as this is rarely a cause of meningococcal disease outside of Africa and Asia [44]. It should be noted that interpretation of the immunogenicity results is limited by the small sample size in each of the groups who had received different schedules of immunisations and as such definitive conclusions are not possible. Furthermore, the participants in this study were drawn from two different populations. Although it would not be expected that UK and Canadian children differ significantly in their immune response to the vaccines studied, demographic, environmental and genetic factors could account for some of the differences in apparent immunogenicity between groups. Within these limitations, there are no clear differences between groups that received the aluminium phosphate adjuvanted or non-adjuvanted formulations. Both vaccine

formulations are shown to be safe with few adverse events occurring, and no serious adverse events attributable to the vaccines.

5. Conclusions In the UK, the newly licensed non-adjuvanted MenACWYCRM197 conjugate vaccine is recommended for travellers to endemic regions, and is used off-licence for vaccination of children with immunodeficiency [45]. Its incorporation into the routine childhood immunisation schedule would allow for broader protection against meningococcal disease. Although bactericidal antibodies against all serogroups wane rapidly after infant immunisation, persistence of antibody against serogroup C appears to be greatest with schedules that incorporate priming doses of a monovalent MenC conjugate vaccine. A 12 month booster dose of quadrivalent vaccine would then potentially allow for optimal protection against MenC disease, while also broadening protection against serogroup W-135 and Y meningococcal disease, though currently few cases of disease caused by these serogroups occur in this age group. Further doses of meningococcal conjugate vaccines in adolescence are necessary to ensure ongoing protection, particularly to maintain herd immunity. Such boosters have recently been recommended in Canada and are being considered in the UK. In this

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age-group, a MenACWY conjugate vaccine booster could offer protection against serogroups A, Y and W135 meningococci in addition to serogroup C bacteria. Acknowledgements The authors acknowledge the contributions of the staff members and nurses who were involved in this study, in particular Rebecca Beckley, Emma Plested and Saima Khalid (University of Oxford). We also thank the participants of this study and their family members. In addition, we thank Liz Kibwana and Jaclyn Bowan for processing serum samples (University of Oxford), Corinna Brenner and Caitlin McCourt for study coordination, Annette Karsten for the serologic analysis, Alessandra Anemona and Claudia Kittel for the statistical analysis (all from Novartis Vaccines and Diagnostics), and Maithili Dokuparti for clinical report writing (Novartis Healthcare Pvt Ltd.), and Thomas Dawson (University of Oxford) for assistance with protocol development. Funding and conflicts of interest: Supported by Novartis Vaccines and Diagnostics. With the exception of the authors employed by Novartis (P.M.D., C.J.G. and T.O.), no authors have received direct payment from Novartis. The sponsor funded the study and developed the study protocol in collaboration with A.J.P., M.D.S and T.D. Employees of the sponsor reviewed the manuscript before submission for publication. The study was also supported by the Oxford Partnership Comprehensive Biomedical Research Centre with funding from the NIHR Biomedical Research Centre Programme (to A.K., M.D.S. and T.J.). A.K. is a James Martin Fellow. AJP is a Jenner Institute Investigator and James Martin Senior Fellow and acts as an investigator for clinical trials conducted on behalf of Oxford University, sponsored by vaccine manufacturers (Novartis Vaccines, GlaxoSmithKline, Sanofi-Aventis, Sanofi-Pasteur MSD, and Pfizer Vaccines), but does not receive any personal payments from them for travel or consultancy. P.M.D., C.J.G. and T.O. are employees of Novartis Vaccines and Diagnostics. References [1] Rosenstein NE, Perkins BA, Stephens DS, Popovic T, Hughes JM. Meningococcal disease. N Engl J Med 2001;344(May (18)):1378–88. [2] Kvalsvig AJ, Unsworth DJ. The immunopathogenesis of meningococcal disease. J Clin Pathol 2003;56(June (6)):417–22. [3] Cartwright K, Strang J, Reilly S, White D. Mortality in meningococcal disease. BMJ 1992;304(January (6819)):116. [4] Healy CM, Butler KM, Smith EO, Hensey OP, Bate T, Moloney AC, et al. Influence of serogroup on the presentation, course, and outcome of invasive meningococcal disease in children in the Republic of Ireland, 1995–2000. Clin Infect Dis 2002;34(May (10)):1323–30. [5] Armand J, Arminjon F, Mynard MC, Lafaix C. Tetravalent meningococcal polysaccharide vaccine groups A, C, Y, W 135: clinical and serological evaluation. J Biol Stand 1982;10(October (4)):335–9. [6] Granoff DM, Pollard AJ. Reconsideration of the use of meningococcal polysaccharide vaccine. Pediatr Infect Dis J 2007;26(August (8)):716–22. [7] Kelly DF, Snape MD, Clutterbuck EA, Green S, Snowden C, Diggle L, et al. CRM197-conjugated serogroup C meningococcal capsular polysaccharide, but not the native polysaccharide, induces persistent antigen-specific memory B cells. Blood 2006;108(October (8)):2642–7. [8] Snape MD, Pollard AJ. Meningococcal polysaccharide–protein conjugate vaccines. Lancet Infect Dis 2005;5(January (1)):21–30. [9] Bilukha OO, Rosenstein N. Prevention and control of meningococcal disease. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2005;54(May (RR-7):):1–21. [10] European Medicines Agency. Menveo: meningococcal group A, C, W135 and Y conjugate vaccine; 2010 [cited 2011 23 March 2011; EPAR summary for the public]. Available from: http://www.ema.europa.eu/docs/ en GB/document library/EPAR - Summary for the public/human/001095/ WC500090148.pdf. [11] Health Canada Summary Basis of Decision (SBD): MENVEOTM ; 2010 [cited 2011 03/06/11]. Available from: http://www.hc-sc.gc.ca/dhp-mps/ alt formats/pdf/prodpharma/sbd-smd/phase1-decision/drug-med/sbd smd 2010 menveo 127046-eng.pdf. [12] Novartis. MENVEO® [Meningococcal (Groups A, C, Y and W-135) Oligosaccharide Diphtheria CRM197 Conjugate Vaccine]; 2011 [cited 2011 23 March 2011; Highlights of Prescribing Information]. Available from:

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