European Journal of Clinical Microbiology & Infectious Diseases

, Volume 29, Issue 3, pp 259–267

Safety and immunogenicity of an investigational quadrivalent meningococcal conjugate vaccine after one or two doses given to infants and toddlers

Authors

    • Clinical Trials Research Center, Canadian Center for VaccinologyDalhousie University and the IWK Health Centre
  • F. Diaz-Mitoma
    • Children’s Hospital of Eastern Ontario
  • P. Dull
    • Novartis Vaccines
  • A. Anemona
    • Novartis Vaccines
  • F. Ceddia
    • Novartis Vaccines
Article

DOI: 10.1007/s10096-009-0848-8

Cite this article as:
Halperin, S.A., Diaz-Mitoma, F., Dull, P. et al. Eur J Clin Microbiol Infect Dis (2010) 29: 259. doi:10.1007/s10096-009-0848-8

Abstract

With the emergence of multiple meningococcal serogroups in different geographic areas, broad vaccine protection from infancy is desirable. One hundred and seventy-five infants received either two doses of a meningococcal quadrivalent (A, C, W-135, Y) conjugate vaccine (MenACWY-CRM) at 6 and 12 months, one dose of MenACWY-CRM at 12 months, or MenC at 12 months and MenACWY-CRM at 18 months. Bactericidal antibody titers using human complement were measured before and 1 month after each dose. Injection-site reactions were reported by 22–45% of participants following MenACWY-CRM given at 6 or 12 months. Similar proportions of subjects had injection-site reactions following two doses of MenACWY-CRM (32–41%) or one dose of MenC (26–44%). The incidence of systemic adverse events was comparable between groups. After two doses of MenACWY-CRM, the percentages of participants reporting hSBA titers ≥8 were 100% for C, W-135, and Y, and 84% for A. Serogroup C titers were more than 10-fold higher after two doses of MenACWY-CRM than after one dose of MenC or MenACWY-CRM at 12 months. Serogroup C titers were comparable following a single dose of MenACWY-CRM or MenC at 12 months. MenACWY-CRM is well tolerated and immunogenic given at 12 months, or two doses at 6 and 12 months of age.

Introduction

Neisseria meningitidis causes severe invasive disease, including septicemia and meningitis [1]. Five serogroups (A, B, C, Y, W-135) are responsible for most of the invasive diseases caused by the meningococcus [2]. Although meningococcal disease has a worldwide distribution, the prevalence of different serogroups varies by region. Serogroup A disease is rarely seen in North America but occurs in epidemics in sub-Saharan Africa, the Middle East, and in areas of Asia [3]. In Europe and North America, disease caused by serogroups B and C predominates, although there was an emergence in the early 1990s of serogroup Y disease in the United States, which has persisted [4]. Serogroup W-135 causes sporadic infections, but has been associated with outbreaks in the Middle East that spread to Africa [5].

Although capsular polysaccharide vaccines against meningococcal serogroups A, C, Y, and W have been available for over 30 years, their use has been restricted to outbreak management rather than disease control because they do not induce long-term memory [6]. Polysaccharide vaccines are also poorly immunogenic in young infants who are at particularly high risk from invasive meningococcal infections [7] and can induce subsequent hyporesponsiveness, in particular with serogroup C [8]. Recently, meningococcal C conjugate (MenC) vaccines that are immunogenic and effective in young infants have been developed using the technology that was so effectively used to produce effective Haemophilus influenzae type b conjugate vaccines [9]. Universal implementation of these MenC vaccines led to the dramatic control of invasive serogroup C disease in the United Kingdom [10] and elsewhere [11, 12]. A quadrivalent meningococcal conjugate vaccine (Menactra®; sanofi pasteur, Swiftwater, PA) has been licensed in several countries and is now recommended for routine use in adolescents in the United States [13]; however, this vaccine is not sufficiently immunogenic in children under 2 years of age [14]. Given the ever-changing epidemiology of meningococcal infections around the world and the changing prevalence of serogroups causing invasive disease, a multivalent meningococcal conjugate vaccine that could be given in infancy is desirable. We report here the results of a phase II clinical trial of one or two doses of an investigational, quadrivalent meningococcal conjugate vaccine in infants and toddlers.

Methods

Vaccines

The quadrivalent meningococcal conjugate vaccine (MenACWY-CRM) vaccine contained (per 0.5-mL dose) 10 μg of meningococcal serogroup A capsular polysaccharide and 5 μg each of serogroup C, W-135, and Y capsular polysaccharides conjugated to CRM197. The vaccine was prepared by mixing, just before injection, the MenCWY liquid suspension and the lyophilized MenA powder; MenACWY-CRM does not contain any adjuvant. The control vaccine was the licensed MenC vaccine (Menjugate®; Novartis Vaccines) containing (per 0.5-mL dose) 10 μg of meningococcal serogroup C capsular polysaccharide conjugated to CRM197 and 1.0 mg aluminum hydroxide adjuvant. Both vaccines were manufactured by Novartis Vaccines and Diagnostics (Siena, Italy); a single lot of each vaccine was used in the study. Concomitant vaccines administered as part of the study included diphtheria-tetanus-acellular pertussis-inactivated poliovirus-Haemophilus influenzae type b conjugate vaccine (DTaP-IPV-Hib; Pentacel™; sanofi pasteur, Toronto, Canada) and pneumococcal conjugate vaccine (PC7; Prevnar®; Wyeth Pharmaceuticals, Pearl River, NY).

Study population

Healthy children at 6 and 12 months of age who had previously received two DTaP-IPV-Hib and PC7 doses (6-month-olds) or three DTaP-IPV-Hib doses (12-month-olds) were recruited into the study. Children were excluded from participation if they had received any meningococcal vaccine or had confirmed or suspected disease caused by N. meningitidis, had known or suspected HIV infection, were immunocompromised or receiving immunosuppressive therapy, had received immunoglobulin, blood, or blood products within the last 90 days, had a history of neurological disease, developmental delay, seizures, bleeding diathesis, had any serious acute or chronic medical condition, or had a hypersensitivity to any component of the vaccine. Infants were also excluded if they had a recent significant acute or chronic infection or if they had recently taken systemic antibiotics.

Study design and procedures

The study was an open-label, partially randomized, controlled, three-center study. Written informed consent was obtained from the parents or guardian prior to any study procedure; the study protocol was approved by the Research Ethics Board of each participating center. Participants at 6 months of age were randomly allocated in a 1:1 ratio to receive two doses of MenACWY-CRM at 6 and 12 months of age (Group 1) or a single dose of MenACWY-CRM at 12 months of age (Group 2) using a center-stratified, computer-generated list provided by the Biostatistics and Clinical Data Management Group of Novartis. Infants at 12 months of age were enrolled and received a single dose of MenC at 12 months of age and MenACWY-CRM at 18 months of age (Group 3).

MenACWY-CRM was given by a 0.5-mL intramuscular injection at 6 and 12 months of age (Group 1) or 12 months of age (Group 2). MenC and MenACWY-CRM were given by intramuscular injection at 12 and 18 months of age (Group 3). Participants were monitored by the study staff for 30 min after each injection for immediate reactions. Parents recorded in a standardized symptom diary daily axillary temperatures, injection-site reactions (tenderness, erythema, induration), and systemic reactions (change in eating habits, sleepiness, vomiting, diarrhea, irritability) for 7 days after each vaccination. Solicited adverse events were either measured (fever, erythema, swelling) or categorized as absent or present. Hospitalizations and other serious adverse events were collected at any time during the study. All unsolicited adverse events were collected and tabulated by body system.

Blood was collected by venipuncture immediately before and approximately 28 days after each vaccination. Functional antibody to each of the four meningococcal serogroups was measured by a serum bactericidal assay using human complement (hSBA) and reported as reciprocal dilution (RD) [1517]. All antibody measurements were performed by Novartis Vaccines.

Data analysis and statistical considerations

The primary objective of the study was to assess the immunogenicity of MenACWY-CRM when given as a two-dose schedule at 6 and 12 months of age. Immunogenicity was defined as the percentage of subjects achieving an hSBA of ≥4 against N. meningitidis serogroups A, C, W, and Y. Secondary objectives included evaluation of the geometric mean hSBA antibody titers (hSBA GMTs) and the proportion of participants achieving hSBA titers ≥8. Additional secondary objectives were to assess the safety and tolerability of all of the vaccines administered and to assess the immunogenicity of MenC at 12 months of age and MenACWY-CRM at 18 months of age in children who had received MenC at 12 months of age.

All subjects who received a dose of vaccine were included in the analysis of safety. Adverse events were tabulated and the maximum severity reported for each time period was used. The proportion of participants having an adverse event by vaccine group was calculated with 95% confidence intervals (CIs).

All subjects who received all of the relevant doses of vaccine correctly, provided evaluable serum samples at the relevant time points, and had no major protocol violation as defined prior to database lock were part of the per-protocol analysis population. A major protocol violation was defined as one that was considered to have a significant impact on the immunogenicity results of the subject. GMTs and 95% CIs were calculated for each vaccine group and for each serogroup pre- and post-vaccination by exponentiating (base 10) the least-squares means of the logarithmically transformed (base 10) titers and their 95% CIs obtained from a two-way analysis of variance (ANOVA) with factors for vaccine group and center. Titers below the detection limit were set to half that limit for the purposes of the analysis. The percentages of subjects with hSBA of ≥4 or ≥8 and associated two-sided 95% Clopper–Pearson CIs were computed for each vaccine group within each serogroup.

A sample size of 100 per group was selected to provide a precision of the estimate of antibody response (hSBA ≥4) of ±10%, as measured by the Clopper–Pearson two-sided 95% CI. Lower than expected enrollment led to a decrease in the precision of these estimates.

Results

Demographics and participant disposition

A total of 175 participants were enrolled in the study and allocated to one of the three vaccine groups (Fig. 1). Participant demographic characteristics were similar between the three groups, except for the age at enrollment (12.1 months in Group 3 rather than 6.0 months in Groups 1 and 2) (Table 1). In total, 157 (90%) participants completed the study, including 59 (92%) of 64 participants in Group 1, 56 (92%) of 61 participants in Group 2, and 42 (84%) of 50 participants in Group 3. None of the 18 withdrawals were due to an adverse event. Six participants were withdrawn because of withdrawal of parental consent, nine participants were lost to follow up, one subject was withdrawn because of refusal to attend two of the visit appointments, and two subjects were inappropriately enrolled (one had already received a MenC vaccine and one had only received one prior dose of pneumococcal conjugate vaccine). All subjects who received a dose of the vaccine were included in the safety analysis to the extent that data were available. The two subjects inappropriately enrolled did not receive a MenACWY-CRM investigational vaccine.
https://static-content.springer.com/image/art%3A10.1007%2Fs10096-009-0848-8/MediaObjects/10096_2009_848_Fig1_HTML.gif
Fig. 1

Flow of participants through the study

Table 1

Characteristics of the study population

Characteristics

Group 1 (MenACWY6/MenACWY12)

Group 2 (MenACWY12)

Group 3 (MenC12/MenACWY18)

Total vaccinated subjects

n

64

61

50

Age

Mean ± SD, months

6.0 ± 0.2

6.0 ± 0.0

12.1 ± 0.2

Gender

Female (%)

39

51

42

Male (%)

61

49

58

Race

Asian (%)

0

0

2

Black (%)

3

3

6

Caucasian (%)

83

79

78

Hispanic (%)

2

0

2

Other (%)

13

18

12

Adverse events

MenACWY-CRM vaccine was well tolerated by participants, whether given as a one- or two-dose series and whether given at 6, 12, or 18 months of age. At least one solicited local or systemic adverse event was reported by 95–100% of participants in the three vaccine groups; 80–94% reported injection-site events and 86–92% systemic adverse events. Erythema was the most common injection-site adverse event, reported by 39–45% of participants after the MenACWY-CRM vaccine and by 44% of participants who received the MenC vaccine at 12 months of age (Table 2). Rates of induration and tenderness were also similar whether MenACWY-CRM was given at 6 and 12 months, 12 months only, or 12 months (MenC) and 18 months (MenACWY-CRM). Most injection-site adverse events were described as mild or moderate; severe tenderness (cried when injected limb was moved) was reported by two participants, each of whom received a single dose of MenACWY-CRM at 12 months or at 18 months of age. There was no severe induration or erythema (>50 mm) reported. Irritability was the most common systemic adverse event, ranging from 52 to 73% of participants. Sleepiness was also commonly reported (24–42%). Fever (axillary temperature ≥ 38.0°C) was reported by 5% (95% confidence interval 1–14%) of participants after each of the two-dose MenACWY-CRM series, 13% (6–25%) of recipients of MenACWY-CRM at 12 months of age, and 4% (0–14%) of MenC recipients at 12 months and 23% (12–38%) of MenACWY-CRM at 18 months of age. One subject had a temperature >40.0°C; it occurred on study day 4 in a 12-month-old subject enrolled to receive a single dose of MenACWY-CRM at 12 months of age. Other systemic adverse events were reported by ≤20% of participants. There was no apparent increase in injection-site or systemic adverse events after the second dose of MenACWY-CRM, nor was there a clear difference in the frequency of adverse events between the MenC and MenACWY-CRM vaccines.
Table 2

Incidence of solicited local and general symptoms after each vaccination. The population analyzed was the total vaccinated cohort (all subjects who received a dose of vaccine)

Adverse event

Age (months)

Proportion reporting event (95% confidence interval)

Group 1 (MenACWY6/MenACWY12)

Group 2 (MenACWY12)

Group 3 (MenC12/MenACWY18)

Erythema

6

41% (29–54)

-

-

12

41% (28–55)

45% (32–59)

44% (30–59)

18

-

-

39% (25–55)

Induration

6

28% (18–41)

-

-

12

36% (24–50)

36% (24–50)

32% (20–47)

18

-

-

25% (13–40)

Tenderness

6

22% (13–34)

-

-

12

32% (21–45)

43% (30–57)

26% (15–40)

18

-

-

52% (36–67)

Changed eating habits

6

31% (20–44)

-

-

12

22% (12–35)

21% (11–34)

28% (16–43)

18

-

-

26% (14–42)

Sleepiness

6

42% (30–55)

-

-

12

34% (22–48)

36% (24–50)

24% (13–38)

18

-

-

39% (25–55)

Irritability

6

73% (60–83)

-

-

12

58% (44–71)

52% (38–66)

58% (43–72)

18

-

-

66% (50–80)

Vomiting

6

9% (3–19)

-

-

12

5% (1–14)

11% (4–22)

8% (2–19)

18

-

-

7% (2–19)

Diarrhea

6

9% (3–19)

-

-

12

14% (6–26)

20% (11–33)

14% (6–27)

18

-

-

11% (4–24)

Fever ≥38ºC

6

5% (1–14)

-

-

12

5% (1–14)

13% (6–25)

4% (0–14)

18

-

-

23% (12–38)

Seven subjects experienced nine serious adverse events during the course of the study, including three participants in Group 1 (respiratory syncytial virus infection, bronchiolitis, lethargy), two in Group 2 (bronchiolitis, asthma, and pneumonia in one participant, and urinary tract infection in a second participant), and two in Group 3 (asthma, infectious mononucleosis). All seven participants with serious adverse events were hospitalized. The bronchiolitis and pneumonia in one participant and the urinary tract infection in another both occurred before the administration of MenACWY-CRM. None of the serious adverse events resulted in withdrawal from the study and none were assessed by the local investigator as vaccine-related.

Antibody response

Pre-vaccination antibody levels against all four serogroups were similar amongst the vaccine groups, regardless of the age at the first meningococcal conjugate vaccination (6 or 12 months; Tables 3 and 4). MenACWY-CRM induced an immune response against all serogroups at 6 months of age, with serogroup C being the most immunogenic. Infants who had been vaccinated at 6 months of age had higher antibody levels (although only marginally so for serogroup A) before their vaccinations at 12 months than infants receiving their first meningococcal vaccinations at 12 months of age. After their second dose, 12-month-old infants had significantly higher antibody levels against all four serogroups than infants being vaccinated with MenACWY-CRM for the first time; the levels achieved ranged from four times higher for serogroup A after a second dose to 7.8–13-fold higher for the other serogroups. A single dose of MenACWY-CRM at 12 months of age was similarly immunogenic for serogroup C compared with the licensed monovalent MenC vaccine. A dose of MenACWY-CRM at 18 months of age in children previously vaccinated with MenC at 12 months of age (i.e., two doses of a serogroup C-containing vaccine) induced similar levels of antibody against serogroups A, Y, and W as were induced with the single dose of MenACWY-CRM at 12 months of age and higher levels of antibody against serogroup C than were achieved by giving two doses of serogroup C containing vaccine at 6 and 12 months of age.
Table 3

Proportion of participants achieving a serum bactericidal assay antibody titer (using human complement) of ≥4 to each meningococcal serogroup before and after each vaccination visit. The population analyzed was that according to the protocol cohort for immunogenicity

Serogroup

Age (months)

Proportion (95% confidence interval) with hSBA ≥1:4

Group 1 (MenACWY6/MenACWY12)

Group 2 (MenACWY12)

Group 3 (MenC12/MenACWY18)

A

6

0 (0–6)

2 (0.046–10)

-

7

28 (17–42)

2 (0.048–10)

-

12

9 (3–21)

0 (0–7)

0 (0–7)

13

87 (75–95)

73 (59–84)

0 (0–8)

18

-

-

0 (0–8)

19

-

-

65 (48–79)

C

6

3 (0–12)

0 (0–6)

-

7

93 (84–98)

0 (0–6)

-

12

86 (74–94)

2 (0.047–10)

0 (0–7)

13

100 (94–100)

96 (87–100)

94 (82–99)

18

-

-

91 (78–97)

19

-

-

100 (91–100)

W-135

6

2 (0.044–9)

2 (0.046–10)

-

7

58 (44–72)

0 (0–7)

-

12

86 (73–95)

2 (0.052–11)

2 (0.058–12)

13

100 (93–100)

94 (82–99)

5 (1–16)

18

-

-

5 (1–16)

19

-

-

82 (66–92)

Y

6

3 (0–12)

0 (0–6)

-

7

42 (29–55)

0 (0–6)

-

12

72 (58–84)

0 (0–7)

2 (0.053–11)

13

100 (94–100)

78 (65–88)

0 (0–8)

18

-

-

0 (0–8)

19

-

-

80 (64–91)

Table 4

Geometric mean hSBA antibody titers at each study visit. The population analyzed was that according to the protocol cohort for immunogenicity

Serogroup

Age (months)

Geometric mean antibody titer (95% confidence interval)

Group 1 (MenACWY6/MenACWY12)

Group 2 (MenACWY12)

Group 3 (MenC12/MenACWY18)

A

6

2 (1.97–2.04)

2.04 (2–2.07)

-

7

3.02 (2.67–3.42)

2.07 (1.82–2.35)

-

12

2.38 (2.17–2.61)

1.99 (1.82–2.19)

2 (1.96–2.04)

13

44 (30–65)

11 (7.41–16)

2 (1.75–2.29)

18

-

-

2 (1.8–2.22)

19

-

-

9.06 (5.77–14)

C

6

2.18 (2.02–2.35)

2 (1.85–2.16)

-

7

25 (20–33)

2.01 (1.56–2.59)

-

12

19 (14–25)

2.07 (1.55–2.76)

1.99 (1.8–2.17)

13

314 (234–421)

40 (29–53)

40 (30–53)

18

-

-

30 (21–41)

19

-

-

679 (479–962)

W-135

6

2.08 (1.94–2.24)

2.03 (1.89–2.18)

-

7

6.15 (5.1–7.41)

2.02 (1.67–2.44)

-

12

15 (12–19)

2.09 (1.72–2.55)

2.08 (1.92–2.25)

13

263 (190–363)

27 (19–37)

2.14 (1.74–2.64)

18

-

-

2.18 (1.76–2.7)

19

-

-

18 (13–26)

Y

6

2.12 (2–2.24)

2 (1.88–2.12)

-

7

3.9 (3.4–4.48)

2 (1.74–2.31)

-

12

7.9 (6.66–9.35)

2.02 (1.7–2.39)

2.05 (1.93–2.19)

13

143 (105–194)

11 (8.24–15)

2.01 (1.72–2.35)

18

-

-

1.99 (1.65–2.41)

19

-

-

13 (9.21–19)

The proportions of participants achieving an hSBA ≥4 or ≥8 after vaccination were similar, so only the more stringent criterion of ≥8 is displayed (Fig. 2). In participants vaccinated with MenACWY-CRM at 6 months of age, 14, 88, 45, and 27% achieved an hSBA ≥1:8 for serogroups A, C, W, and Y, respectively. After the second dose at 12 months of age, hSBA ≥8 was achieved by 83, 100, 100, and 100% against serogroups A, C, W, and Y, respectively. In the group that received MenACWY-CRM at 12 months of age only, the responses against A, C, W, and Y were 60, 93, 93, and 57%, respectively. The 93% response rate against serogroup C in MenACWY-CRM recipients at 12 months of age was similar to the response rate (89%) after the monovalent MenC vaccine at 12 months of age. In this latter cohort, a dose of MenACWY-CRM at 18 months of age induced an hSBA ≥8 in 53, 100, 77, and 65%, respectively.
https://static-content.springer.com/image/art%3A10.1007%2Fs10096-009-0848-8/MediaObjects/10096_2009_848_Fig2_HTML.gif
Fig. 2

Proportion of participants with a serum bactericidal assay with human complement (hSBA) of 1:8 or higher after one or two doses of the quadrivalent MenACWY-CRM or one dose of MenACWY-CRM following one dose of monovalent MenC vaccine

Discussion

The purpose of this study was to assess the safety and immunogenicity of a quadrivalent vaccine, MenACWY-CRM, in a two-dose schedule at 6 and 12 months of age compared with a single dose at 12 months of age or a single dose at 18 months of age following a dose of MenC vaccine at 12 months of age. The results of the study demonstrate that MenACWY-CRM was well-tolerated and was immunogenic at 6 months of age, primed for an enhanced response at 12 months of age, had a similar adverse event profile and immunogenicity against serogroup C as the monovalent MenC vaccine, and could be safely used to broaden (and boost) the immune response in toddlers already immunized with the MenC vaccine. These results expand the previously published data on the safety and immunogenicity of MenACWY-CRM in a two- or three-dose schedule to young infants in an adjuvanted [17] or, as in this study, unadjuvanted formulation [18].

In this study, a single dose of MenACWY-CRM given at 6 months of age elicited bactericidal antibodies against all four serogroups contained in the vaccine. The highest GMTs observed were against serogroups C and W-135, with the lowest GMT against serogroup A. Although care must still be taken when comparing antibody results across studies, the immunogenicity results reported previously with MenACWY-CRM were generated by the same laboratory using the same internally standardized and validated assay [17, 18]. The relative immunogenicity of the four serogroups in this study is the same as that found in infants vaccinated at 2 and 4 months, 2, 3, 4 months, or 2, 4, and 6 months of age with a formulation adjuvanted with aluminum phosphate [17], or at 2 and 4 months of age with the same unadjuvanted formulation used in this study [18]. In contrast to the infant studies where antibody levels declined significantly between the doses given at 2 and 4 months, 2, 3, and 4 months, or 2, 4, and 6 months of age and the 12-month dose, with the 6- and 12-month schedule used in this study, hSBA GMTs were relatively stable for serogroup C (falling from 25 to 19 from 7 to 12 months of age) and actually rising for serogroups W-135 (6.15 rising to 15) and serogroup Y (rising from 3.9 to 7.9). This is in contrast to hSBA GMTs for the group receiving only MenACWY-CRM at 12 months of age, where serogroups W-135 and Y antibodies were absent at 7 months of age were again absent at 12 months of age, prior to the initial MenACWY-CRM vaccination. Serogroup A antibody levels dropped slightly from 3.02 to 2.38, which is marginally higher than the pre-6 month dose baseline levels (2.0). The higher levels of W-135 and Y antibody may be due to a slower antibody response resulting in the peak antibody level occurring after the 7-month sample with a subsequent drop to the 12-month specimen or a priming event where other exposures between 7 and 12 months further increased hSBA GMTs. Although interpreting immunogenicity data across studies should be done with caution, antibody levels after a single dose of MenACWY-CRM against serogroups C, W, and Y at 12 months of age were all equivalent to or greater than titers in infants who had received two or three doses of MenACWY-CRM before 6 months of age. Finally, a dose of MenACWY-CRM at 6 months of age served to prime the immune system for a second dose at 12 months of age. Antibody levels one month after the second 12-month dose were significantly higher for all serogroups than after a single 12-month dose (ranging from 4- to 13-fold). Although antibody titers tended to be higher in infants in previous studies given three doses at 2, 4, and 12 months of age or four doses at 2, 3, 4, and 12 months or 2, 4, 6, and 12 months of age, the proportion of participants having antibody titers ≥4 was similar with the two-dose 6- and 12-month schedule as the three- or four-dose schedules used in the previous studies.

In the United States and Canada, a quadrivalent polysaccharide-diphtheria toxoid conjugate MenACWY vaccine is licensed for use in children 2 years of age and older [19]; the vaccine was insufficiently immunogenic in younger infants and toddlers [14]. In the US, this vaccine is recommended for universal use as an early adolescent dose. Monovalent MenC vaccines are not available in the US [13]. In Canada, although some provinces and territories use a MenC infant schedule of 2, or 2 and 4 months with a booster at 12 months of age, most jurisdictions immunize with a single dose of MenC at 12 months of age and some use the licensed quadrivalent MenACWY vaccine for an adolescent dose [20]. In this study, a single dose of the quadrivalent MenACWY-CRM elicited similar antibody levels to a licensed monovalent MenC vaccine. If larger phase 3 studies validate this finding, this may allow these jurisdictions to achieve broader serogroup protection at 1 year of age without any loss of protection against serogroup C meningococcal disease (assuming that bactericidal antibody levels correlate with protection). The safety and enhanced immunogenicity of the serogroup C component when MenACWY-CRM was given at 18 months of age after MenC at 12 months of age provides further flexibility for jurisdictions that wish to provide broader serogroup protection by a ‘catch-up’ program for toddlers previously immunized with the monovalent MenC vaccine. Of note, as with the group who received two doses of MenACWY-CRM, there was little serogroup C antibody decline in the 6-month interval between the MenC and MenACWY-CRM doses.

In view of the diminution of antibody levels with these infant schedules and with the experience of loss of effectiveness of the vaccine in the second year of life with monovalent MenC vaccines when no booster vaccination is given [21], a dose after 12 months of age will likely be required for MenACWY-CRM. Previous studies have investigated infant schedules including doses at 2, 3, 4 months, 2 and 4 months, and 2, 4, and 6 months, in most cases with a booster at 12 months of age [17, 18]. This study provides data on the safety and immunogenicity of a 6- and 12-month schedule or a single-dose 12-month schedule with MenACWY-CRM, as well as the use of MenACWY-CRM for boosting toddlers previously immunized with the monovalent MenC vaccine. The results of this study demonstrate the potential additional flexibility that would be available with MenACWY-CRM for the prevention of meningococcal infections in children.

Acknowledgments

We thank the nurses and staff for their careful attention to detail and to the children and their families for participating in the study. We also thank Dr. Bruce Smith at the Canadian Center for Vaccinology for his independent evaluation of the statistical analysis plan and report and statistical analysis.

Financial interest

A. Anemona and P. Dull are employees of Novartis Vaccines. F. Ceddia was an employee of Novartis Vaccines; current address GlaxoSmithKline Biologicals, Rixensart, Belgium. S. Halperin and F. Diaz-Mitoma had no financial interest in the vaccine or its manufacturer, but received research funding to undertake the study.

The study was funded by Novartis Vaccines.

Copyright information

© Springer-Verlag 2009