Update on Quadrivalent Meningococcal Vaccines available in Canada

An Advisory Committee Statement (ACS) National Advisory Committee on Immunization (NACI)

1. What

Invasive meningococcal disease (IMD) is a potentially fatal disease usually presenting as an acute febrile illness with rapid onset and features of meningitis or septicemia (meningococcemia), or both, and a characteristic non-blanching rash.

Nimenrix^™ is a newly licensed quadrivalent (serogroups A, C, Y and W135) meningococcal vaccine conjugated to the tetanus toxoid (TT).

This Statement provides information regarding the immunogenicity, safety and recommended use of Nimenrix^™, and provides updated immunogenicity and safety information about Menactra^® (Men-C-ACYW-DT) with respect to its expanded age indication.

2. Who

For routine vaccination in adolescents, either monovalent meningococcal C conjugate or quadrivalent conjugate meningococcal vaccines can be used depending on local epidemiology and other programmatic considerations. If using a quadrivalent product, any of the three available products can be chosen.

For high risk individuals 2 years of age and older or for travellers 2 years and older going to areas where the meningococcal vaccine is recommended, any of the available quadrivalent products can be used.

For high risk children 2 months to less than 2 years of age or travellers 2 months to less than 2 years of age who are going to areas where the meningococcal vaccine is recommended, Menveo^™ (Men-C-ACYW-CRM) is the recommended product.

Schedules are provided in the Meningococcal Chapter of the Canadian Immunization Guide.

3. How

Nimenrix^™ is authorized for use for immunization of individuals from 12 months to 55 years of age, but can be used for those ≥ 56 years of age if indicated. It should not be administered to subjects with known hypersensitivity to any component of the vaccine.

Nimenrix^™ may be administered alone or concomitantly with other routinely administered vaccines in Canada. The National Advisory Committee on Immunization (NACI) recommends periodic boosters for individuals at high risk for meningococcal disease or who have ongoing increased risk of  exposure. Additional information is provided in the Meningococcal Chapter of the Canadian Immunization Guide..

Nimenrix^™ has a safety profile similar to other monovalent and quadrivalent conjugated meningococcal vaccines that are authorized for use in Canada.

4. Why

IMD mortality is approximately 10%. Of IMD survivors, up to a third may experience long term sequelae.

Approximately one-third of all IMD is associated with Neisseria meningitidis serogroups A, C, Y and W-135; immunization against vaccine preventable IMD serogroups is important, particularly for those at higher risk for infection.

I. Introduction

The purpose of this Statement is to supplement previous conjugate meningococcal vaccine statements^Footnote 1,^Footnote 2,^Footnote 3,^Footnote 4 which have outlined the use of monovalent meningococcal C and quadrivalent conjugate meningococcal vaccines. This statement will:

• Review existing NACI recommendations on the use of conjugate meningococcal vaccines;
• Update the epidemiology of meningococcal disease in Canada;
• Review and update information on quadrivalent conjugate meningococcal vaccines and vaccination schedules used in Canada following the approval of a new quadrivalent conjugate meningococcal vaccine Nimenrix^™ (GlaxoSmithKline [GSK]) and of a new age indication for Menactra^® (Sanofi Pasteur).

Background:

Three monovalent conjugate meningococcal vaccines (using CRM197 or TT as carrier proteins) are available in Canada, and with the authorization of Nimenrix^™, three quadrivalent conjugate meningococcal vaccines (using CRM197, diphtheria toxoid [DT], or TT as carrier proteins) are also available in Canada. NACI recommends that healthy children be immunized with monovalent conjugate meningococcal C vaccine vaccine routinely at 12 months of age; however, they may begin meningococcal immunization earlier depending on provincial/territorial schedules. In addition, NACI recommends the routine use of a conjugate vaccine, either monovalent or quadrivalent (depending on local epidemiology and other programmatic considerations), for a routine adolescent booster dose at around 12 years of age. For specific vaccine recommendations, please refer to the Canadian Immunization Guide.

NACI recommends the use of quadrivalent conjugate meningococcal vaccine for serogroups A, C, W135 and Y for immunization in the following groups:

Those at high risk due to medical conditions:

• Persons with functional or anatomic asplenia (including sickle cell disease);
• Persons with congenital complement, properdin, factor D or primary antibody deficiencies;
• Persons with acquired complement deficiency due to receipt of the terminal complement inhibitor eculizumab (Soliris^™);
• In addition, immunization should be considered for individuals with HIV, especially if congenitally acquired.

Those at increased risk due exposures:

• Travellers when meningococcal vaccine is recommended or required, including travellers to sub-Saharan Africa and pilgrims to the Hajj in Mecca, Saudi Arabia;
• Laboratory personnel who are potentially routinely exposed to N. meningitidis;
• Military personnel during recruit training and on certain deployments.

For high risk individuals due to medical conditions, 2 years of age and over, either Men-C-ACYW-CRM or Men-C-ACYW-DT vaccine should be given as a 2 dose series at least 8 weeks apart. Men-C-ACYW-135 vaccines are not authorized for use in those 56 years of age and older; however, based on limited evidence and expert opinion their use is considered appropriate. For high risk children from 2 months to less than 2 years of age, Men-C-ACYW-CRM should be preferentially used; for children 1 to less than 2 years of age, a 2 dose series is recommended with each dose given at least 8 weeks apart, and for infants 2 months to less than 1 year of age a schedule using 2 or 3 doses with another dose at 12 to 23 months of age is recommended.^{Footnote 5}

Those at high risk for meningococcal disease due to medical conditions should receive periodic boosters^{Footnote 5} for those vaccinated at 6 years of age or younger, a booster dose should be provided 3-5 years after the last dose and then every 5 years thereafter; for those vaccinated at 7 years of age or older, booster doses should be provided every 5 years after the last dose. Schedules for those at high risk due to medical conditions are provided in Table 3 of the Meningococcal Chapter of the Canadian Immunization Guide.

Those at increased risk due to exposures, including travellers to areas where meningococcal vaccine is recommended, should receive the quadrivalent conjugate meningococcal vaccine, along with periodic boosters if they remain at ongoing increased risk of exposure. Schedules for travellers are provided in Table 1 of the Meningococcal Chapter of the Canadian Immunization Guide. Revaccinated for close contacts of an IMD case is recommended as per Table 2 of the Meningococcal Chapter of the Canadian Immunization Guide.

In December 2012, Health Canada (HC) approved the expansion of the age indication for Menactra^® (Men-C-ACYW-DT) starting at 9 months of age. In March 2013, HC authorized the use of a new quadrivalent conjugate vaccine for individuals 12 months to 55 years of age, Nimenrix^™ (Men-C-ACYW-TT) produced by GlaxoSmithKline (GSK). The purpose of this statement is to provide recommendations for the new product Nimenrix^™ and for the new age indication for Menactra^®.

II. Methods

NACI reviewed key questions for the literature review as proposed by the Meningococcal Working Group, including such considerations as the burden of disease to be prevented; the target population, safety, immunogenicity, efficacy and effectiveness of the vaccine; vaccine schedules; and other aspects of the overall immunization strategy. The knowledge synthesis was performed by medical specialists at the Agency and supervised by the Working Group. Following critical appraisal of individual studies, summary tables were prepared with ratings of the quality of the evidence using NACI's methodological hierarchy (Tables 4 and 5), and proposed recommendations for vaccine use were developed. The Working Group chair and Agency medical specialist presented the evidence and proposed recommendations to NACI on October 8, 2013. Following thorough review of the evidence and consultation at the NACI meeting, the Committee voted on specific recommendations. The description of relevant considerations, rationale for specific decisions, and knowledge gaps are described in the text.

III. Epidemiology

N. meningitidis (meningococcus) is a potentially serious pathogen that colonizes up to 10% of healthy individuals. Meningococci can be classified based on the immunologic reactivity of the polysaccharide capsule into at least 12 different serogroups, of which five (A, B, C, W-135 and Y) are associated most frequently with IMD.

IMD usually presents as an acute febrile illness with rapid onset and features of meningitis or septicemia (meningococcemia), or both, and a characteristic non-blanching rash. Overall case fatality is approximately 10%, and up to a third of survivors may have long-term sequelae, which can include hearing loss, neurologic disabilities and digit or limb amputations.^{Footnote 4},^{Footnote 6} All probable and confirmed IMD cases are reported from the provinces and territories to the Agency's Enhanced IMD Surveillance System. Provincial and territorial public health and/or hospital laboratories send all meningococcal isolates to the Agency’s National Microbiology Laboratory for strain characterization, including confirmation of serogroup and determination of serotype, serosubtype and sequence type/clonal complex.

Although IMD is reported year round, there is considerable variation in geographical and temporal incidence, with the majority of cases occurring between November and March. The incidence of IMD in Canada has ranged from 0.45 to 1.18 cases per 100,000 population from 1995 to 2011. Between 2007 and 2011, an average of 193.8 cases of IMD were reported annually in Canada, with an average incidence of 0.58 cases per 100,000 population.

In Canada, serogroups B is now the most common cause of IMD followed by serogroup Y. Following the occurrence of localized serogroup C outbreaks in the late 1990s and early 2000s, conjugate serogroup C vaccination programs were implemented in all Canadian provinces and territories between 2002 and 2006 (Table 1), resulting in significant decreases in serogroup C incidence in all age groups and regions.^Footnote 6,^Footnote 7,^Footnote 8,^Footnote 9,^Footnote 10,^Footnote 11,^Footnote 12,^Footnote 13,^Footnote 14,^Footnote 15,^Footnote 16,^Footnote 17,^Footnote 18,^Footnote 19,^Footnote 20,^Footnote 21,^Footnote 22,^Footnote 23,^Footnote 24,^Footnote 25,^Footnote 26,^Footnote 27 With the declining incidence, cases of serogroup C are rare, and serogroup B now makes up the greatest proportion of reported IMD cases in Canada (62% due to serogroup B versus 2% due to serogroup C in 2011). Serogroup A is exceedingly rare in Canada, and tends to be associated with travel to areas of the world where it remains endemic (e.g. the African meningitis belt).

Table 2 presents the average annual number and range of IMD cases and incidence rates for 2007 to 2011. It also indicates the median age and case fatality ratio (CFR) by serogroup from 2007 to 2011.

As demonstrated in Figure 2, geographic differences in the serogroup distribution of IMD exist across Canada. The highest incidence of IMD and serogroup B-specific IMD occurred in Québec where, on average, 77% of cases were due to serogroup B from 2007 to 2011. Among remaining provinces, the serogroup distribution varied, with serogroup B making up between 32% and 67% of cases from 2007 to 2011, depending on the province. Very few cases were reported in the three territories and Prince Edward Island (1 to 3 cases per year) from 2007 to 2011. The small numbers mean that proportions may vary greatly from year to year, and should thus be interpreted with caution.

The serogroup distribution of IMD also differs by age, with serogroup Y cases having the highest median age from 2007 to 2011 (47 years), followed by C (44.5 years) and W-135 (38 years). As seen in Figure 3, the proportion of cases due to serogroup B decreases with age while conversely, the proportion of cases due to serogroups C and Y tends to increase with age.

IV. Vaccine

A note about carrier proteins: While vaccines containing CRM197 and TT in general demonstrate greater immunogenicity compared to those containing DT, controversy remains concerning the comparative superiority of these two proteins.^Footnote 6,^Footnote 7,^Footnote 8,^Footnote 9,^Footnote 10,^Footnote 11

IV.2 Efficacy or effectiveness

Pre-authorization efficacy trials are difficult to conduct because of the relative rarity of meningococcal disease; therefore, antibody-dependent, complement-mediated, bactericidal activity measured using serum bactericidal assay (SBA) is used as an immunological correlate of protection.

The efficacy of new conjugate meningococcal vaccines can be inferred from the demonstration of immunologic non-inferiority to authorized meningococcal vaccines. Regulatory approval therefore is based on post-vaccination immunogenicity data only. Post-licensure effectiveness of conjugate vaccines has relied on the screening method^{Footnote 28} which requires accurate coverage data as well as the immunization status of cases. In Canada, the number of cases of meningococcal disease is small and it would take many years to have sufficient cases to be able to estimate vaccine effectiveness (VE). In addition, the current quality of data from surveillance of coverage and cases is not high enough to enable VE to be measured. Immunogenicity is therefore the best method available.

IV.3 Immunogenicity (include evidence for adequacy of correlates of protection)

Conjugate meningococcal vaccines available in Canada are licensed based on the induction of seroresponse measured by SBA using human (hSBA) or baby rabbit serum (rSBA) as the source of exogenous complement. Because human serum that lacks bactericidal antibodies against meningococci is difficult to obtain, infant rabbit sera that lack intrinsic bactericidal activity is a preferred source of complement for assessing bactericidal responses to meningococcal vaccines. However, the assessment of immune response to conjugated meningococcal vaccines with the use of rSBA results in much higher bactericidal titres and demonstrates various levels of correlation with hSBA for different serotypes. Seroresponse for the purpose of licensure is most often defined as rSBA titre ≥1:8 or a fourfold titre increase in individuals with an rSBA titre ≥1:4 at baseline. For the purpose of Nimenrix^™ licensure, seroresponse was defined as:

• For subjects < 2 years of age: rSBA antibody titre ≥ 1:8
• For subjects ≥ 2 years of age: rSBA titre ≥ 1:32 for individuals with pre-vaccination titre < 1:8, or a 4-fold increase in titre for individuals with pre-vaccination titre ≥ 1:8

There is currently no consensus on the preferential use of rSBA or hSBA in determining short-term protection against IMD. Because of the rapid onset of illness, protection is more reliant on circulating antibody rather than immunologic memory. At this time, the GMT titre required for long term protection is unknown.^{Footnote 14} Non-functional quantification of Immunoglobulin G (IgG) antibodies is measured using a standard enzyme-linked immunosorbent assay (ELISA) and provides supplementary information to SBA results; however, these are not a direct correlate of protection. For more information about the correlates of protection refer to the previous NACI Update on the use of quadrivalent conjugate meningococcal vaccines.

Although suitable for within-study comparison of vaccines, due to differences in methodologies, results of SBA assays using human or rabbit complement are not comparable between studies. Similarly, because of inter-laboratory differences in methodology, caution is needed when comparing results generated from different laboratories.^Footnote 15,^Footnote 16,^Footnote 17 The impact of vaccination on carriage and herd immunity cannot be predicted using data available from immunogenicity studies.

IV.3.1 Immunogenicity of Nimenrix^™

Immunogenicity of Nimenrix^™ in children less than 12 months of age

The immunogenicity of the one- or two-dose (second dose at 12 months) Men-C-ACYW-TT schedule was assessed in 149 infants 9 months of age and compared with vaccination only at 12 months of age.^{Footnote 18} Following initial vaccination, an rSBA titre ≥1:8 was elicited in all infants against all serogroups except for serogroup C where 1 infant did not reach the predefined seroprotection level. Although the proportion of patients with rSBA titres ≥1:8 was comparable between 9 months and 12 months groups (that had received 1 vaccine dose), the proportion with hSBA titre ≥1:8 was significantly higher in the 12-month age group (1 dose of vaccine) for all serogroups except C; similarly rSBA geometric mean titres (GMTs) were also significantly higher after a single vaccine dose at 12-months of age than at 9 months of age for all serogroups except A. The study did not include a comparator vaccine because no meningococcal vaccine was licensed for this age group at the time of the study.

Immunogenicity of Nimenrix^™ in children 12 to 23 months of age

Immunogenicity of Men-C-ACYW-TT in toddlers 12-23 months of age was reported in approximately 1,000 children in five phase II and III clinical trials 4-6 weeks following vaccination.^Footnote 18,^Footnote 19,^Footnote 20,^Footnote 21,^Footnote 22 An rSBA titre ≥1:8 was elicited in more than 99% of toddlers against all four groups. Non-inferiority^{Footnote 19})^{Footnote 20} was demonstrated in all studies which investigated the immunogenicity of Men-C-ACYW-TT versus monovalent Men-C-CRM197. In two studies that measured hSBA at 4 and 6 weeks post-vaccination, individuals who had received Men-C-ACYW-TT achieved significantly higher bactericidal antibody levels, as measured by hSBA titre and GMT, compared with those elicited by vaccination with Men-C-CRM197.

Immunogenicity of Nimenrix^™ in children 2 to 10 years of age

A total of four published studies evaluated immunogenicity 1 month following a single dose of Nimenrix^™ in over 1,400 children 2-10 years of age. In the immunogenicity cohort of the randomized controlled trial (RCT) study by Memish et al.,^{Footnote 23} children were randomized to receive either a single dose of Men-C-ACYW-TT or Men-P-ACYW-135. Immune protection, as measured with rSBA>1:8 was non-inferior in the Men-C-ACYW-TT group when compared to the Men-P-ACYW-135 group. The GMTs were statistically significantly higher for all four serogroups in the Men-C-ACYW-TT group. Seroresponse was also significantly higher in the Men-C-ACYW-TT than the Men-P-ACYW-135 group. Similarly, using the same comparator vaccine, Vesikari et al.,^{Footnote 24} demonstrated non-inferiority (rSBA >1:8) of Men-C-ACYW-TT for all four serogroups. Compared with Men-P-ACYW-135, rSBA GMT values were also higher for each serogroup in the Men-C-ACYW-TT group, after adjusting for pre-vaccination measurements. An exploratory analysis also demonstrated a significantly higher seroresponse for serogroups A and C in the Men-C-ACYW-TT group than in the Men-P-ACYW-135 group.

In an RCT study done by Knuf et al.,^{Footnote 25} non-inferiority to Men-C-CRM197 was demonstrated with greater than 99% of subjects in the Men-C-ACYW-TT group achieving>1:8 rSBA titres. The rSBA GMT values were significantly higher in the monovalent Men-C-CRM197 group for serogroup C, suggesting a more robust antibody response.

Baxter et al.^{Footnote 26} assessed the immunogenicity of Men-C-ACYW-TT in 79 healthy children 10 years of age and compared vaccine response to that elicited in adolescents and adults 11-25 years of age. Immune response was similar except for relatively higher but statistically non-significant hSBA-MenA GMT values in the 10 year old group.

Immunogenicity of Nimenrix^™ in individuals 11 to 19 years of age

Although several studies investigated the immunogenicity of Men-C-ACYW-TT in individuals over 10 years of age, only five reported results for the 11 -19 year age  group. In a study of 115 individuals 11-17 years of age who received Men-C-ACYW-TT conducted by Østergaard et al.^{Footnote 27} all achieved an rSBA titre ≥1:8 one month following vaccination. In another RCT trial conducted by Østergaard et al.^{Footnote 29Footnote 30} 50 individuals received Men-C-ACYW-TT or Men-P-ACYW-135. All individuals achieved rSBA titres ≥1:8 for all serogroups and there were no significant differences in rSBA GMT between groups, except for that of serogroup W-135 at month 42 which was significantly higher in the Men-C-ACYW-TT group (n=19) than in the Men-P-ACYW-135 group (n=17). Seroresponse rates in the Men-C-ACYW-TT group were higher than 90.2% for all serogroups. In both groups, most subjects (58.8%-90.9%) had high pre-vaccination rSBA titres for all serogroups. Similarly, a study of 1,025 individuals by Bermal et al.^{Footnote 31Footnote 32} using the same comparison vaccine demonstrated non-inferiority of Men-C-ACYW-TT to Men-P-ACYW-135. Prior to vaccination, the percentage of subjects in each group with rSBA titres ≥1:8 was between 78.6% and 90.9% for serogroups A, W-135 and Y, and was between 58.6% and 59.4% for serogroup C. One month following vaccination, at least 99.6% of subjects in both groups had rSBA titres of ≥1:8 against each meningococcal vaccine serogroup; seroresponse rates were significantly higher in the Men-C-ACYW-TT group for serogroups A, W-135 and Y, and non-inferior to serogroup C compared with the Men-P-ACYW-135 group. After vaccination, rSBA GMTs, against each serogroup increased by between 29.2-fold and 274.3-fold in Men-C-ACYW-TT vaccinees, and by 16.4-fold to 185.9-fold in Men-P-ACYW-135 vaccinees. Unlike the study conducted by Østergaard et al., rSBA GMTs were significantly higher following Men-C-ACYW-TT than Men-P-ACYW-135 for all serogroups; however, the Østergaard study was much smaller and underpowered to detect differences.

In two trials, the immunogenicity of Men-C-ACYW-TT was compared against another conjugate quadrivalent vaccine (Men-C-ACYW-DT, Menactra^®). Baxter et al.^{Footnote 26} randomized 784 healthy individuals between the ages of 11- and 25 years. Both vaccines led to similar responses in terms of hSBA >1:4 for serogroup C after vaccination. For serogroups A, W-135 and Y, Men-C-ACYW-TT led to a greater response than Men-C-ACYW-DT. Adjusted GMT values were higher for all serogroups in the Men-C-ACYW-TT group. The percentage of vaccine responders was also higher in the Men-C-ACYW-TT group. Halperin et al.^{Footnote 33} randomized 1,016 healthy individuals between the ages of 10- and 25 to receive a single dose of 1 of 2 lots (A or B) of Men-C-ACYW‐TT or a single lot of Men-C-ACYW‐DT. In the study, the Men-C-ACYW‐TT vaccine elicited a non-inferior immune response compared with the Men-C-ACYW‐DT vaccine.

Immunogenicity of Nimenrix^™ in individuals 19 to 55 years of age

Dbaibo et al.^{Footnote 34} compared the immunogenicity of Men-C-ACYW-TT to Men-P-ACYW-135 in a study of over 1,100 individuals. In the Men-C-ACYW-TT group 99.3% of vaccine recipients achieved rSBA >1:8 demonstrating non-inferiority to Men-P-ACYW-135. After vaccination with Men-C-ACYW-TT, rSBA GMTs increased by at least 20-fold for serogroups A, W-135 and Y, and 109-fold for serogroup C. Based on GMT values and exploratory analysis, statistically significantly higher GMTs were found in the Men-C-ACYW-TT group for all serogroups except C, in which there was no significant difference. In a study by Borja-Tabora et al.^{Footnote 35}, a total of 500 individuals aged 11-55 years received either Men-C-ACYW-TT or Men-P-ACYW-135. One month following vaccination more than 99.7% of Men-C-ACYW-TT recipients achieved rSBA titres of >1:8. Based on their rSBA titres, Men-C-ACYW-TT was non-inferior to Men-P-ACYW-135; GMT values 1 month post vaccination were higher in the Men-C-ACYW-TT group for each serogroup. Seroresponse rates ranged from 82.7% to 96.3% in the Men-C-ACYW-TT group and 69.7% to 91.7% in the Men-P-ACYW-135 group, with a statistically significant response demonstrated for serogroups A and Y following the administration of Men-C-ACYW-TT. 

Immunogenicity of Nimenrix^™ in individuals more than 55 years of age

In a study by Dbaibo et al.^{Footnote 36} immunogenicity of MenACWY-TT was compared with that of Men-P-ACYW-135 in 369 healthy adults between 56 and 103 years of age. One month following vaccination there were no significant differences in rSBA >1:8; however, those vaccinated with Men-P-ACYW-135 did achieve a significantly higher vaccine response for serogroup A and rSBA GMT values for serogroups A and C than those receiving the conjugate vaccine. Lower vaccine response was primarily observed in individuals receiving MenACWY-TT who had very high titres (≥1:128) pre-vaccination.

Persistence of the immune response

Five studies (N=1,306) looked at the persistence of immune response after administration of Men-C-ACYW-TT 12 to 48 months after immunization. All studies are extension studies of RCT aimed at assessing non-inferiority of Men-C-ACYW-TT against other meningococcal vaccines (Men-C-CRM197 or Men-P-ACYW-135) among age-appropriate comparators. In all studies antibody persistence measured by rSBA was similar or higher in the Men-C-ACYW-TT vaccine recipients than other vaccines for all serogroups.

The Knuf et al.^{Footnote 37} study followed toddlers aged 12-14 months at vaccination and children aged 3-5 years at the time of vaccination for a total of 15 months to determine antibody persistence. The percentage achieving a rSBA titre ≥ 1:8 for serogroup C was higher in the Men-C-ACYW-TT group than in the control group receiving Men-C-CRM197 (12-14 month group). Comparing the Men-C-ACYW-TT group for serogroups C and Y, the Men-C-ACYW-TT group also had higher rSBA titres than in the control group which received Men-P-ACYW-135 (3-5 year group). GMT values were also reported to be higher.

In two studies Vesikari et al.^{Footnote 19Footnote 38} reported immune responses following Men-C-ACYW-TT administration in toddlers aged 12-23 months. In a study of 170 toddlers, 3 years post vaccination 90.8% of Men-C-ACYW-TT recipients retained rSBA titres ≥ 1:8 for all serogroups, and 73.6% hSBA titres ≥ 1:4 for serogroups C, W and Y; only 28.1% had hSBA titres ≥ 1:4 for serogroup A. There was no significant difference in rSBA titre between Men-C-ACYW-TT and Men-C-CRM197 recipients 3 years following vaccination. In the first 2 years post vaccination the GMTs were higher among the group immunized with Men-C-ACYW-TT than Men-C-CRM197, whereas in year 3 no significant difference was observed. Similarly, in a study that followed 225 infants, rSBA titres and GMT values between Men-C-ACYW-TT and Men-C-CRM197 vaccine recipients were comparable 4 years following initial vaccination.^{Footnote 38} 

Vesikari et al.^{Footnote 24} also followed children aged 2-10 years for a total of 3 years post vaccination. Children in the Men-C-ACYW-TT group showed higher rSBA GMT values for all serogroups in year 1 and 2 post vaccination when compared to those who received Men-P-ACYW-135. In year 3, all serogroups except C, showed higher GMT values in the Men-C-ACYW-TT group compared to the Men-P-ACYW-135 group.

In the Østergaard et al.^{Footnote 30} study, 36 adolescents who received Men-C-ACYW-TT or Men-P-ACYW-135 were followed for a total of 42 months. In both groups, rSBA titres ≥1:8 and GMT values were similar for all serogroups except for that of serogroup W-135 at month 42 which was significantly higher in the Men-C-ACYW-TT group.

In a larger study of 535 adolescents reported by Bermal et al^{Footnote 31} and Quiambao et al.^{Footnote 43} using Men-P-ACYW-135 as the comparator vaccine, in years 3 and 4 following immunization, the Men-C-ACYW-TT group showed higher rSBA titres ≥ 1:8 and GMT values for all serogroups except C than the Men-P-ACYW-135 comparator group.

In a persistence study done by Borja-Tabora et al.,^{Footnote 35} 500 individuals 11-55 years of age were randomized to receive either Men-C-ACYW-TT or Men-P-ACYW-135. The rSBA titres were higher in the Men-C-ACYW-TT compared with the Men-P-ACYW-135 group in year 3 and 4, with more than 82.8% of Men-C-ACYW-TT recipients retaining titres ≥1:8 for all serogroups at year 4.

In the only study that reported data using hSBA, Baxter et al.^{Footnote 44} compared the persistence of immune response in 403 adolescents and young adults 11-25 years of age following immunization with Men-C-ACYW-TT and Men-C-ACYW-DT. Three years following vaccination, the proportion of the Men-C-ACYW-TT group with hSBA titres >1:8 was marginally superior for serogroup C and W-135, while GMT values were significantly higher for all serogroups except A.

Based on the available immune persistence data, Men-C-ACYW-TT appears to have superior immune persistence when compared with non-conjugated, and non-inferior when compared with conjugated meningococcal vaccines up to 4 years after immunization. No peer-reviewed articles of individuals over the age of 1 year related to boosting were available at the time of the conducted literature review. There have been no studies that have looked at the three meningococcal quadrivalent conjugate vaccines head to head, and Menveo^™ has not been compared directly with Nimenrix^™.

IV.3.2 Immunogenicity of Menactra^®

Pina et al.^{Footnote 39} reported immunogenicity data from two studies (A and B) following vaccination of infants and toddlers with Menactra^® at 9 and 12 months of age respectively. The vaccine was provided in a two-dose schedule either separately or together with one or more licensed childhood vaccines (measles, mumps, rubella and varicella vaccine [MMRV], Haemophilus influenzae type b [Hib], pneumococcal conjugate vaccine [Pneu-C-7] and hepatitis A) at 12 months of age. All studies used human serum (hSBA) as the source of complement with the primary immunogenicity endpoint being the percentage of participants who achieved a titre >1:8 30 days following the administration of the second dose.

Immunogenicity was assessed in 724 children. After two doses of Men-C-ACYW-DT in Study A the percentage of participants achieving hSBA titres ≥1:8 ranged from 90.5% to 100% for serogroups A, C and Y, and 81.2% to 88.2% for serogroup W-135. Concomitant administration with MMRV and Pneu-C-7 demonstrated non inferiority compared with administration of Men-C-ACYW-DT alone (upper limit of the 95% confidence interval [CI] of the difference was <10%) for all serogroups except W-135 when Men-C-ACYW-DT was administered along with the fourth dose of Pneu-C-7. In Study B, responses to the MMRV and Hib vaccine antigens were similar between groups that received MMRV and Hib alone or concomitantly with Men-C-ACYW-DT. In the case of Pneu-C-7, statistical non-inferiority was not demonstrated for serotypes 4, 6B and 18C (upper limit of the 95% CI of the antipneumococcal antibody ratio was >2); when given with Men-C-ACYW-DT; however, more than 98% of participants achieved pneumococcal multiplex opsonophagocytic assay titres ≥1:8, and ELISA antibody concentrations ≥35 µg/mL were achieved for all serotypes. When using an hSBA titre ≥1:4, seroprotection was achieved by more than 91% of those who received Men-C-ACYW-DT.

In a poster presented at the 2013 European Society for Paediatric Infectious Diseases meeting, Noya et al^{Footnote 40} reported an RCT of 122 children who received either Men-C-ACYW-DT or meningococcal C conjugate vaccine. The rSBA titres following a two-dose schedule were reported at 18 and 19 months of age in 55 children. One month following second dose (19 months of age), more than 96% of those who had received Men-C-ACYW-DT achieved rSBA titres ≥1:8 for all serogroups (≥96%).

IV.4 Vaccine administration and schedule

Schedule: Nimenrix^™ has been approved for use in individuals aged 12 months to 55 years.

Dosage: 0.5ml of reconstituted vaccine should be administered.

Route of administration: This vaccine is intended for intramuscular injection. It may be given in the deltoid muscle or for children 12-23 months of age in the anterolateral thigh.

Booster doses: The manufacturer has not yet determined the need for a booster dose, however NACI recommends periodic boosters doses for individuals at high risk for meningococcal disease or who have ongoing increased risk of exposure.

IV.5   Storage requirements

As per the product monograph, Nimenrix^™ should be stored in a refrigerator between 2˚C to 8˚C, the diluent can be stored at room temperature (25^oC). This product should not be frozen and should be protected from light.

IV.6   Simultaneous Administration with other Vaccines

Men-C-ACYW-TT vaccine has been given simultaneously with a 10-valent pneumococcal conjugate vaccine, hexavalent infant vaccine, MMRV vaccine, seasonal influenza vaccine, and combined hepatitis A and B vaccine.

In a study by Ruiz-Palacios et al.^{Footnote 21} infants aged 12 to 23 months received Men-C-CYW-TT and Pneu-C-10. A comparable immunogenicity was demonstrated when these products were co-administered except for a reduced response for pneumococcal serotype 18C which is conjugated to TT. This may suggest potential interference requiring further research. Pneu-C-10 is licensed for use in Canada, but at this time all provinces and territories are using Pneu-C-13.

Knuf et al ^{Footnote 22} investigated the use of Men-C-ACYW-TT co-administered with DTaP-HBV-IPV/Hib with additional arms of the study which include participants who received both vaccines with 1 month separating each shot as well as a control group that only received Men-C-CRM197. The study reported a similar safety profile and immune response measured by rSBA titres for separate and concomitant administration of Men-C-ACYW-TT with DTaP-HBV-IPV/Hib. However, rSBA GMTs for serogroups A, C and W-135 were significantly lower in the group that received Men-C-ACYW-TT 1 month after DTaP-HBV-IPV/Hib compared with the group that received Men-C-ACYW-TT first. However, this finding is likely to be of limited clinical significance since more than 97.3% of these individuals achieved rSBA titres ≥ 1:8.

In a Finnish study by Vesikari et al.^{Footnote 20} Men-C-ACYW-TT was administered with MMRV in children aged 12 - 23 months; comparison groups included Men-C-ACYW-TT alone, MMRV alone and Men-C-CRM197 alone. Based on this study, MMRV with Men-C-ACYW-TT was found to have similar immune responses as MMRV alone except for rubella for which GMT values were lower in the co-administration group 1 month after vaccination. However, all children in both groups reached the protective immune cut off of >4IU/ml. The Men-C-ACYW-TT+MMRV group and Men-C-ACYW-TT groups were similar in their ability to elicit an immune response to all meningococcal serogroups. The rSBA GMT values were greater for serogroup C in both groups given Men-C-ACYW-TT than in the Men-C-CRM197 group 1 month after vaccination. This information suggests that based on one study, co-administration of these two vaccines is possible, bearing in mind that there may be lower GMTs for rubella.

In adolescents, a study by Østergaard et al.^{Footnote 27} investigated providing Men-C-ACYW-TT along with hepatitis A and B vaccines. Co-administration was found to be non-inferior in terms of immunogenicity and safety.

Reyes et al.^{Footnote 41} investigated the co-administration of Men-C-ACYW-TT with an unadjuvanted seasonal influenza vaccine in adults age 18-55. Non-inferiority was demonstrated in terms of predefined rSBA GMT ratios for all serogroups except C (only marginally exceeded, therefore did not meet non-inferiority criteria). However, more than 99% of subjects in both groups achieved post-vaccination rSBA titers ≥ 1:8 for all serogroups. Individual and simultaneous administration of the two vaccines had a similar safety profile.

NACI has reviewed the available data on the co-administration of Men-C-ACYW-TT with the above products. The product monograph from the manufacturer recommends co-administration with additional vaccine products (hepatitis A and hepatitis B vaccines, MMR). There are no clinical studies available that specifically address the co-administration of these products with Men-C-ACYW-TT. However, based on expert opinion, co-administration of Men-C-ACYW-TT with products containing single or fewer antigens than the products cited in the above studies should not compromise safety or efficacy of either product.

IV.7 Adverse Events

IV.7.1 Safety of Nimenrix^™

Safety of Nimenrix^™ in children less than 12 months of age

Two safety profiles reported by Klein et al.^{Footnote 18} in a group of 160 infants who had received Men-C-ACYW-TT at 9 months of age showed a safety profile similar to that following vaccine administration at 12 months of age.

Safety of Nimenrix^™ in children 12-23 months of age

The Safety of Men-C-ACYW-TT in this age group was reported in four studies. In an RCT of 304 healthy toddlers Vesikari et al.^{Footnote 19} reported similar reactogenicity and safety profiles of the Men-C-ACYW-TT and the Men-C-CRM197 vaccines. Unsolicited symptoms were reported by approximately half of the participants, the most common being rhinitis in the Men-C-ACYW-TT group (8.3%) and pyrexia in the Men-C-CRM197 group (13.3%). Solicited local and general symptoms of grade 3 intensity were reported in no more than 3.5% of toddlers in both groups, and no serious adverse events (SAEs) considered causally related to the vaccination were reported throughout the study. Grade 3 was defined as redness and swelling > 30mm in diameter, pain/cried when limb was moved spontaneously, loss of appetite to not eating at all, fever >39.5 C and/or all other symptoms that prevent normal activity. Another RCT of 749 toddlers conducted by Vesikari et al.^{Footnote 20} reported similar safety results in the group that received only the Men-C-ACYW-TT vaccine.

In a study conducted Ruiz-Palacios et al.^{Footnote 21} that randomized 343 toddlers to receive Pneu-C-10 and Men-C-ACYW-TT vaccines, pain at the injection site and irritability were the most frequently reported solicited symptoms. Grade 3 intensity was reported in less than 2.2% of toddlers. 

The study by Klein et al.^{Footnote 18} that compared the safety of 1 versus 2 doses of Men-C-ACYW-TT reported a tendency toward an increase in the percentage of subjects with fever and loss of appetite in the two dose group. A higher percentage of asthma, emergency department visits and rash was also noted in those receiving two doses.

Safety of Nimenrix^™ in children 2-10 years of age
Three studies assessed the safety of Nimenrix^™ in children aged 2-10 years. In the study conducted by Memish et al,^{Footnote 23} Men-C-ACYW-TT and Men-P-ACYW-135 vaccines administered to 1125 children resulted in a similar safety profile, including fewer than 1% of grade 3 solicited and unsolicited general symptoms in both treatment groups. There were no SAEs due to vaccination in this study. In the RCT done by Knuf et al.,^{Footnote 25} which included 414 children, fewer grade 3 adverse events were seen in participants who had received Men-C-ACYW-TT (6.8% of participants) versus Men-C-CRM197 (15.1%). In this study, fewer overall grade 3 adverse events were noted in either group. Among 309 children in the study by Vesikari et al.^{Footnote 24} the most common adverse event was pain at the injection site (45.1% Men-C-ACYW-TT vs 71.8% Men-P-ACYW-135). Grade 3 unsolicited adverse events occurred in (6.5% vs 5.1% of vaccine recipients). Only one grade 3 symptom was considered related to immunization: a hematoma reported in a child who had received Men-C-ACYW-TT. 

Safety of Nimenrix^™ in individuals 11-17 years of age

In the study by Østergaard et al.,^{Footnote 12} which included only 50 individuals, pain was reported by half of Men-C-ACYW-TT recipients and was the most common adverse event, with headache being reported by one third of subjects. In the Bermal et al.^{Footnote 31} study, in which Men-C-ACYW-TT was compared with Men-P-ACYW-135, results were reported for 1,025 individuals aged 10-18 years: grade 3 general symptoms were reported by 1.6% vs. 0.4% of vaccine recipients respectively. The most common adverse event reported was pain at the injection site (26.2% vs 26.8%). Of the other local adverse events, redness at the injection site was reported by 12.3% vs 9.6% (p=0.0075), which was the only statistically significant event. Of the general symptoms, fatigue and headaches were the most commonly reported (up to 14.3% and 13.4%, respectively). There was no symptom that was statistically significantly different when compared. No SAEs were associated with the administration of either vaccine.

Safety of Nimenrix^™ in individuals 18-55 years of age

Three studies evaluated the safety of Men-C-ACYW-TT in this age group. Dbaibo et al.^{Footnote 34} reported pain and redness at the site of injection (19.5% [16.9%-22.1%] and 13.5% [9.9%-17.9%]) as the most common adverse events. Grade 3 general symptoms were reported rarely (less than 2% of study participants) with the most common being headache. Only two SAEs that were reported in one subject (0.6%) were considered to be related to vaccination; these were abdominal pain and gastritis 5 days after vaccination. No new-onset chronic illnesses (NOCI) were reported.

In a pooled analysis done by Bermal et al.,^{Footnote 31} that compared Men-C-ACYW-TT against Men-P-ACYW, the pre-specified primary objective (non-inferiority in terms of the grade 3 solicited and unsolicited systemic symptoms within 4 days of vaccination) was not met. This may have been due to a poor estimation of the incidence of grade III adverse events, therefore the sample size was inadequate. Further analysis did not show statistically significant differences in the percentage of subjects with any general symptom. Although this study did not do a separate analysis on individuals 18-55 years of age, there were no significant differences between rates of any solicited symptoms in the 11-17 and 18-55 study cohorts with either the Men-C-ACYW-TT or the Men-P-ACYW group.

In the study by Borja-Tabora,^{Footnote 35} very similar results were found as those outlined above. Grade 3 general symptoms were reported in 1.3% of participants in the Men-C-ACYW-TT group, with none in the Men-P-ACYW-135 group. The most common symptoms were pain at the site of injection and headache. Both vaccines demonstrated a comparable safety profile, although injection site redness and swelling were more frequent in Men-C-ACYW-TT recipients. In the 6 month follow-up phase, one case of new onset of chronic illness was reported (food allergy) and two SAEs (costochondiritis and mental disorder). None of these were considered related to vaccination by the investigators.

Safety of Nimenrix^™ in individuals more than 55 years of age

In the study by Dbaibo et al.^{Footnote 36} fewer than 3.0% of subjects reported adverse events; no SAEs were considered vaccine related. Overall, few adverse events were reported in the studies available, and most of these were local pain, redness and swelling. Other reported adverse events included irritability, drowsiness, headache, loss of appetite, fatigue, gastrointestinal symptoms and fever. No cases of idiopathic thrombocytopenic purpura, Guillain-Barré Syndrome (GBS), nephrotic syndrome or brachial neuritis were reported. Compared with vaccines used as controls, adverse events in the Men-C-ACYW-TT groups, although clinically not relevant, were more commonly cited, possibly due to the TT component of the vaccine which is known to be more reactogenic than other protein carriers.

IV.7.2 Safety of Menactra^®

Pina et al.^{Footnote 39} reported safety data in infants and toddlers given Men-C-ACYW-DT at 9 and 12 months of age from three studies (A, B and C) following separate and concomitant administration of Men-C-ACYW-DT with one or more licensed childhood vaccines (MMRV, Hib, Pneu-C-7, Hep A) at 12 months of age. The reported safety parameters included solicited and unsolicited adverse events in more than 3000 children up to 6 months after the last vaccination.

The majority of solicited injection-site reactions were similar across all study groups and included grade 1 tenderness, erythema and swelling. Irritability was the most frequently reported adverse event, with abnormal crying or drowsiness being reported by approximately one third to one half of the participants. Unsolicited adverse events were reported by 40%-50% of children, but were mostly grade 1 or 2 in intensity and comparable across groups. Fever was more frequently reported in subjects when Men-C-ACYW-DT was administered concomitantly with MMRV and Pneu-C-7 (20.7%-24.5%) than when it was given alone (12.4%-13.7%). Rates of grade 3 fever were similar across all groups. SAEs were uncommon.

IV.8   Contraindications and Precautions

As per the product monograph, Nimenrix^™ should not be given to patients with known hypersensitivity to any component of the vaccine.

IV.9   Other Considerations

In a study conducted by Dbaibo et al.^{Footnote 42} of 271 subjects, immune response following administration of Men-C-ACYW-TT was tested in individuals aged 4.5-34 years who had 30-42 months earlier received Men-P-ACYW-135 vaccination; a separate group of controls (had not received Men-P-ACYW-135 in past 10 years) was also recruited. For all four serogroups, 1 month post vaccination, all study participants achieved rSBA titres >1:8. However, rSBA GMT values and vaccine response rates were significantly higher in the group that had not previously received Men-P-ACYW-135, for all serogroups, indicating better immune response in those naïve to polysaccharide vaccine. In evaluating the safety, Grade 3 symptoms were noted in 11.5% of the Men-P-ACYW-135/Men-C-ACYW-TT group as compared with 3.8% of the non Men-P-ACYW-135/Men-C-ACYW-TT group. Pain, related fever, related headache and fatigue were reported more frequently in the Men-P-ACYW-135/Men-C-ACYW-TT group (p<0.05).

Knuf et al.^{Footnote 37} assessed the induction of immune memory with a challenge dose of Men-P-ACYW-135 (one fifth of a dose) to children primed with Men-C-ACYW-TT or Men-C-CRM197 15 months earlier. After 1 month following vaccination with Men-P-ACYW-135, all study participants achieved rSBA titres >1:8; rSBA GMT values were significantly higher for serogroups A, W-135 and Y in the Men-C-ACYW-TT compared with the Men-C-CRM197 group and were comparable for serogroup C in both study groups, suggesting a similar memory induction by both vaccines. Safety post Men-P-ACYW-135 administration was similar in both groups.

V. Recommendations

Please note that provinces and territories must consider economic factors and other local programmatic/operational factors when considering inclusion of the following recommendations in publicly funded immunization programs.

Recommendation #1

For routine immunization of adolescents, any of the quadrivalent or monovalent C conjugate meningococcal vaccines registered in Canada may be used. The choice between quadrivalent and monovalent C conjugate vaccines is dependent on local epidemiology and other programmatic considerations. (NACI Recommendation Grade B)

Recommendation #2

For the immunization of high risk individuals 2 years of age and older, any of the quadrivalent conjugate meningococcal vaccines registered in Canada may be used. (NACI Recommendation Grade B)

Recommendation #3

For the immunization of high risk individuals between 2 months and less than 2 years of age, Men-C-ACYW-CRM (Menveo^™) is the recommended product. Schedules are provided in Table 3 of the Meningococcal Chapter of the Canadian Immunization Guide. (NACI Recommendation Grade B)

Recommendation #4

For immunization of individuals 2 years of age and older travelling to areas where meningococcal vaccine is recommended, any of the quadrivalent conjugate meningococcal vaccines may be used. (NACI Recommendation Grade B)

Men-C-ACYW-CRM (Menveo™) is recommended for immunization of individuals 2 months to less than 2 years of age who are travelling to areas where meningococcal vaccine is recommended. Refer to Table 1 of the Meningococcal Chapter of the Canadian Immunization Guide.

Proof of meningococcal immunization may be required by certain countries. For example, Saudi Arabia requires proof of meningococcal immunization for pilgrims to the Hajj in Mecca. Please refer to the yearly Hajj recommendations and requirements published by the Agency to ensure that individual travellers have appropriate vaccine documentation. Information on countries experiencing outbreaks of meningococcal disease is kept up to date by the World Health Organization.

Additional travel-related recommendations are available at and in the CATMAT statement on Meningococcal Vaccination in Travellers.

VI. Research Priorities

Research to address the following outstanding questions is encouraged:

• Duration of projection/immunity to allow assessment of recommendations for booster doses of quadrivalent vaccines.
• Comparative study of the three available conjugate quadrivalent vaccines.
• Efficacy, effectiveness, immunogenicity and safety of quadrivalent vaccines in high risk groups, including splenectomized individuals.
• The immunogenicity and safety of co-administration of quadrivalent vaccines with routine age appropriate vaccines, including the newly authorized meningococcal B vaccine. 

VII. Surveillance Issues

Surveillance should also be encouraged and conducted to address the following outstanding issues:

• The impact of meningococcal vaccination programs on the epidemiology of IMD in Canada.
• Immunization coverage of individual quadrivalent meningococcal vaccines and the impact on carriage and herd immunity.
• The potential occurrence of serogroup replacement.
• Potential alterations in the ecological niche of meningococcus such that other bacteria that will replace meningococcus as carriage of this organism decreases.
• The impact on rubella and invasive pneumococcal disease following co-administration with Nimenrix^™ and the infant vaccines PCV and MMR.

Tables

List of Abbreviations

Acknowledgments

†NACI Members: Dr. I. Gemmill (Chair), Dr. C. Quach-Thanh (Vice-Chair), Dr. S. Deeks, Dr. B. Henry, Dr. D. Kumar, Dr. M. Salvadori, Dr. B. Seifert, Dr. N. Sicard, Dr. W. Vaudry, Dr. R. Warrington.

Former NACI Members: Dr. N. Crowcroft, Dr. B. Warshawsky (Chair).

Liaison Representatives: Dr. J. Blake (Society of Obstetricians and Gynaecologists of Canada), Dr. J. Brophy (Canadian Association for Immunization Research and Evaluation), Dr. J. Emili (College of Family Physicians of Canada), Dr. M. Lavoie (Council of Chief Medical Officers of Health), Dr. C. Mah (Canadian Public Health Association), Dr. D. Moore (Canadian Paediatric Society), Dr. A. Pham-Huy (Association of Medical Microbiology and Infectious Disease Canada), Ms. E. Sartison (Canadian Immunization Committee).

Former Liaison Representative: Dr. A. Mawle (Centers for Disease Control and Prevention, United States)

Ex-Officio Representatives: Ms. G. Charos (Centre for Immunization and Respiratory Infectious Diseases [CIRID], Public Health Agency of Canada [PHAC], Dr. G. Coleman (Biologics and Genetic Therapies Directorate [BGTD], Health Canada [HC]), Dr. (LCol) P. Eagan (National Defence and the Canadian Armed Forces), Dr. J. Gallivan (Marketed Health Products Directorate [MHPD], HC), Dr. B. Law (CIRID, PHAC), Ms. M. St-Laurent (CIRID, PHAC), Dr. T. Wong (First Nations and Inuit Health Branch [FNIHB], HC).

Former Ex-Officio Representatives: Dr. M. Carew (FNIHB, HC), Dr. D. Garcia (FNIHB, HC), Dr. A. Klein (BGTD, HC), Dr. B. Raymond (CIRID, PHAC), Dr. E. Taylor (MHPD, HC).

†This statement was prepared by Dr. S. Desai, Dr. O. Baclic, Dr. N. Crowcroft, Dr. B. Henry, Ms. J. Rotondo, Dr. M. Tunis and approved by NACI.

NACI also gratefully acknowledges the contribution of Dr. J. Bettinger, Dr. P. De Wals, Dr. J. Embree.

References

Footnotes