UPDATE ON THE USE OF QUADRIVALENT CONJUGATE MENINGOCOCCAL VACCINES

The National Advisory Committee on Immunization (NACI) provides the Public Health Agency of Canada with ongoing and timely medical, scientific and public health advice relating to immunization. The Public Health Agency of Canada acknowledges that the advice and recommendations set out in this statement are based upon the best current available scientific knowledge and is disseminating this document for information purposes. People administering the vaccine should also be aware of the contents of the relevant product monograph(s). Recommendations for use and other information set out herein may differ from that set out in the product monograph(s) of the Canadian manufacturer(s) of the vaccine(s). Manufacturer(s) have sought approval of the vaccine(s) and provided evidence as to its safety and efficacy only when it is used in accordance with the product monographs. NACI members and liaison members conduct themselves within the context of the Public Health Agency of Canada’s Policy on Conflict of Interest, including yearly declaration of potential conflict of interest.

The following table highlights key information for immunization providers. Please refer to the remainder of the statement for details. Meningococcal disease 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 mortality is approximately 10%, and 10-20% of survivors have long term sequelae which include hearing loss, neurologic disabilities, and digit or limb amputations. In 2007, 229 cases of meningococcal disease were reported in Canada, the majority (131 cases) was serogroup B, for which the highest rates occur in infants. There is currently no vaccine against serogroup B disease in Canada. Rates of serogroup C meningococcal disease have decreased due to vaccination programs, and in 2007, the number of serogroup Y cases slightly exceeded the number of serogroup C cases (30 serogroup C cases and 35 serogroup Y cases). The median age for serogroup Y disease (46 years) is older than for serogroups C and W135. Very little serogroup A disease occurs in Canada.
What are meningococcal conjugate vaccines?

Who
Who is immunized?
Menveo™ is authorized for use in people 2-55 years of age. Its use may also be considered in individuals ≥ 56 years of age. Immunogenicity and safety data indicate that Menveo™ may be used in infants as young as 2 months of age although it is not currently authorized for use in this age group.
This NACI statement recommends the use of conjugate meningococcal vaccines as follows: 1. Adolescents: • In addition to routine meningococcal C conjugate vaccine for infants and/or young children, NACI recommends a routine conjugate meningococcal vaccination for adolescents at around 12 years of age. If a quadrivalent conjugate product is chosen for this adolescent dose, either Menactra™ or Menveo™ may be used. (NACI Recommendation Grade B).

High-Risk Individuals:
• NACI recommends a conjugate quadrivalent meningococcal vaccine for high risk individuals. (NACI Recommendation Grade B): • Persons with anatomic or functional asplenia (including sickle cell disease); • Persons who have complement, properdin, factor D or primary antibody deficiencies; • Persons with acquired complement deficiency (eg. those receiving eculizumab (Soliris™); • Travellers when meningococcal vaccine is recommended (meningitis belt of Subsaharan Africa) or required (pilgrims to the Hajj in Mecca); • Research, industrial and clinical laboratory personnel who are routinely exposed to N. meningitidis; and • Military personnel during recruit training and on certain deployments NACI also suggests consideration of a quadrivalent conjugate meningococcal vaccine for individuals with HIV.
• For high risk individuals 2 years of age and older, use either Menactra™ or Menveo™ (NACI Recommendation Grade B). Two doses at least 8 weeks apart are recommended for those in the above high risk group due to underlying medical conditions (asplenia; complement, properdin, factor D or primary antibody deficiencies; or HIV). For those at ongoing risk due to underlying medical conditions or exposure, booster doses are recommended as outlined in this statement.
• For high risk individuals less than 2 years of age, based on available published data, the quadrivalent conjugate meningococcal vaccine that should be used is Menveo™ (NACI Recommendation Grade B). Possible schedules are provided in this statement.
• For those who only receive one dose of quadrivalent meningococcal vaccine (e.g. Travellers) and who are 2 to 10 years of age, routine monovalent meningococcal C conjugate vaccine should already have been administered and if not previously given, should also be administered at least one month after the quadrivalent conjugate vaccine.

Close contacts and outbreaks:
• Serogroup C: • For those 11 years of age and older, use either a monovalent conjugate C vaccine or one of the available quadrivalent conjugate meningococcal vaccines. • For those less than 11 years of age, use a monovalent meningococcal C conjugate product (NACI Recommendation Grade A).
• For those 2 years of age and older, use either Menactra™ or Menveo™ (NACI Recommendation Grade A).
• For children less than 2 years of age, use only Menveo™ (NACI Recommendation Grade B). Possible schedules for infants and young children are provided in this statement.
For those previously vaccinated who are now close contacts or during outbreaks, revaccination as follows is recommended, based on expert opinion: • Those previously vaccinated with a serogroup that differs from the index case or outbreak strain should be vaccinated immediately with the appropriate vaccine (as outlined above); • Those previously vaccinated with a serogroup that is the same as the index case or outbreak strain should be revaccinated with the appropriate vaccine(as outlined above): • If they were less than 1 year of age at last meningococcal vaccination and more than 4 weeks have passed since their last meningococcal vaccine; • If they have an underlying medical condition that puts them at risk for meningococcal disease and more than 4 weeks have passed since their last meningococcal vaccine; • If more than a year has passed since their last meningococcal vaccine if they were not less than 1 year of age at the time of their last meningococcal vaccination and if they have no underlying medical condition that puts them at risk for meningococcal disease.

How
Administration of Menveo™: • For those 2-55 years of age, Menveo™ is given as 0.5 ml IM dose.
• The product is reconstituted by mixing the liquid (containing serogroups C, W135, and Y) with the lyophylized powder (containing serogroup A). The reconstituted product should be used immediately, but may be held at or below 25 ºC for up to 2 hours.

Menveo™ contraindications:
A history of anaphylaxis to a previous dose of meningococcal vaccine, to any vaccine that contains diphtheria toxoid or CRM 197 , or to any other component of Menveo™.

Menveo™ precautions:
Menveo™ has not been studied in pregnancy; its use may be considered when the benefits outweigh the risks. A past history of GBS is not considered a need for caution when administering Menactra™ or Menveo™. An acute febrile illness which is severe warrants deferral until symptoms resolve.

Co-administration with other vaccines:
Menactra™ or Menveo™ may be given concomitantly with other age appropriate adolescent and adult vaccines. A lower antibody response to pertussis antigens was noted when Tdap was co-administered with Menveo™; the highest immunological response to pertussis antigens was achieved when Tdap was given one month after Menveo™. Menveo™ has been studied with many routine paediatric vaccines and no immunological interference has been observed. Menveo™ co-administration with the 13-valent conjugate pneumococcal vaccine requires further study.

Re-vaccination:
For high risk individuals who remain at ongoing or recurring risk of exposure to meningococcal disease (research, industrial and clinical laboratory personnel who are potentially routinely exposed to N. meningitidis; or traveller who remain in or revisit areas where meningococcal vaccine is recommended); or high risk individuals with underlying medical conditions (asplenia; complement, properdin, factor D or primary antibody deficiencies; or HIV), the following re-vaccination schedule is recommended by NACI, based on expert opinion: • For those vaccinated at 6 years of age and under: provide a booster dose 3-5 years after the last dose, followed by every 5 years.
• For those vaccinated at 7 years of age and older: provide a booster dose 5 years after the last dose, followed by every 5 years.
• Travellers to Hajj should check recommendations for re-vaccination at: http://www.hajinformation.com/main/p3001.htm as more frequent re-vaccination may be required.
A quadrivalent conjugate meningococcal vaccine should be used for re-vaccination of the above groups and based on expert opinion, either Men-C-ACYW-135-D (Menactra™) or Men-C-ACYW-135-CRM (Menveo™) can be used, regardless of what meningococcal vaccine was used for the initial vaccination.
See above for revaccination of close contacts or during outbreaks.

Why
"Counseling Points" for providers to emphasize with clients when discussing these recommendations IMD mortality is approximately 10%. Of IMD survivors, 10% to 20% have long term sequelae which include hearing loss, neurologic disabilities, and digit or limb amputations. Therefore, immunization against vaccine preventable IMD serogroups is important for those at higher risk.
• Menactra™ and Menveo™ are currently authorized for use in those 2-55 years of age. They have been shown to be immunogenic in clinical trials for individuals 2-55 years of age, with one study of Menveo™ extending to 65 years of age. • Immunogenicity studies suggest that Menveo™ induces a good response in young children and infants, with several schedules being assessed. • Both Menactra™ and Menveo™ have been studied with several age-appropriate vaccines given at the same time.
A study in the US among those primarily 11 to 18 years of age indicates that Menactra™ has an effectiveness of approximately 80-85% within 3 to 4 years of administration. Preliminary results from a case control study of Menactra™ found it to be approximately 78% effective, with effectiveness decreasing over time up to 5 years after administration. There is currently no effectiveness data for Menveo™ but post-licensure data may become available in the future.
No significant safety concerns were found with regard to Menactra™ and Menveo™ in clinical trials. Two recent studies in the United States have not found any association between Menactra™ and Guillain-Barré Syndrome.

I. Introduction
This statement will supplement previous conjugate meningococcal vaccine statements (1)- (5) which have outlined the use of monovalent meningococcal C conjugate vaccines and the only previously available quadrivalent conjugate meningococcal vaccine, Men-C-ACYW-135-D (Menactra™). This statement provides information and recommendations for use of a second quadrivalent conjugate vaccine against meningococcal disease, Men-C-ACYW-135-CRM (Menveo™) produced by Novartis Vaccines Inc. which was authorized for use in Canada in May 2010 for individuals aged 11 to 55 years, and extended to include 2-10 year olds in June 2011.
This statement will: • Review existing National Advisory Committee on Immunization (NACI) recommendations on the use of conjugate meningococcal vaccines; • Update the epidemiology of meningococcal disease in Canada by providing data to 2007, which includes one additional year of data compared to the previous NACI statement (5) ; • Provide an update on the available conjugate meningococcal vaccines and the vaccination schedules used in Canada; • Describe indicators of immunogenicity for invasive meningococcal disease (IMD); • Provide information and recommendations for use of the newly authorized quadrivalent conjugate meningococcal vaccine, Men-C-ACYW-135-CRM (Menveo™); • Provide updated safety information and information regarding the concomitant use of Men-C-ACYW-135-D (Menactra™) with other vaccines; • Recommend two or more doses of quadrivalent meningococcal vaccine, dependent on age, for those at high risk for meningococcal disease due to underlying medical conditions; and • Recommend re-vaccination with a quadrivalent conjugate meningococcal vaccine for people at ongoing risk due to underlying medical conditions, potential ongoing or recurring exposure, or who are close contacts of a case of IMD or during an outbreak. It could be considered, in addition to unconjugated polysaccharide quadrivalent vaccine, for others at high risk for meningococcal disease. (1) In May 2007, NACI recommended the use of quadrivalent conjugate meningococcal vaccine for serogroups A, C, W135 and Y (Men-C-ACYW-135-D Menactra™-sanofi pasteur) for immunization of persons 2-55 years of age in the following high-risk groups: • Persons with anatomic or functional asplenia; • Persons who have complement, properdin, or factor D deficiencies; • Travellers when meningococcal vaccine is indicated or required, including pilgrims to the Hajj in Mecca; • Research, industrial and clinical laboratory personnel who are routinely exposed to N. meningitidis; and • Military recruits.
In addition, the vaccine was recommended for close contacts of persons with IMD caused by serogroups A, W135, or Y and for the control of outbreaks caused by these serogroups.
The monovalent meningococcal C conjugate vaccine was recommended for close contacts of cases of serogroup C IMD and to control outbreaks caused by serogroup C IMD. NACI also stated that the quadrivalent conjugate meningococcal vaccine could be considered for high-risk individuals, as defined above, who are ≥ 56 years of age and also for individuals with HIV. For routine immunization of adolescents 11-24 years of age, NACI recommended use of a meningococcal C conjugate vaccine unless local epidemiology warranted the use of the quadrivalent conjugate meningococcal vaccine. (3) In November 2007, NACI recommended that if meningococcal C conjugate vaccine is given to infants < 12 months of age, a booster dose should be given in the second year of life (from 12 to 23 months of age). This replaced NACI's previous recommendation for infants that stated that one dose of a primary infant immunization series of meningococcal C conjugate vaccine be given after 5 months of age. (4) In its statement published in April 2009, NACI recommended the addition of a routine adolescent dose of conjugate meningococcal vaccine, optimally at 12 years of age. (5) This dose was in addition to any infant or toddler meningococcal conjugate vaccinations. The choice of vaccine could be either a monovalent meningococcal C conjugate vaccine or the quadrivalent conjugate meningococcal vaccine. It was recommended that the choice of product be determined by provinces / territories based on their burden of illness from serogroups A, Y and W135, cost and other programmatic considerations. The April 2009 statement also expanded the list of individuals considered at high risk for IMD by recommending that persons with primary antibody deficiencies receive the quadrivalent conjugate meningococcal vaccine.

II. Methods
NACI reviewed the burden of illness of meningococcal disease by serogroup and the safety and immunogenicity of the newly authorized Men-C-ACYW-135-CRM (Menveo™) vaccine, vaccine schedules in Canada, and other aspects of the overall immunization strategy. The knowledge synthesis was performed by the Meningococcal Working Group. Following critical appraisal of individual studies, a summary table (Table 8) with ratings of the quality of the evidence using NACI's methodological hierarchy (outlined in Table 9, 10 and 11) was prepared, and proposed recommendations for vaccine use developed. The Working Group Chair presented the evidence and proposed recommendations to NACI on February 2 and June 2, 2010. Following thorough review of the evidence and consultation, NACI voted on specific recommendations. The description of relevant considerations, rationale for specific decisions, and knowledge gaps are described in the text. The Public Health Agency of Canada (PHAC) maintains documentation of these processes throughout knowledge synthesis and recommendation development.

III. Epidemiology of invasive meningococcal disease in Canada
Epidemiological data for the burden of invasive meningococcal disease (IMD) in Canada has previously been reviewed. (5) One additional year of data, 2007, has been included in the figure and tables provided below which summarize Canadian epidemiological data on IMD. Figure 1 shows IMD trends over the past ten years (1998)(1999)(2000)(2001)(2002)(2003)(2004)(2005)(2006)(2007). The introduction of paediatric meningococcal C programs beginning in 2001 in Canada appears to have been associated with a decline in the incidence of IMD caused by serogroup C. (  the 10 year average median ages and case fatality rates by serogroup are also outlined. The numbers of cases of serogroup C IMD have fallen to their lowest level in the past 10 years such that in 2007, reported cases of serogroup Y disease slightly exceeded cases of serogroup C disease. Table 3 provides information on the number and rates of IMD cases by serogroup for all provinces and territories in 2007. Table 4 provides similar data averaged over the 10-year period from 1998 to 2007. These tables indicate that Quebec has notably higher rates of serogroup B disease compared to other provinces and territories. Table 5 provides numbers and rates of IMD cases by age group and serogroup for 2007. The incidence of IMD is highest in infants less than one year of age with an incidence rate of 6.94 per 100 000 in 2007,the majority of which is due to serogroup B disease. The tendency for serogroup Y to occur at older ages is also evident in Table 5. 0.31 (11) 0.50 (5) 0.08 (1) 0.23 (30) 0.86 (66) 0.12 (9) 0.27 0.17 (2) 0.12 (15) 0.07 Other Serogroups  1.93 (27) 0.78 (14) 0.34 (7) 1.30 (29) 0.93 (21) 0.54 (12) 0.25 (11) 0.45 (45) 0.59 (36) 0.01  Table 6 provides an overview of the meningococcal vaccines available in Canada. Table 7 provides a summary of the routine childhood schedules being used in the provinces and territories as of February 2011. In its April 2009 statement, NACI recommended the inclusion of a dose of conjugate meningococcal vaccine in adolescence with the choice of product determined by local epidemiology. Subsequently, some provinces and territories changed to using the quadrivalent conjugate meningococcal vaccine, Men-C-ACYW-135-D (Menactra™) from the monovalent meningococcal C conjugate vaccine for their adolescent program.   The vaccine is packaged in two separate vials (one containing conjugate meningococcal C, W135, Y as a liquid and the other containing conjugate meningococcal A as a powder) that are mixed prior to administration. All the liquid from the meningococcal C, W135,Y vial is withdrawn and injected into the vial containing the lyophilized meningococcal A powder and then shaken vigorously until the components dissolve to yield a solution that is a clear, colourless liquid. Subsequently, 0.5 ml of the reconstituted solution is withdrawn from the vial that previously contained the meningococcal A powder. There may be a small amount of reconstituted vaccine remaining in the vial after the 0.5 ml is withdrawn.

IV.3 EFFICACY AND EFFECTIVENESS OF MEN-C-ACYW-135-CRM (MENVEO™) AND MEN-C-ACYW-135-D (MENACTRA™)
It is generally not feasible to perform efficacy studies of conjugate meningococcal vaccines because the disease is relatively rare, and prohibitively large populations would have to be studied. Regulatory authorities have established immunogenicity criteria as correlates of protection from IMD, and these correlates are used as outcome measures in clinical trials which compare new conjugate meningococcal vaccines to previously authorized meningococcal vaccines.

IV.3.2 Men-C-ACYW-135-D (Menactra™)
Effectiveness data for Men-C-ACYW-135-D (Menactra™) is now becoming available in the United States after four years of increasing use, primarily among those 11-18 years of age. The Active Bacterial Core (ABC) and MeningNet surveillance systems (these systems represent 54% of the US population) identified 14 reported cases of IMD (8 serogroup C and 6 serogroup Y) from January 1, 2005 to December 31, 2008 among individuals previously vaccinated with Men-C-ACYW-135-D (Menactra™). The median age of the cases at disease onset was 19 years (range 15-21 years) and the median time from Three cases were fatal resulting in a case fatality rate of 21%. Based on the number of vaccine failures, early estimates of vaccine effectiveness of Men-C-ACYW-135-D (Menactra™) within 3-4 years of vaccination are 80 to 85%. (11) Preliminary results from a case control study in the US involving 108 cases and 158 controls ranging in age from 10 to 23 years demonstrated a 78% overall vaccine effectiveness for Men-C-ACYW-135-D (Menactra™)(95% CI: 29 to 93%) (serogroup C 77% (95% CI: 14 to 94%); serogroup Y 88% (95%CI: -23 to 99%). These preliminary results indicated that vaccine effectiveness waned over time when assessed up to less than 5 years post vaccination. (12) (13) It should be noted that individual vaccine effectiveness may not predict the impact on meningococcal disease burden in the community due to the additional benefit conferred by herd immunity. This is particularly true for serogroup C against which large numbers of Canadian children and adolescents have been vaccinated.

IV.4 IMMUNOLOGICAL CORRELATES OF PROTECTION
Regulatory approval of conjugated vaccines for meningococcal disease has been based primarily on short-term immunogenicity studies. (14) It would be difficult to conduct efficacy and effectiveness studies because of the relative rarity of meningococcal disease. The immunogenicity outcomes that are most commonly used are serum bactericidal antibody (SBA) levels using either human or rabbit serum as a source of complement, and enzyme linked immunosorbent assays (ELISA).
SBA levels are the standard measure used to determine susceptibility and immunity to IMD. These measure the titres of bactericidal antibody in a serum sample that can kill a proportion of a particular strain of N.meningitidis in a specified time frame. This test is done in vitro in the presence of added complement. Traditionally, human serum has been the exogenous complement source for this assay, and most tests of Men-C-ACYW-135-CRM (Menveo™) use this methodology. Using human serum complement, a human serum bactericidal antibody (hSBA) titre of ≥1:4 has been found to correlate with protection against serogroup C meningococcal disease (15) and hSBA ≥1:4 has also been used as a correlate for serogoup A meningococcal disease. There are no confirmed immunological correlates of protection for serogroups Y or W135. Baby rabbit serum, which is more readily available, has replaced human complement in some studies. A baby rabbit serum bactericidal antibody (rSBA) titre of ≥1:8 has been proposed as a correlate of short-term immunity against serogroup C IMD. (16) Geometric mean titres (GMTs) of SBA are also reported as a measure of immune response to meningococcal vaccine. ELISA tests are used to determine the serogroup C meningococcal polysaccharide specific IG concentrations (17) which can be expressed as geometric mean antibody concentrations (GMC). ELISA methodology is also available to assess meningococcal C IgG antibody avidity. (18) Studies of meningococcal vaccines may also use "seroresponse" as an immunological indicator. Seroresponse is defined as the percentage of people who meet the following criteria: • for subjects with an hSBA titre <1:4 at baseline, a post-vaccination hSBA titre >=1:8; • for subjects with an hSBA titre of >=1:4 at baseline, a post-vaccination titre of at least 4 times their baseline titre.
Seroresponse endpoints can be found in the publications referred to in this statement, but will generally not be summarized in this NACI statement.
Statistical analysis of immunological data uses the concepts of inferiority, non-inferiority and superiority for GMTs, hSBA titres and seroresponse. For GMTs these are defined based on the ratio of GMTs for the study vaccine and the comparator vaccine. The two vaccines were considered non-inferior if the lower limit of the 2-sided 95% confidence interval around the ratio was > 0.5 and superior if this value was > 1. For the hSBA titre and seroresponse, the difference in the proportion of people achieving this response using the study vaccine and the comparator vaccine are calculated. Non-inferiority is defined by the lower limit of the 2-sided 95% confidence interval greater than -10% and superiority was defined as a lower limit of greater than 0%.
It is well established that vaccination with conjugate meningococcal vaccine primes the immune system for memory and induces good anamnestic responses after challenges with meningococcal C polysaccharide or conjugate vaccines. (19)- (23) However, because of the short incubation period of IMD (range 2 to 10 days, commonly 3 to 4 days), (24) it is now generally accepted that the anamnestic response cannot be relied upon to prevent disease and that circulating antibodies are necessary for protection. (5) Therefore, immunogenicity studies likely predict short-term effectiveness; however, their ability to determine long-term effectiveness is uncertain as antibody levels decline post-vaccination (25)- (27) even within 6-8 months post-vaccination in early childhood. (23) (28) It is hoped that the higher the antibody titre achieved post-vaccination, the longer circulating antibodies will persist and the longer the duration of protection from vaccination, but evidence is currently awaited to support this idea.
Immunogenicity studies do not predict the impact of vaccination on carriage and herd immunity. Herd immunity may offer protection if sufficient numbers of people are vaccinated, even when individual protection has waned. This has been illustrated in research conducted by Campbell et al. (29)

IV.5 IMMUNOGENICITY OF MEN-C-ACYW-135-CRM (MENVEO™)
A total of 24 trials involving Men-C-ACYW-135-CRM are ongoing or completed. These include approximately 18 500 individuals who received a formulation of Men-C-ACYW-135-CRM. Of these, 14 000 received the final formulation of Menveo™ that has been authorized for use (10 μg serogroup A and 5 μg of each of serogroups C, W135, Y without adjuvant). (30) An aluminum-adjuvanted formulation was also tested, however the final formulation does not contain an adjuvant because the adjuvant was not found to significantly improve the immunogenicity of the vaccine.
In the sections below, information related to the immunogenicity of Men-C-ACYW-135-CRM in infants, toddlers, adolescents and adults is reviewed. It should be noted that in these studies, blinding of those administering the vaccine is not possible due to the unique appearance of Men-C-ACYW-135-CRM, including the requirement to reconstitute the product before administration. The studies are summarized in Table 8.

IV.5.1 Children less than 2 years of age
Two phase II randomized controlled trials in infants have been conducted, both involving subjects from the UK and Canada. In each study the vaccines were administered concomitantly with infant vaccines routinely used in those jurisdictions. The first study by Snape et al (28) enrolled a total of 421 infants who were randomized to receive an earlier formulation of Menveo™ which contained an aluminium phosphate adjuvant (Men-C-ACYW-135-CRM with adjuvant). Various schedules were studied as follows: 2, 3, 4 months of age used in the UK; 2, 4, 6 months of age used in Canada; and 2 and 4 months of age used in both the UK and Canada. The results were compared to a monovalent meningococcal C conjugate vaccine (Menjugate ® -Novartis Vaccines) given at 2 and 4 months of age in the UK. Immunity was measured using human complement serum bactericidal activity (hSBA) of >= 1:4. At one month after completing their vaccination series, a higher proportion of subjects achieved this level of immunity with the three dose schedules (2, 3, 4 months or 2, 4, 6 months of age) than with the two dose schedules (2, 4 months of age) for all four serogroups. The geometric mean titres (GMTs) were also higher with the three dose schedule than a two dose schedule. Except for serogroup A, the 2, 4, 6 month Canadian schedule achieved slightly higher proportions of infants with immunity and slightly higher GMTs than the 2, 3, 4 month UK schedule. For the 2, 4, 6 month Canadian schedule, the percent of infants who achieved an hSBA titre of >=1:4 at 1 month after completion of the series was as follows: • serogroup A 81% (95% CI: 71-89%); • serogroup C 98% (95% CI: 92-100%); • serogroup W135 99% (95% CI: 93-100%); • serogroup Y 98% (CI: 92-100%).
GMTs had also fallen substantially from one month post vaccination at 2, 4 and 6 months compared to 12 months of age. As an example, for serogroup C the GMT was 124 (95%CI: 89-172) at one month post vaccination, and 13 (95% CI: 8.72-18) at 12 months of age.
One month following a challenge with either another dose of Men-C-ACYW-135-CRM with adjuvant or one-fifth of a dose of an unconjugated polysaccharide quadrivalent vaccine (Men-P-ACYW-135 -Menomune™, sanofi pasteur) at 12 months of age, all schedules demonstrated a good booster response. The highest response for serogroup C one month after the 12 month Men-C-ACYW-135-CRM with adjuvant dose was achieved in toddlers who had received the monovalent meningococcal C conjugate vaccine at 2 and 4 months of age (GMTs for serogroup C were 912 (95% CI: 538-1545)). The Men-C-ACYW-135-CRM with adjuvant was not used as a booster dose after the 2, 4 and 6 month Canadian primary series, but with the 2, 3, and 4 month UK primary series, the 12 month booster of Men-C-ACYW-135-CRM with adjuvant achieved a GMT of 429 (95% CI:288-639) for serogroup C one month post-vaccination.
However, the GMTs were much lower in this group for serogroups A, Y and W135 than in those groups who received the booster of Men-C-ACYW-135-CRM with adjuvant at 12 months and had received 2 or 3 doses of the same vaccine in infancy. This finding suggests that the duration of protection with one toddler dose of Men-C-ACYW-135-CRM with adjuvant may be shorter than when using this vaccine to prime in infancy and giving a booster dose in the second year of life.
The second study by Perrett et al. (31) enrolled 180 children in the UK and Canada using a similar protocol to the Snape et al. study described above (28) . In the Perrett et al study, children received non-adjuvanted Men-C-ACYW-135-CRM, which is the final formulation of Menveo™, given at 2 and 4 months of age with other routine infant vaccines. Responses at 1 month post-vaccination (5 months of age) were slightly higher in the Canadian arm of the study than in the UK arm with the percentage of infants who achieved a hSBA of >=1:4 in the Canadian arm as follows: • serogroup A 57% (95% CI: 45-67%); • serogroup C 93% (95% CI: 85-97%); • serogroup W135; 95% (95% CI: 87-99%); • serogroup Y 91% (CI: 82-96%).
In an abstract by Vesikari et al. (33) a dose-finding study which enrolled 620 toddlers aged 12-16 months was reported. These children were randomized to receive one or two doses of different formulations of the vaccine. Using the vaccine formulation chosen for further development, the range of hSBA GMTs for the various serogroups was 5.2-12 after one dose and 28-76 after two doses. The percentage of subjects with an hSBA titre of >=1:4 for the various serotypes was 49-70% after one dose and 91-96% after two doses.
A study by Gill et al. (37) extends the immunogenicity data on a subset of patients included in the Jackson study described above. (36) Of the original cohort vaccinated between 11-18 years of age, 278 of those who received Men-C-ACYW-135-CRM (Menveo™) and 191 of those who received Men-C-ACYW-135-D (Menactra™) were assessed a median of 22 months post-vaccination. The immunological response was compared to 128 controls who had not been previously vaccinated. The percentage of subjects who achieved an hSBA titre >=1:8 was significantly higher for those who received Men-C-ACYW-135-CRM compared to Men-C-ACYW-135-D for serogroups A, W135 and Y and non-significantly higher for serogroup C. GMTs were also significantly higher for the Men-C-ACYW-135-CRM group compared to Men-C-ACYW-135-D for serogroups A and Y and non-significantly higher for serogroups C and W135. It is hypothesized that the higher rates of persistence of the immune response for Men-C-ACYW-135-CRM are related to the higher GMTs that were achieved one month post-vaccination. For the Men-C-ACYW-135-CRM group, the percentage who had a hSBA titre of >=1:8 at a median of 22 months post-vaccination were as follows: • serogroup A 36%; • serogroup C 62%; • serogroup W135 84%; • serogroup Y 67%.

IV.5.4 Adults
Men-C-ACYW-135-CRM (Menveo™) has also been studied in adults aged 19-55 years of age by Reisinger et al. (38) using similar methodology to the phase III adolescent study by Jackson described above. (36)  Further study is required to determine if these findings translate to superior clinical protection from invasive meningococcal disease and the impact on duration of protection.

IV.5.5 Summary of Immunogenicity Data for Men-C-ACYW-135-CRM (Menveo™)
Thirteen studies of the immunogenicity of Men-C-ACYW-135-CRM (Menveo™) with or without the adjuvant were reviewed, some with concomitant administration of other age-appropriate vaccines, involving subjects from 2 months to 65 years of age. These studies are summarized in Table 8.
Men-C-ACYW-135-CRM has been found to be immunogenic in infants and toddlers; however as previously recommended by NACI, infants vaccinated at less than one year of age show a waning immune response indicating the need for a booster dose in the second year of life (from 12 to 23 months of age).
Men-C-ACYW-135-CRM in those 2 to 65 years of age was compared with unconjugated quadrivalent polysaccharide vaccines (Men-P-ACYW-135 -Menomune™), and/or the other available quadrivalent conjugate meningococcal vaccine, Men-C-ACYW-135-D (Menactra™). In every comparison assessing serogroups C, Y, and W135, and in most comparisons assessing serogroup A, Men-C-ACYW-135-CRM was found to be non-inferior to these vaccines and in several instances, Men-C-ACYW-135-CRM was found to have a statistically superior immune response. The implication of the higher immune response on clinical effectiveness, and particularly on duration of protection, is not certain.

IIV.7 BOOSTER DOSES AND RE-IMMUNIZATION
Circulating antibodies are considered necessary to protect an individual against invasive meningococcal disease (IMD). Indirect protection (to non-immunized persons) through herd immunity also contributes to decreased frequency of IMD when meningococcal vaccine programs are in place.
NACI has previously recommended an adolescent dose of conjugate meningococcal vaccine, even if conjugate serogroup C vaccination was previously received as an infant or toddler. The need for further booster doses after adolescence has not yet been determined and will be dependent on the duration of protection achieved by the conjugate meningococcal dose in adolescence and the burden of meningococcal disease in older age groups.
The Advisory Committee on Immunization Practices in the United States has recommended that those previously vaccinated with a quadrivalent meningococcal vaccine at age ≥7 years and who are at prolonged increased risk should be revaccinated 5 years after their previous dose, and persons previously vaccinated at 2-6 years of age and who are at prolonged increased risk should be revaccinated 3 years after their previous dose. (40) In addition, the Advisory Committee on Immunization Practices has recommended a booster dose of quadrivalent vaccine at 16 years of age in those vaccinated routinely with quadrivalent meningococcal vaccine at 11 to 12 years of age, and 2-dose primary series 2 months apart for those 2 to 54 years of age with certain high-risk medical conditions. (13) It should be noted that unlike Canada, the United States does not have an infant or toddler meningococcal vaccine program.
For high risk individuals who remain at ongoing or recurring risk of exposure to meningococcal disease (research, industrial and clinical laboratory personnel who are potentially routinely exposed to N. meningitidis; or travellers or military personnel who remain in or revisit areas where meningococcal vaccine is recommended) or high risk individuals with underlying medical conditions (asplenia; complement, properdin, factor D or primary antibody deficiencies; or HIV), the following re-vaccination schedule is recommended by NACI, based on expert opinion: • For those vaccinated at 6 years of age and under: provide a booster dose 3-5 years after the last dose, followed by every 5 years.
• For those vaccinated at 7 years of age and older: provide a booster dose 5 years after the last dose, followed by every 5 years.
• Travellers to Hajj should check recommendations for re-vaccination at: http://www.hajinformation.com/main/ p3001.htm as more frequent re-vaccination may be required.
A quadrivalent conjugate meningococcal vaccine should be used for re-vaccination and based on expert opinion, either Men-C-ACYW-135-D (Menactra™) or Men-C-ACYW-135-CRM (Menveo™) can be used, regardless of what meningococcal vaccine was used for the initial vaccination.
For those previously vaccinated who are now close contacts or during outbreaks, revaccination as follows is recommended, based on expert opinion: • Those previously vaccinated with a serogroup that differs from the index case or outbreak strain should be vaccinated immediately with the appropriate vaccine (as outlined in Recommendation 3 below); • Those previously vaccinated with a serogroup that is the same as the index case or outbreak strain should be revaccinated with the appropriate vaccine(as outlined in Recommendation 3 below): • If they were less than 1 year of age at last meningococcal vaccination and more than 4 weeks have passed since their last meningococcal vaccine; • If they have an underlying medical condition that puts them at risk for meningococcal disease and more than 4 weeks have passed since their last meningococcal vaccine; • If more than a year has passed since their last meningococcal vaccine if they were not less than 1 year of age at the time of their last meningococcal vaccination and if they have no underlying medical condition that puts them at risk for meningococcal disease.

IV.8 SEROLOGICAL TESTING
There is no indication for routine pre-or post-immunization serology.

IV.9 STORAGE REQUIREMENTS FOR MEN-C-ACYW-135-CRM (MENVEO™)
Store Menveo™ in the refrigerator between 2ºC to 8ºC and protect from light. Do not freeze Menveo™ and discard it if it is accidently frozen. Once reconstituted, use Menveo™ immediately, but it may be held at or below 25 ºC for up to 2 hours.
Concomitant administration resulted in similar rates of local reactions when the three vaccines were given at the same visit or when Men-C-ACYW-135-CRM was given one month before or after Tdap; The reported rates of systemic reactions when Men-C-ACYW-135-CRM was administered concomitantly was 58%, when given alone was 51% or when given after Tdap was 43%. No serious adverse events were considered to be possibly or probably related to the Men-C-ACYW-135-CRM vaccine.
The immunogenicity of HPV 6, 11, 16 and 18; meningococcal A, C, and Y; and diphtheria and tetanus were similar regardless of the schedule of administration, although higher geometric mean concentrations were achieved for diphtheria when administered concomitantly with Men-C-ACYW-135-CRM and HPV compared to other schedules. The pertussis toxoid, filamentous hemagglutinin, and pertactin had statistically significantly higher responses as measured by geometric mean concentrations when Tdap was given one month after Men-C-ACYW-135-CRM than when Tdap was given alone. When Tdap was administered concomitantly with Men-C-ACYW-135-CRM and HPV, the geometric mean concentration for the filamentous hemagglutinin and pertactin antigens were statistically significantly lower compared to the group that received Tdap alone. The clinical relevance of this is uncertain. Using the percentage of recipients who achieved an hSBA titre of >=1:8, all schedules resulted in a similar immune response for meningococcal serogroups; however, using seroresponse as a measure of immunity, the response to meningococcal W135 was lower when Men-C-ACYW-135-CRM was given one month after Tdap than when the two vaccines were given concomitantly or when Men-C-ACYW-135-CRM was given alone. The clinical relevance of these findings is uncertain.
There were no clinically significant adverse events related to any vaccine. In general, local and systemic reactions were reported more frequently in the group that received Tdap and Men-C-ACYW-135-CRM concomitantly and in the Tdap alone group, compared to the Men-C-ACYW-135-CRM group.
Significantly higher responses to diphtheria were found in the concomitant group. The response to two pertussis antigens (pertussis toxoid, and pertactin) was slightly lower in the concomitant group compared to when Tdap was administered alone. The response to tetanus toxoid and the meningococcal serogroups were unaffected by co-administration.

IV.10.2 Men-C-ACYW-135-D (Menactra™)
In an open labelled, multicentered, randomized controlled study by Reisinger et al. (43) 394 boys and 648 girls who were between the ages of 10 and 17 years were randomized to one of two groups.
• Group B received the human papillomavirus vaccine on day 1, and at months 2 and 6; Men-C-ACYW-135-D and Tdap were received at month 1.
On day 1 in Group A, the human papillomavirus vaccine was given in one arm and Men-C-ACYW-135-D and Tdap were both given in the opposite arm. At month 1 in Group B, the Men-C-ACYW-135-D and Tdap were both given in the same arm using the arm opposite to the day 1 human papillomavirus vaccine. Blood was drawn from Group A on day 1 and at months 1 and 7, and from Group B on day 1 and at months 1, 2 and 7.  : 235-302), respectively). The difference in GMTs was more marked at 16 months of age when the GMT for meningococcal C was 432 (95% CI: 361-517) in the group that received the 13-valent pneumococcal vaccine compared to 731 (95% CI: 642-832) in the group that received the 7-valent pneumococcal vaccine; however, the proportion of responders was > 97% in both groups. It is possible that the larger amount of CRM 197 in the 13-valent pneumococcal vaccine is interfering with the response to the CRM 197 -containing meningococcal C vaccine. (45) The clinical significance of this as it relates to meningococcal C CRM 197 -conjugate vaccines or Men-C-ACYW-135-CRM (Menveo™) co-administered with the 13-valent conjugate pneumococcal vaccine is unknown. Additional studies of co-administration of these vaccines are required.

IV.11.1 Men-C-ACYW-135-CRM (Menveo™)
Eleven studies of the safety and reactogenicity of Men-C-ACYW-135-CRM with or without the adjuvant were reviewed, some with concomitant administration of other vaccines. The safety and adverse events data are summarized in Table 8. No significant safety concerns have been raised with the use of Men-C-ACYW-135-CRM (Menveo™). In almost all studies, when compared to either the monovalent meningococcal C conjugate vaccine, the unconjugated quadrivalent polysaccharide vaccine (Men-P-ACYW-135 -Menomune™), or the other available quadrivalent conjugate meningococcal vaccine, Men-C-ACYW-135-D (Menactra™), the rate of local and systemic adverse events following Men-C-ACYW-135-CRM with or without adjuvant have been similar. In all but one study, no serious adverse events were felt by the investigators to be related to Men-C-ACYW-135-CRM.
In the study using Men-C-ACYW-135-CRM with adjuvant in infants (28) , the investigators reported two serious adverse events which were thought to be related to the Men-C-ACYW-135-CRM: thrombocytopenic purpura and supraventricular tachycardia. The child with the thrombocytopenic purpura had an antecedent viral infection and the thrombocytopenic purpura resolved spontaneously. The child with the supraventricular tachycardia had a history of recurrent supraventricular tachycardia and was enrolled in violation of the study's exclusion criteria. Based on the information provided, it is possible both of these events could be related to antecedent conditions in the individuals immunized. Severe acute febrile illness warrants deferring the vaccine until symptoms have resolved.
Conjugate vaccines have not been studied in pregnancy and there are very limited data on the use of Men-C-ACYW-135-CRM (Menveo™) in pregnancy; however in specific circumstances in which the benefits outweigh the risks, its use may be considered.

IV.13 INTERCHANGEABILITY BETWEEN MENINGOCOCCAL VACCINES
There are several examples where more than one type of meningococcal vaccine product is administered to the same individual. Men-C-ACYW-135-CRM with and without adjuvant has been used after meningococcal C conjugate vaccines resulting in an excellent booster response to serogroup C. (28) (32) Similarly, Men-C-ACYW-135-D (Menactra™) has been shown to induce an excellent booster response after meningococcal C conjugate vaccination. (48) The unconjugated bivalent (serogroups A and C) or quadrivalent polysaccharide vaccines are often used after conjugate vaccines to simulate exposure to disease and induce a good booster immune response. (19)

V.2 HIGH-RISK GROUPS
As previously recommended, individuals with the following risk factors should receive quadrivalent conjugate meningococcal vaccine.
• Persons with anatomic or functional asplenia (including sickle cell disease); • Persons who have complement, properdin, factor D or primary antibody deficiencies; • Persons with acquired complement deficiency (eg. those receiving eculizumab (Soliris™); • Travellers when meningococcal vaccine is recommended (meningitis belt of Subsaharan Africa) or required (pilgrims to the Hajj in Mecca); • Research, industrial and clinical laboratory personnel who are routinely exposed to N. meningitidis; and • Military personnel during recruit training and on certain deployments (Military personnel may be at increased risk when accommodated in close quarters or through deployment to endemic / epidemic countries).

NACI Recommendation Grade B
NACI has previously stated that the quadrivalent conjugate meningococcal vaccine could be considered for individuals with HIV.

NACI Recommendation Grade B
Age Considerations for the Above-High-Risk Groups: In reviewing the following age considerations for the above high risk groups, it should be noted that both Menveo™ and Menactra™ have been authorized for use in Canada in individuals aged 2-55 years.

AGE LESS THAN 2 YEARS WITH THE ABOVE HIGH-RISK CONDITIONS
Men-C-ACYW-135-CRM (Menveo™) has been found to be safe and immunogenic in children less than 2 years of age. (28)(31)(32) Men-C-ACYW-135-D (Menactra™) has been found to be only modestly immunogenic in infants, but appears to prime the immune response in the majority of infants given three doses. (49) Based on available published data,Men-C-ACYW-135-CRM (Menveo™) is the recommended product in this age group. Possible schedules for vaccinating high-risk infants and young children based on clinical trials of immunogenicity can be found in Table 12.

AGE 2-10 YEARS WITH THE ABOVE HIGH-RISK CONDITIONS
Based on expert opinion, either quadrivalent conjugate meningococcal vaccine can be used for children in this group. Two doses at least 8 weeks apart are recommended for those in the high risk group due to underlying medical conditions (asplenia; complement, properdin, factor D or primary antibody deficiencies; or HIV). A minimum 4 week interval can be used if rapid protection is required. If only one dose was previously given, then give another at the earliest opportunity and proceed with booster doses as outlined below based on the interval from the second dose.
For those who only receive one dose of quadrivalent meningococcal vaccine (eg. travellers) routine monovalent meningococcal C conjugate vaccine should already have been administered to children 2-10 years of age and if not previously given, should also be administered at least one month after the quadrivalent conjugate vaccine to ensure optimal serogroup C protection.

11-55 YEARS WITH THE ABOVE HIGH-RISK CONDITIONS
Based on expert opinion, either quadrivalent conjugate meningococcal vaccine can be used for individuals in this group. Two doses at least 8 weeks apart are recommended for those in the high risk group due to underlying medical conditions (asplenia; complement, properdin, factor D or primary antibody deficiencies; or HIV). A minimum 4 week interval can be used if rapid protection is required. If only one dose was previously given, then give another at the earliest opportunity and proceed with booster doses as outlined below based on the interval from the second dose.

AGE 56 YEARS AND OLDER WITH THE ABOVE HIGH-RISK CONDITIONS
Based on expert opinion, either quadrivalent conjugate meningococcal vaccine may be considered for individuals in this group. Two doses at least 8 weeks apart are recommended for those in the high risk group due to underlying medical conditions (asplenia; complement, properdin, factor D or primary antibody deficiencies; or HIV). A minimum 4 week interval can be used if rapid protection is required. If only one dose was previously given, then give another at the earliest opportunity and proceed with booster doses as outlined below based on the interval from the second dose.

Serogroup C
For close contacts of serogroup C IMD when the contact is 11 years of age or older, and to control outbreaks of serogroup C in those 11 years of age and older, either a monovalent meningococcal C conjugate vaccine or one of the available quadrivalent conjugate meningococcal vaccines may be used. For close contacts of serogroup C who are less than 11 years of age or to control outbreaks of serogroup C in children less than 11 years of age, a monovalent meningococcal C conjugate vaccine is recommended as more experience is available with these products.

Serogroups A, W135 and Y
A quadrivalent conjugate meningococcal vaccine is recommended for close contacts of persons with invasive meningococcal disease (IMD) caused by serogroups A, W135 or Y, and for the control of outbreaks caused by these serogroups. Either Men-C-ACYW-135-CRM (Menveo™) or Men-C-ACYW-135-D (Menactra™) may be used for this purpose in those 2 years of age and over.

NACI Recommendation Grade A
For children less than 2 years of age who are close contacts of a person with IMD caused by serogroups A, W135 or Y or for outbreaks caused by these serogroups, Men-C-ACYW-135-CRM (Menveo™) should be used. Protection from vaccination post-exposure to IMD should last at least one year as this is the period where increased risk has been noted for household contacts. (50) Possible schedules for vaccinating infants and young children for post-exposure protection against serogroups A, Y or W135 or for management of outbreaks caused by these serogroups are outlined in Table 12.
There is no data on the use of Men-C-ACYW-135-CRM (Menveo™) in infants younger than 2 months of age.

NACI Recommendation Grade B
For those previously vaccinated who are now close contacts or during outbreaks, revaccination as follows is recommended, based on expert opinion: • Those previously vaccinated with a serogroup that differs from the index case or outbreak strain should be vaccinated immediately with the appropriate vaccine (as outlined above); • Those previously vaccinated with a serogroup that is the same as the index case or outbreak strain should be revaccinated with the appropriate vaccine (as outlined above): • If they were less than 1 year of age at last meningococcal vaccination and more than 4 weeks have passed since their last meningococcal vaccine; • If they have an underlying medical condition that puts them at risk for meningococcal disease and more than 4 weeks have passed since their last meningococcal vaccine; • If more than a year has passed since their last meningococcal vaccine if they were not less than 1 year of age at the time of their last meningococcal vaccination and if they have no underlying medical condition that puts them at risk for meningococcal disease.

NACI Recommendation Grade B
See the Canadian Immunization Guide for further details regarding the vaccination of close contacts.

V.4 REVACCINATION FOR CERTAIN HIGH RISK CIRCUMSTANCES AND HIGH RISK GROUPS
For high risk individuals who remain at ongoing or recurring risk of exposure to meningococcal disease (research, industrial and clinical laboratory personnel who are potentially routinely exposed to N. meningitidis; or travellers or military personnel who remain in or revisit areas where meningococcal vaccine is recommended) or high risk individuals with underlying medical conditions (asplenia; complement, properdin, factor D or primary antibody deficiencies; or HIV), the following re-vaccination schedule is recommended by NACI, based on expert opinion: • For those vaccinated at 6 years of age and under: provide a booster dose 3-5 years after the last dose, followed by every 5 years.
• For those vaccinated at 7 years of age and older: provide a booster dose 5 years after the last dose, followed by every 5 years.
• Travellers to Hajj should check recommendations for re-vaccination at: http://www.hajinformation.com/main/ p3001.htm as more frequent re-vaccination may be required.

VII. Surveillance priorities
Surveillance should also be conducted to address the following outstanding questions: 1. The impact of meningococcal vaccination programs on the epidemiology of invasive meningococcal disease (IMD) in Canada.
2. The coverage rates of Men-C-ACYW-135-CRM (Menveo™) and Men-C-ACYW-135-D (Menactra™) and the impact of these coverage rates on carriage and herd immunity as reflected by IMD in unvaccinated individuals.    Jackson's phase III study above (36)   Local and systemic reactions were generally reported more frequently in the concomitant group and in the Tdap alone group, compared to the Men-C-ACYW-135-CRM alone group.

II-1
Evidence from controlled trial(s) without randomization.

II-2
Evidence from cohort or case-control analytic studies, preferably from more than one centre or research group using clinical outcome measures of vaccine efficacy.

II-3
Evidence obtained from multiple time series with or without the intervention. Dramatic results in uncontrolled experiments (such as the results of the introduction of penicillin treatment in the 1940s) could also be regarded as this type of evidence.

III
Opinions of respected authorities, based on clinical experience, descriptive studies and case reports, or reports of expert committees. A study (including meta-analyses or systematic reviews) that meets all design-specific criteria* well.

Fair
A study (including meta-analyses or systematic reviews) that does not meet (or it is not clear that it meets) at least one design-specific criterion* but has no known "fatal flaw".

Poor
A study (including meta-analyses or systematic reviews) that has at least one design-specific* "fatal flaw", or an accumulation of lesser flaws to the extent that the results of the study are not deemed able to inform recommendations.
* General design specific criteria are outlined in Harris et al., 2001. (52)  B NACI concludes that there is fair evidence to recommend immunization.
C NACI concludes that the existing evidence is conflicting and does not allow making a recommendation for or against immunization, however other factors may influence decision-making.
D NACI concludes that there is fair evidence to recommend against immunization.
E NACI concludes that there is good evidence to recommend against immunization.
I NACI concludes that there is insufficient evidence (in either quantity and/or quality) to make a recommendation, however other factors may influence decision-making.