ARCHIVED - Canada Communicable Disease Report
An Advisory Committee Statement (ACS)
National Advisory Committee on Immunization (NACI)Footnote †
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Update on the Invasive Meningococcal Disease and Meningococcal Vaccine Conjugate Recommendations
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.
This statement provides an update with regard to meningococcal disease and the currently available quadrivalent conjugate meningococcal vaccine, Menactra® (sanofi pasteur) and makes additional recommendations for the use of meningococcal conjugate vaccines. This statement will:
- Review past National Advisory Committee on Immunization (NACI) recommendations regarding meningococcal vaccines;
- Update the Canadian epidemiology of meningococcal disease with data up to and including 2006;
- Provide an update of the meningococcal vaccination schedules used in Canada;
- Define indicators of immunogenicity for meningococcal disease;
- Update information about Menactra® with regard to immunogenicity and safety;
- Recommend that a routine dose of a meningococcal conjugate vaccine be offered in early adolescence;
- Recommend the quadrivalent conjugate meningococcal vaccine for children with primary antibody deficiencies who are two years of age or older; and
- Outline outstanding research questions.
Overview of Past National Advisory Committee on Immunization Recommendations on Meningococcal Vaccines
Since 2001, NACI has recommended the use of meningococcal C conjugate vaccine for infants (i.e. children < 1 year of age), children from 1-4 years of age, adolescents and young adults. NACI recommended that the vaccine be considered for children ≥ 5 years of age who have not reached adolescenceFootnote 1 .
In May 2007, NACI recommended the use of conjugate meningococcal vaccine for serogroups A, C, Y and W135 (quadrivalent conjugate meningococcal vaccine - Menactra®) 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 invasive meningococcal disease (IMD) caused by serogroups A, Y or W135, and for the control of outbreaks caused by these serogroups. NACI also stated that the quadrivalent conjugate meningococcal vaccine could be considered for individuals with HIV, as well as for high-risk individuals, as defined above, who are ≥56 years of age. 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 MenactraFootnote 2 .
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 ageFootnote 3 .
Epidemiology of Meningococcal Disease in Canada
Invasive meningococcal disease (IMD) is endemic to Canada. The epidemiology of IMD changes over time and varies depending on geographic location, season and age. Serogroup C can occur as sporadic cases or as part of community outbreaks, whereas serogroups Y and W135 tend to occur sporadically. Serogroup A is mainly a risk for travelers to endemic areas. Winter is typically a time of increased incidence. Various ages are affected differently in terms of incidence, as well as with respect to circulating serogroups that cause disease.
Since the 1950's the overall incidence of IMD in Canada has remained <2.1 cases per 100 000 population per year (range 0.5 - 2.1 per 100, 000). Over the 12 years from 1995-2006, the incidence of IMD has averaged 0.77 cases per 100 000 population per year. On average, 235 cases have been reported annually. Using the 12 year average, the highest incidence is observed in infants < 1 year of age (8.7 cases per 100 000), followed by children 1-4 years of age (2.3 per 100,000). The rates decrease until adolescence and peak again in 15-19-year-olds (1.9 per 100,000) and 20-24-year-olds (1.0 per 100,000).
Figure 1 illustrates the trends in incidence of IMD by serogroup and year. Table 1 allows for a comparison of 12-year average rates and numbers of IMD cases for 1995-2006 compared to 2006, the most recent year for which there is complete data. Median ages and case fatality rates are also provided. Table 2 provides a breakdown of the IMD cases and rates by serogroup and province / territory for 2006. Table 3 provides the same data for a 12-year period from 1995-2006. Table 4 provides the IMD number and rates by serogroup and age group for 2006. The data for the figure and tables is derived from the national reporting system which receives and integrates reports from all provinces and territoriesFootnote 4 . The figure and tables illustrate the following serogroup specific information:
Serogroup C: Outbreaks of serogroup C were fairly common in the past. Between 1999 and 2001, 8 outbreaks of serogroup C meningococcal disease occurred in CanadaFootnote 5 . In more recent years, there has been a significant decline in incidence of serogroup C IMD, likely, although not conclusively, due to the introduction of meningococcal C conjugate vaccine in routine vaccination programs and/or catch-up programs or mass immunization campaigns in all provinces and territories (see Table 5 for vaccination schedules in the provinces and territories).
Serogroup B: After serogroup C, serogroup B has caused the second highest burden of disease within Canada. Rates are particularly high in infants and children < 4 years of age, but disease can occur at any age. In 2006, Québec had a higher rate of serogroup B disease compared to other provinces. Since 2003, Québec has seen the introduction and increase of a strain of serogroup B Neisseria meningitidis identified as B:17:P1.19 sequence type ST-269Footnote 6. From March 2003 to June 2005, 38 cases of IMD have been attributed to this strain. Approximately 45% of the patients were aged 10 to 19 years and 26% were aged 20 to 39. The increase in serogroup B IMD two years after the introduction of a mass meningococcal vaccination program using conjugate C meningococcal vaccine for individuals 2 months to 20 years of age raises the possibility of serogroup replacement. The observed change in epidemiology could also be due to natural fluctuations in the circulating clones or due to capsular switching. There is currently no vaccine available in Canada for serogroup B. Serogroup Y: Rates and numbers of serogroup Y IMD have remained stable over time. Cases of serogroup Y IMD have a higher median age because of the number of cases in the 25 - 65 and >65 age groups; however, serogroup Y IMD can occur at any age.
Serogroup W135 and A: These serogroups remain rare in Canada.
Figure 1 - Incidence rates of invasive meningococcal disease by serogroup and year, 1995-2006Footnote 4
|Serogroup||2006||1995 - 2006|
|Number of cases||Incidence
(IMD cases/100,000 population)
|Average annual number of cases
|Average annual incidence
(IMD cases/100,000 population)
|Median Age in years||Case Fatality Rate|
|A||2||0.01||1 (0-2)||0.002||48||No deaths reported|
|Incidence (Number of cases)||0.51 (21)||0.42 (14)||0.52 (5)||0.17 (2)||0.53 (64)||1.15 (87)||0.82 (6)||0.33 (3)||0 (0)||0.99 (5)||0 (0)||2.41 (1)||6.79 (2)||0.66 (210)|
|Serogroup A||0.05 (2)||0 (0)||0 (0)||0 (0)||0 (0)||0 (0)||0 (0)||0 (0)||0(0)||0 (0)||0(0)||0 (0)||0 (0)||0.01 (2)|
|Serogroup B||0.17 (7)||0.27 (9)||0.31 (3)||0.17 (2)||0.22 (27)||0.74 (56)||0.41 (3)||0.11 (1)||0 (0)||0.40 (2)||0 (0)||2.41 (1)||6.79 (2)||0.36 (113)|
|Serogroup C||0.10 (4)||0 (0)||0.10 (1)||0 (0)||0.14 (17)||0.27 (20)||0.14 (1)||0 (0)||0 (0)||0 (0)||0 (0)||0 (0)||0 (0)||0.13 (43)|
|Serogroup Y||0.12 (5)||0.09 (3)||0.10 (1)||0 (0)||0.11 (13)||0.03 (2)||0 (0)||0.11 (1)||0 (0)||0.40 (2)||0 (0)||0 (0)||0 (0)||0.09 (27)|
|Serogroup W-135||0 (0)||0 (0)||0 (0)||0 (0)||0.03 (3)||0.01 (1)||0.27 (2)||0 (0)||0 (0)||0 (0)||0 (0)||0 (0)||0 (0)||0.02 (6)|
|Other Serogroups||0.07 (3)||0.06 (2)||0 (0)||0 (0)||0.03 (4)||0.11 (8)||0 (0)||0.11 (1)||0 (0)||0.20 (1)||0 (0)||0 (0)||0 (0)||0.06 (19)|
|Incidence (Number of cases)||0.83 (34)||1.03 (31)||0.5 (5)||0.69 (8)||0.63 (75)||0.91 (67)||0.72 (5)||0.56 (5)||0.12 (0.2)||0.80 (5)||0.54 (0.2)||1.6 (0.7)||1.3 (0.4)||0.76 (235)|
|Serogroup A||0.004 (2)||0 (0)||0.22 (2.2)||0 (0)||0.004 (0.4)||0 (0)||0 (0)||0 (0)||0 (0)||0 (0)||0 (0)||0 (0)||0 (0)||0.01 (0.6)|
|Serogroup B||0.27 (11.1)||0.23 (6.7)||0.22 (2.2)||0.27 (3.1)||0.20 (23)||0.53 (39)||0.41 (3)||0.2 (2)||0.06 (0.1)||0.24 (1.3)||0.27 (0.7)||0.6 (0.3)||1.3 (0.4)||0.3 (93)|
|Serogroup C||0.32 (13)||0.6 (18)||0.13 (1.3)||0.17 (2)||0.19 (22)||0.24 (17)||0.13 (1)||0.08 (0.8)||0 (0)||0.18 (1)||0.27 (0.7)||0.4 (0.2)||0 (0)||0.25 (76)|
|Serogroup Y||0.1 (4)||0.08 (2.4)||0.07 (0.7)||0.08 (0.9)||0.10 (12)||0.07 (5)||0.08 (0.6)||0.09 (0.8)||0.06 (0.1)||0.1 (0.5)||0 (0)||0.19 (0.1)||0 (0)||0.09 (27)|
|Serogroup W-135||0.03 (1.3)||0.03 (0.9)||0.02 (0.2)||0.02 (0.3)||0.05 (5)||0.01 (1)||0.03 (0.2)||0.01 (0.1)||0 (0)||0 (0)||0 (0)||0 (0)||0 (0)||0.03 (9)|
|Other Serogroups||0.09 (3.7)||0.11 (3.2)||0.07 (0.7)||0.15 (1.7)||0.11 (12)||0.05 (4)||0.07 (0.5)||0.13 (1.3)||0 (0)||0.26 (1.4)||0 (0)||0.4 (0.2)||0 (0)||0.1 (29)|
|Province/Territory||< 1 yr||1-4 yrs||5-9 yrs||10-14 yrs||15-19 yrs||20-24 yrs||25-64 yrs||65+ yrs||Total|
|Incidence (Number of Cases)||7.83 (27)||1.82 (25)||0.43 (8)||0.48 (10)||1.43 (31)||1.24 (28)||0.30 (54)||0.62 (27)||0.64 (210)|
|Serogroup A||0 (0)||0 (0)||0 (0)||0 (0)||0 (0)||0 (0)||0.01 (1)||0.02 (1)||0.01 (2)|
|Serogroup B||6.38 (22)||1.31 (18)||0.33 (6)||0.24 (5)||0.97 (21)||0.80 (18)||0.09 (17)||0.14 (6)||0.34 (113)|
|Serogroup C||0.58 (2)||0.15 (2)||0.05 (1)||0.05 (1)||0.23 (5)||0.27 (6)||0.12 (22)||0.09 (4)||0.13 (43)|
|Serogroup Y||0 (0)||0.22 (3)||0 (0)||0 (0)||0.18 (4)||0.04 (1)||0.05 (9)||0.23 (10)||0.08 (27)|
|Serogroup W-135||0 (0)||0.07 (1)||0 (0)||0 (0)||0 (0)||0.04 (1)||0 (0)||0.09 (4)||0.02 (6)|
|Other Serogroups||0.87 (3)||0.07 (1)||0.05 (1)||0.19 (4)||0.05 (1)||0.09 (2)||0.03 (5)||0.05 (2)||0.02 (19)|
Meningococcal vaccination schedules used in Canada
Table 5 provides the most current immunization schedules for meningococcal disease by province / territory. Provinces began implementing routine meningococcal C conjugate vaccination programs in 2002. Full implementation across Canada had occurred by the beginning of 2007.
|Province/Territory||Schedule for routine meningococcal C conjugate||Product and schedule for catch-up|
|British Columbia||2 and 12 months||Meningococcal C conjugate
• Grade 6
|Alberta||2, 4 and 12 months||Mass immunization campaign in 2001 targeting 2 -24 year-olds using bivalent (A + C) polysaccharide meningococcal vaccine. For children less than 2 years of age, meningococcal C conjugate vaccine was usedFootnote 8|
|Saskatchewan||12 months||Meningococcal C conjugate
• 4 - 6 years of age
• Grade 6
|Manitoba||As of January 1, 2009, offered at 12 months of age Prior to January 1, 2009, of-fered to children in Grade 4|
|Ontario||12 months||Meningococcal C conjugate
• Grade 7
• 15 - 19 years of age
|Québec||12 months||Mass immunization campaign in 2001 targeting 2 months - 20-year-olds using meningococcal C conjugate vaccine|
|New Brunswick||12 months||Quadrivalent conjugate meningococcal vaccine
• Grade 9
|Nova Scotia||12 months||Meningococcal C conjugate
• Grade 7
• 14 to 16 years of age
|Prince Edward Island||12 months||Quadrivalent conjugate meningococcal vaccine
• Grade 9
|Newfoundland||12 months||Meningococcal C conjugate
• Grade 4
• Grade 9
|North West Territories||2 and 12 months||Meningococcal C conjugate
• Children < 5 years of age
• Grade 9
Conjugate meningococcal vaccine for serogroups A, C, Y and W135
• For students attending post-secondary schools outside of the North West Territories
|Yukon||2 and 6 months||Meningococcal C conjugate
• Grade 9
• Post secondary school students leaving school and / or not previously vaccinated
|Nunavut||12 months||Meningococcal C conjugate
• 14 to 16 years of age
Indicators of immunogenicity for meningococcal disease
Regulatory approval of conjugated vaccines for meningococcal disease has been based primarily on short-term immunogenicity studiesFootnote 9 . 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 for this purpose 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. 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 diseaseFootnote Footnote 10 . Baby rabbit serum, which is more readily available, has replaced human complement in more recent 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 IMDFootnote Footnote 11 . 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 concentrationsFootnote Footnote 12 which can be expressed as geometric mean antibody concentrations (GMC). ELISA methodology is also available to assess meningococcal C IgG antibody avidityFootnote Footnote 13 .
Although immunogenicity studies likely predict short-term effectiveness, their ability to determine long-term effectiveness is uncertain. Additionally, immunogenicity studies do not predict the impact of vaccination on carriage and herd immunity. There are no immunologic correlates of protection for the serogroups A, Y or W135.
Update on the Quadrivalent Conjugate Meningococcal Vaccine for Serogroup A, C, Y and W135
The quadrivalent conjugate meningococcal vaccine, Menactra® (sanofi-pasteur), was approved for use in May 2006. In May 2007, NACI recommended the vaccine for individuals at high risk for meningococcal disease and advised that the vaccine be considered where warranted based on local epidemiology for routine immunization of 11-24-year oldsFootnote Footnote 2 . As can be seen from Table 5, two provinces use Menactra® for their catch-up program in Grade 9. The following provides an update with regard to the immunogenity and safety of Menactra®.
Immunogenicity in 2-10-year-olds:
The product monograph for Menactra® Footnote Footnote 14 has been updated with regard to the immunogenicity in 2-10 year-olds based on the results of the study by Pichichero et alFootnote Footnote 15 . In this study, 696 children were randomized to receive Menactra®. The mean age of participants was 3.7 years and > 80% were between 2 and 5 years of age. The percentage of children achieving a rSBA titre for serogroup C of ≥ 1:8 at 28 days after vaccination was 96.2%. Six months following immunization, the proportion with a titre ≥ 1:8 was just under 90%. Data for 2-year-olds, who represented 37% of the study population, indicated that 93% and 81% achieved a rSBA titre ≥ 1:8 for serogroup C at 28 days and 6 months after vaccination, respectivelyFootnote Footnote 16 .
Menactra® is not approved for use in children less than 2 years of age and NACI has not recommended its use for routine immunization in young children. As of January 2009, all provinces and territories have infant or toddler meningococcal C vaccine programs so most infants or young children will have received meningococcal C conjugate vaccine. Menactra® was found to induce a good booster response in children previously vaccinated with meningococcal C conjugate vaccine in a randomized double-blind study by El Bashir et al.Footnote 17 . At least one year after receipt of a meningococcal C conjugate vaccine, 52 2-4-year-olds were given Menactra®; on day 28 post the Menactra® booster, 100% of children had a rSBA titre of >=1:8 for all four serogroups.
Children considered at high-risk for IMD were recommended in a previous NACI statement to receive quadrivalent conjugate meningococcal vaccine (Menactra®) followed one month later by a single dose of a monovalent conjugate meningococcal C vaccine if the latter has not already been givenFootnote Footnote 2 (See "Overview of Past National Advisory Committee on Immunization Recommendations on Meningococcal Vaccines" and "Quadrivalent Conjugate Meningococcal Vaccine for Children with Primary Antibody Deficiencies" sections of this statement for a list of high-risk conditions). Although all provinces have introduced or are introducing infant or one-year old monovalent meningococcal C conjugate vaccination programs, there are likely some of children aged 2 - 10 years considered at high risk for IMD who have not received a dose of monovalent meningococcal C conjugate vaccine. Menactra® may provide adequate serogroup C protection in 2 - 10 year olds, but it has not been directly compared in immunogenicity trials to the three currently available monovalent meningococcal C conjugate vaccines and has not been studied in immunocompromised children. NACI therefore continues to recommend that these high-risk children between 2 and 10 years of age receive Menactra® followed by monovalent meningococcal C conjugate vaccine, if not previously vaccinated with the latter vaccine. NACI recommends at least a one-month interval between these products.
In the United States, Menactra® is being used for routine vaccination of adolescents aged 11-18 years of ageFootnote Footnote 18 . Between 2005 and 2007, 15 million doses of vaccine have been distributedFootnote Footnote 16 . It is currently too early for the effectiveness of this vaccination program to be apparent, however evaluations are ongoing in the United States.
Guillain-Barré Syndrome (GBS): At the time of publication of the May 2007 NACI statement on conjugate meningococcal vaccine for serogroups A, C, Y and W135, post-marketing surveillance using the Vaccine Adverse Event Reporting System (VAERS) in the United States had identified 17 cases of Guillain-Barré Syndrome (GBS) occurring within 6 weeks after receipt of Menactra®. Fifteen of the 17 cases occurred in adolescents between the ages of 11 and 19 years, which is the age group most commonly vaccinated with Menactra® in the United States. The cases were reported to be significantly clustered around days 9 to 15 postvaccination. Calculations from the Centers for Disease Control and Prevention (CDC) in the United States estimated with substantial uncertainty that 1.25 (95% CI, 0.058 to 5.99) excess cases of GBS could be anticipated for every 1 million doses of vaccine distributed to persons 11 to 19 years of ageFootnote Footnote 19 .
Since the publication of the NACI statement, the CDC has continued to actively monitor the frequency of GBS temporally associated with receipt of Menactra®. As of April 2008, VAERS has reported 29 cases of GBS following receipt of Menactra® broken down by age as follows: 5 cases in 11-14-year-olds; 22 cases in 15-19-year-olds and 2 cases in those 20 years of age and older. None of these 29 cases were fatal. Of the GBS cases among 11-19-year-olds, 52% had received Menactra® alone while the remaining 48% received one or more additional vaccines. The temporal clustering of GBS cases between 11 and 15 days after vaccination was still notedFootnote 20 .
The CDC calculated the expected number of GBS cases by age group using data from the Healthcare Cost and Utilization ProjectFootnote Footnote 20 . Based on comparing the number of observed to expected GBS cases, the CDC estimated an incidence rate ratio of 1.3 (95% CI: 0.86 - 1.9) in 11-19-year-olds and an excess of 0.5 GBS cases per million doses of Menactra® distributed. For 15-19-year-olds, the incidence rate ratio was estimated at 1.6 (95% CI: .99 - 2.3) with an excess of 1 case of GBS per million doses of Menactra® distributed. It should be noted that these numbers may be underestimated if there is less than complete reporting of GBS cases or if the number of doses administered is significantly less than the number of doses distributedFootnote 20. As well, these numbers may be overestimated if the cases that were counted as GBS were misdiagnosed. The diagnosis of GBS is hampered by the absence of a reference test to confirm the diagnosisFootnote Footnote 21 .
It should be noted that the reporting of GBS cases did not increase after the publication of any of the three Morbidity and Mortality Weekly Report (MMWR) articles on the possible association between GBS and Menactra®. This suggests that there was not a significant amount of underreporting. The frequency of GBS is also under study by the Vaccine Safety Data Link (VSD), a collaborative effort between CDC's Immunization Safety Office and eight large managed care organizations, which provide health care to more than 5.5 million people. Based on their background rate of GBS, the VSD would have expected 0-1 cases of GBS in 11-19-yearolds in the 6 weeks after vaccination. No cases of GBS after Menactra® have been reported through the VSD following the administration of 285,248 dosesFootnote Footnote 20 .
The risk of meningococcal disease from serogroups A, Y and W135 far exceeds the very small estimated risk of GBS following vaccination. Based on a 12 year average from 1995-2006, the combined rate for serogroups A, Y and W-135 IMD for 10-24- year-olds is 1.5 cases per million per year. This compares to an estimated, and still uncertain, GBS risk following vaccination of 0.5 to 1.0 per million doses. As well, the case-fatality rate for serogroups Y and W135 is estimated at 6%. By comparison, the mortality rate in patients 18 years of age and over hospitalized for GBS was found to be 2.58% in a large US study. Older age is considered a predictor of GBS-associated mortalityFootnote Footnote 22 , and therefore mortality is expected to be even lower in adolescents. A study in QuebecFootnote Footnote 23 found that the rate of GBS hospitalizations in those 5 - 22 years of age was 0.6 cases per 100,000 person-years (95% CI: 0.3 to 0.8) based on approximately 2 years of observation. Among the 33 cases of GBS between the ages of 1 and 22, none were fatal.
Harvard Pilgrim Health Care is working with the CDC, Food and Drug Administration and other organizations in the United States to more closely study the background rates of GBS and the possible risk of GBS associated with Menactra®. The study, which is funded by sanofi pasteur and referred to as the Health Plan Consortium GBS Study, will primarily focus on 11-18 year-olds. It involves the research arms of five US health plans and will be sufficiently large to study GBS in this age group, where the disease is quite rare. Results of the study are not expected until late 2009 or 2010Footnote Footnote 16 .
Although the risk of recurrent GBS is unknown, caution should be used in administering Menactra® to an individual with a previous episode of GBS especially when alternate products are availableFootnote Footnote 2 .
Administration of Menactra® and Tdap: According to manufacturer data, randomized controlled trials have been conducted to determine the safety of administering Menactra® one month before, at the same time as, and one month after Tdap (Adacel® - sanofi pasteur)Footnote 16 . Approximately 440 individuals participated in each of the three study groups which were: Adacel® and placebo at the same visit and Menactra® 30 days later; Adacel® and Menactra® at the same visit and placebo 30 days later; and Menactra® and placebo at the same visit and Adacel® 30 days later. Local reactions at the Menactra® site were not affected by the timing of vaccine administration related to Adacel®. As well, systemic reactions occurred at similar frequencies regardless of the order of the vaccines. The only exception was that myalgia occurred more frequently when Adacel® was administered one month after Menactra®.
The following provides recommendations for:
- A routine meningococcal conjugate vaccine dose in early adolescence; and
- Quadrivalent conjugate meningococcal vaccine for children 2 years of age and older with primary antibody deficiencies
The evidence to support these recommendations is outlined below.
Routine meningococcal conjugate vaccine dose in early adolescence
It can be seen from Table 5 that most provinces and territories offer catch-up meningococcal vaccination programs for adolescents using either meningococcal C conjugate vaccine or quadrivalent conjugate meningococcal vaccine. The programs that use meningococcal C conjugate vaccine were initially designed to "catch-up" the vaccinations in one or more cohorts; it was originally thought that these programs would no longer be necessary once the cohort vaccinated as infants or young children reached the age of the catch-up program.
NACI is now recommending that a dose of meningococcal conjugate vaccine be offered in early adolescence, ideally around 12 years of age, even if the adolescent was previously vaccinated as part of a routine infant or toddler vaccination program. The rationale for this adolescent dose is to ensure that circulating antibodies are present as adolescents enter the peak years for IMD beyond infancy, which are between 15 and 24 years of age. As well, carriage of meningococci is highest during adolescenceFootnote Footnote 24 and preventing carriage in adolescents may have an impact on herd immunity in the communityFootnote Footnote 25 , indirectly protecting infants.
The following reviews the literature in support of this recommendation including the literature indicating that memory response is not sufficient for IMD protection and the evidence to support a waning of immunity following meningococcal C conjugate vaccination in infants and young children. The literature regarding the age of vaccination for adolescents and the choice of meningococcal vaccines is also reviewed. Based on the grading scheme used for NACI recommendations as outlined in Tables 6-8, the literature in support of the above recommendations is summarized in Table 9.
Memory response not sufficient for IMD protection:
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 vaccinesFootnote 26 Footnote 27 Footnote 28 Footnote 29 Footnote Footnote 29 Footnote 30 . However, because of the short incubation period of IMD (range 2 to 10 days, commonly 3 to 4 daysFootnote Footnote 31 ) it is now generally accepted that the anamnestic response cannot be relied upon to prevent disease and that circulating antibodies are necessary for protection.
Vaccine failures after meningococcal C conjugate vaccination were first reported from the United Kingdom (UK) when Trotter et al.Footnote Footnote 32 analysed surveillance data for IMD up to 4 years after the introduction of a mass immunization campaign in 1999. The researchers found that at more than 1 year after the series, effectiveness in infants vaccinated at 2, 3 and 4 months had fallen to -81% (95% CI: -7430% to 71%). Those vaccinated at 5-11 months of age and 1-2 years of age had somewhat better long-term protection with vaccine effectiveness at more than 1 year and up to 4 years after vaccination of 82% (95% CI: -8% to 97%) and 61% (95% CI: -327% to 94%) respectively, although the confidence intervals are very wide due to the small numbers of individuals with IMD. These data suggested that immunity wanes over time, and that immunization after one year of age provided longer term protection against IMD than immunization in infancy. NACI subsequently recommended that a dose of meningococcal conjugate vaccine be given at or after one year of ageFootnote Footnote 3 .
Auckland et al.Footnote Footnote 33 provide evidence that circulating antibodies are necessary to prevent IMD, and that the ability to mount a memory response is not sufficient. The researchers studied 56 individuals who received the meningococcal C conjugate vaccine, mostly as part of the UK mass immunization program, but nonetheless developed serogroup C IMD 10 days or more after completing their vaccination series (vaccine failures). The vaccine failures were compared to unvaccinated individuals who developed IMD (controls). The vaccine failures with IMD had a median age of 3.4 years at onset (range 0.9 to 19.7 years). The median time from completion of the vaccine series to onset of disease was 17 months (range 1.8 to 44 months). Most vaccine failures were not found to have underlying medical conditions and they did not have an excess of inherent immunodeficiencies compared to the control group. The researchers demonstrated that using the putative correlate of protection for rSBA of ≥ 1:8 for serogroup C IMD, 59% of vaccine failures and 65% of controls had titres below this level based on acute blood tests (within 3 days of onset). It was noted that the number of individuals who lacked protective levels of rSBA at the onset of disease may have been even lower as it is possible that the date of onset could not be accurately determined and so the acute blood test may have been taken later into the course of illness. Auckland et al. were also able to demonstrate that vaccine failures with IMD mounted a memory response to disease, since their convalescent titres (taken 7 days or more after onset) were significantly higher than the convalescent titre in unvaccinated controls with IMD.
The delay in mounting an anamnestic response in vaccinated individuals was demonstrated in a study by Snape et al.Footnote Footnote 34 in the UK. Investigators studied healthy individuals between the ages of 13 and 15 who were vaccinated with Menjugate® (Chiron Vaccines) approximately 3.7 years previously, at a mean age of 10.8 years (range 9.1 to 12.5 years). The immune response in 171 adolescents was measured on various days after receiving one fifth of a dose of bivalent (A + C) polysaccharide vaccine, a dose intended to simulate exposure to natural disease in immunized individuals, so that overall the immune response on days 0, 2, 3, 4, 5, 6 and 7 could be assessed. The study determined that no rise in all three measures of immunity were observed until 5 days after the polysaccharide vaccine challenge. This delayed anamnestic response would therefore be too late to prevent rapidly progressive IMD if the individual's vaccine induced immunity had waned to below protective levels at the time of exposure.
Waning effectiveness and immunity after vaccination in early childhood:
In November 2007, NACI reviewed the effectiveness and immunogenicity of infant meningococcal C conjugate vaccinationsFootnote Footnote 3 . Based on decreasing effectiveness and waning immunity, NACI recommended that those vaccinated in infancy receive a booster dose of meningococcal C conjugate vaccine in the second year of life, which could be conveniently administered at 12 or 18 months of age.
As can be seen from Table 5, some provinces / territories do not use an infant schedule but instead provide 1 dose of meningococcal C conjugate vaccine to children at 12 months of age. There is evidence that meningococcal vaccination at age 12 to 18 months may not produce optimal long term immunogenicity or effectiveness against IMD.
Trotter et al.Footnote 32 showed that children vaccinated with one dose of meningococcal C conjugate vaccine at 1-2 years of age had a vaccine effectiveness (VE) of 83% (95% CI 60%-93%) up to 4 years post vaccination. The VE within one year post vaccination was 88% (95% CI 65%-96%) which is considerably higher than the VE at more than 1 year and up to 4 years after vaccination of 61% (95% CI: -327% to 94%); the confidence intervals are very wide due to the small numbers of individuals with IMD but indicate waning immunity with time.
A similar surveillance study conducted in Spain up to 4 years after the introduction of meningococcal C conjugate vaccination program showed that overall vaccination effectiveness (VE) in those vaccinated at 7 months to 5 years of age was high at 97.8% (95% CI: 96.0%-98.8%)Footnote Footnote 35 . This study also demonstrated waning VE with time. The VE within one year post-vaccination was 99.5% (95% CI 98.1%-99.9%) which was significantly higher than the VE in the 1-4 years post-vaccination which was 94.3% (95% CI 71.2%-98.8%), p<0.001.
Immunologic evidence suggests that, similar to infants, those vaccinated in the second year of life will experience waning immunity. A study conducted by Richmond et al.Footnote Footnote 30 compared the immunogenicity of the three available meningococcal C conjugate vaccines in toddlers 12 to 18 month of age at vaccination. There were 68 to 75 toddlers in each vaccination group. The GMTs using rabbit complement at 4-6 weeks after vaccination were 123 for Menjugate® (Chiron), 141 for Meningitec™ (Wyeth) and 564 for NeisVac-C® (North American Vaccine). Six months after vaccination, GMTs had fallen in all groups but remained higher for Neis- Vac-C® (19 for Menjugate®, 51 for Meningitec™ and 166 for Neis-Vac-C™). Furthermore, the percentage of individuals having a rSBA of ≥ 1:8 had fallen from 92% 4-6 weeks after vaccinations to 57% 6 months after immunization with Menjugate®, with the corresponding 4-6 week and 6 month data being 91% and 75% for Meningitec™ and 100% and 86% for NeisVac-C®.
A cross-sectional study was conducted by Snape et al.Footnote Footnote 36 in 94 toddlers at a median age of 2.3 years (range 1.4 to 3.2 years), who had been vaccinated with Meningitec™ (Wyeth Vaccines) a median of 1.8 years earlier (range 1.2 to 2.7 years). The children were assessed for circulating meningococcal antibody and 63% had a rSBA titre of < 1:8, and therefore were not considered protected.
McVernon et al.Footnote Footnote 37 assessed 16 four-year-olds who had been previously vaccinated with one dose of meningococcal C conjugate vaccine at 12 months of age. Only 25% of participants had what is considered a protective hSBA titre of ≥ 1:4 an average of 3 years after vaccination.
Age for vaccination of adolescents:
Primary vaccination at 10 years of age and older appears to provide good immune response up to approximately 4 to 5 years later, as demonstrated by the following two studies by Snape et al. It is anticipated that booster doses provided to adolescents in this age group who have been previously vaccinated as infants or toddlers will provide an even better immunologic response against serogroup C.
Snape et al.Footnote Footnote 38 retrospectively studied 987 adolescents aged 11-20 years of age (mean age 14.8 years) who were immunized with one of three meningococcal C conjugate vaccines (the majority receiving Menjugate® - Novartis) at 6-15 years of age. The mean time since immunization was 4.9 years. Among participants aged 11-13 (who were vaccinated at approximately 6-8 years of age), 79.1% (95% CI: 75.1 to 83.0%) still had a rSBA titre of ≥ 1:8. By comparison, of those aged 14-16 years (vaccinated at approximately 9-11 years of age) and those aged 17-20 years (vaccinated at approximately 12-15 years of age), 87.3% (95% CI: 84.1 to 90.5%) and 88.2% (95% CI: 83.4 to 93.0%) had protective titres respectively. As well, the GMTs were significantly higher in the older two age groups compared to the younger age group - 147 (95% CI: 115 to 188) in 11-13 year olds, 300 (95% CI: 237 to 380) in 14-16 year olds and 360 (95% CI: 252 to 515) in 17-20 year olds.
Similarly, Snape et al.Footnote Footnote 34 studied 260 13-15-years-olds vaccinated an average of 3.7 years previously (range 3.2-4.3 years) with Menjugate® (Chiron Vaccines). Of these adolescents, 83.9% (95% CI: 79.4-88.3%) had a hSBA of ≥1:4.
It has been postulated that immunologic maturation may explain the different immunologic responses of adolescents, infants and toddlers to meningococcal vaccines.
De Wals et al.Footnote Footnote 39 estimated the life-time effectiveness of different immunization schedules using meningococcal C conjugate vaccine in a simulation model based on Canadian epidemiology. Herd immunity was not incorporated into the simulation model. The investigators determined that for long term control of IMD, the most efficient approach would be to offer a dose at 12 months of age and a catchup around 12 years of age. The researchers postulated that the catch-up dose would need to be transformed to a booster if the immunity after the dose at 12 months of age waned by 3% or more per year. Data from the UK suggest that children immunized between 5 months and 2 years of age have a waning rate of 10% per year, and 3% per year in individuals immunized at an older age. Based on this data, a booster dose would be necessary to provide protection for adolescents immunized as infants or young children in current Canadian immunization schedules.
In those provinces / territories that currently offer adolescent programs, the most practical approach would be to continue these programs when previously vaccinated cohorts reach that age group. For provinces / territories without adolescent programs, the adolescent dose could be incorporated into existing opportunities for vaccination.
For children vaccinated with meningococcal C conjugate vaccine in later childhood, Trotter et al.Footnote Footnote 32 showed vaccine effectiveness of 100% (95% CI: 71 to 100 %) up to almost 4 years post-vaccination for children vaccinated at 4-6 years of age, and 88% (95% CI: 38 to 98%) for children vaccinated at 7-10 years of age. Snape et al. showed persistence of protective titres in most adolescents approximately 4Footnote Footnote 34 and 5 years after vaccination with meningococcal C conjugate vaccineFootnote Footnote 38 .
No data is available to determine the duration of protection for meningococcal C conjugate vaccine beyond 4 to 5 years if given in later childhood; hence NACI is not providing guidance at this time regarding the timing of revaccination for provinces with a Grade 4 meningococcal C conjugate program or who conducted a mass catch-up immunization program using meningococcal C conjugate vaccine in 2001. Available evidence indicates that re-vaccination with a conjugate meningococcal vaccine after a previous dose of meningococcal C conjugate vaccine does not result in significant adverse effectsFootnote 17 Footnote 34 .
Re-immunization with a conjugate vaccine after polysaccharide meningococcal vaccination is recommended 6 months to 5 years after initial vaccination, depending on the age when first immunized and ongoing riskFootnote 2 Footnote 40 . Therefore, children who received polysaccharide vaccination as a part of a mass immunization campaign in 2001 should receive a conjugate meningococcal vaccine in early adolescence.
Choice of products for early adolescent dose:
The early adolescent dose could be given using either meningococcal C conjugate vaccine or quadrivalent conjugate meningococcal vaccine. Provinces / territories will need to consider their burden of illness from serogroups A, Y and W135 (as outlined in Tables 2 and 3) and the age distribution of cases by serogroup (as outlined in Table 4) which provide an indication of the number of IMD cases that might be prevented. They will also need to consider the differential in cost between monovalent and quadrivalent products and other local factors.
De Wals et al.Footnote 41 used a model that incorporates herd immunity and waning immunity to determine the IMD cases averted comparing three options: meningococcal C conjugate vaccine at 1 year of age; meningococcal C conjugate vaccine at 1 year of age and 12 years of age; and meningococcal C conjugate vaccine at 1 year of age and quadrivalent conjugate vaccine at 12 years of age. For a study population of one million persons with no meningococcal vaccination, there would be 5.7 vaccine preventable IMD cases per year. Vaccination at 1 year of age with meningococcal C conjugate prevents 1.6 IMD cases per million population per year compared to no vaccination (28% reduction). Adding meningococcal C vaccine at 12 years of age prevents an additional 2.3 cases per million population per year, for an overall reduction of IMD reduction of 68% compared to no vaccination. Using quadrivalent conjugate meningococcal vaccine instead of meningococcal C conjugate vaccine for the 12 year booster prevents an additional 0.9 IMD cases per million population per year for a total reduction of 85%. The model estimates the cost per quality adjusted life years of each option and the incremental cost of each option.
The duration of protection for Menactra® is currently unknown; however, assuming a duration of protection of 10-15 years after an adolescent booster dose and using 2006 data, 6 additional cases of IMD per year could be prevented in Canada (5 cases of serogroup Y and 1 case of serogroup W-135) with a 100% effective quadrivalent vaccine compared to similarly effective meningococcal C conjugate vaccine given to adolescents. Under the 10-15 year duration assumption, the number needed to vaccinate to prevent one case of IMD would be 362,419 using the quadrivalent meningococcal vaccine and 543,628 using the monovalent conjugate C vaccine.
Based on the evidence presented above and summarized in Table 9, NACI is now recommending that an adolescent dose of meningococcal vaccine be incorporated into the routine schedule, even if the adolescent was previously vaccinated as part of a routine infant or 1-year old vaccination program. The adolescent dose will help to ensure circulating antibody titres against serogroup C which appear to be important for ongoing protection against IMD. The optimal age for the adolescent dose appears to be around age 12. The adolescent dose can be provided using monovalent meningococcal C conjugate vaccine or quadrivalent conjugate meninogococcal vaccination for A, C, Y and W135; the choice will be influenced by several previously noted considerations.
NACI Recommendation B - There is fair evidence to recommend.
Quadrivalent Conjugate Meningococcal Vaccine for Children with Primary Antibody Deficiencies
Primary antibody deficiencies are a group of at least 20 different disorders which involve decreased serum levels of one or more immunoglobulin types and increased susceptibility to encapsulated organisms such as Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidisFootnote 42 Footnote 43 . NACI previously recommended that persons with antibody defects should be immunized against these pathogensFootnote 44 . Studies are not available assessing the effectiveness of conjugate meningococcal vaccine in this group. A study of 24 children 2 years of age or over (mean age 11.2 years) with primary antibody deficiencies was conducted to determine the immune response to bivalent (A + C) polysaccharide meningococcal vaccineFootnote 45 . In those receiving immunoglobulin replacement therapy, the vaccine was given three weeks after the last infusion. A total of 16 of the 24 (66.7%) patients with primary antibody deficiency developed a rSBA titre of ≥ 1:8 and/or a 4-fold rise in SBA from pre-vaccination to 3-weeks post-vaccination compared to 100% of the 15 age- and sex-matched controls. This study is summarized in Table 10.
Based on this study, two-thirds of the children with primary antibody deficiency responded to the polysaccharide vaccine. Given that vaccination with a conjugate vaccine results in higher GMTs than polysaccharide vaccines in this age group in healthy childrenFootnote 15 Footnote 46 , it is expected that better responses will be observed using a conjugate meningococcal vaccine. NACI therefore recommends that children 2 years of age or older with primary antibody deficiencies be included in the high-risk group for which NACI recommends the quadrivalent conjugate meningococcal vaccine. Children with other immunodeficiency states in which it is possible that humoral function may be abnormal should also be considered as part of this group. Children from 2-10 years of age in high-risk groups should also receive a monovalent conjugate C vaccine if they have not already received this vaccine with at least a one-month interval between products.
NACI Recommendation B - There is fair evidence to recommend.
Recommended research priorities
Research to address the following outstanding questions is encouraged:
- the effectiveness of Menactra® and the duration of protection;
- comparison of the immunogenicity of Menactra® and meningococcal C conjugate vaccines;
- the impact of Menactra® on meningococcal carriage and herd immunity;
- the outcome of the Health Plan Consortium GBS Study and ongoing monitoring of the possible association between Menactra® and GBS;
- a safe and effective quadrivalent meningococcal vaccine for infants and children < 2 years of age;
- a safe and effective meningococcal vaccine against serogroup B IMD;
- the safety, immunogenicity and effectiveness of Menactra® in adults ≥ 56 years;
- the safety, immunogenicity and effectiveness of Menactra® in certain high-risk groups, such as the immunocompromised;
- the safety and/or immunogenicity of concomitant administration of Menactra® with other vaccines, such as dTap, human papillomavirus, hepatitis A and hepatitis B; and
- the epidemiology of meningococcal disease in Canada and the impact of provincial / territorial vaccination programs
|I||Evidence from randomized controlled trial(s)|
|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.|
|Good||A study (including meta-analyses or systematic reviews) that meets all designspecific 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.Footnote 47.|
|A||NACI concludes that there is good evidence to recommend immunization.|
|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.|
|Study||Study Type/Description||Number of participants||Outcome measure||Level of Evidence||Quality Rating|
|Summary of evidence that memory response not sufficient for IMD protection|
|Auckland et al. 2006 Footnote 33||Case-Control
||serogroup C IMD cases
||Serological indicators at disease onset and at convalescence: rSBA GMTs or titre = 8, IgG concentrations and avidity indices||II-2||Fair
|Snape et al. 2006Footnote 34||Randomized Trial
||274 healthy 13-15 years olds who had received Menjugate 3.2 to 4.3 years previously||Serological indicators: hSBA titres = 8 and GMTs and IgG GMCs measured prebooster vaccination and on various days post vaccination||I||Good
|Summary of evidence of waning effectiveness and immunity after vaccination in early childhood|
|Trotter et al. 2004Footnote 32||Cohort study
||53 vaccine failures||Laboratory confirmed serogroup C IMD > 10 days 4 years post-vaccination||II-2||Fair
|Larrauri et al. 2005 Footnote 35||Cohort
||32 vaccine failures||Laboratory confirmed serogroup C IMD up to up to 4 years post-vaccination||II-2||Laboratory confirmed serogroup C IMD up to 4 years post-vaccination|
|Richmond et al. 2001 Footnote 30||Randomized Trial
||Indicators of immunity measured before vaccination and 4-6 weeks after vaccination using rSBA = 8 and = 32 and GMTs, GMC and GMAI||I||Good
|Snape et al. 2005Footnote 36||Cross sectional
Age 1.4 to 3.2 years at vaccination and 3.5 to 4.7 years at follow up
|Persistence of immunity using rSBA GMTs and titres < 1/8, and IgG GMC||II-2||Fair
|McVernon et al. 2002M Footnote 37||Follow up to a randomized trial
||Indicators of immunity measured before and 28 to 42 days after vaccination using hSBA >1/4 and > 1/8 and GMTs, and high avidity IgG CMCs||II-2||Fair
|Summary of evidence regarding the age of vaccination of adolescents|
|Snape et al. 2008Footnote 38||Cross Sectional
||987 adolescents||Serological indicators: rSBA GMTs and titres of = 1:8 and 1:128 and IgG GMC.||II-3||Fair
|Snape et al. 2006Footnote 34||See above|
|DeWals et al. 2006 Footnote 39||Model based evaluation
||n/a||Modelling studies do not fit into current evidence-based medicine evaluation schemes|
|Trotter et al. 2004 Footnote 32||See above|
|Summary of evidence regarding the choice of products for early adolescent booster dose|
|DeWals et al. 2007 Footnote 41||Model based cost effectiveness analysis||Modelling studies do not fit into current evidence-based medicine evaluation schemes|
|hSBA- Serum bactericidal assay using human complement; rSBA- Serum bactericidal assay using rabbit complement; GMT- Geometric mean titres; GMC - Geometric mean antibody concentration; GMAI - Geometric mean avidity indices|
|Study||Study Type/Description||Number of participants||Outcome measure||Level of Evidence||Quality Rating|
|Summary of evidence that memory response not sufficient for IMD protection|
|Rezaei et al.
|Non-randomized controlled trial
measured before and 3
weeks after vaccination,
rSBA ≥ 1/8 and ≥ 4 fold
rise and GMTs
† Members: Dr. J. Langley (Chairperson), Dr. B. Warshawsky (Vice-Chairperson), Dr. S. Ismail (Executive Secretary), Ms. A. Hanrahan, Dr. K. Laupland, Dr. A. McGeer, Dr. S. McNeil, Dr. B. Seifert, Dr. D. Skowronski, Dr. B. Tan.
Liaison Representatives:Dr. B. Bell (CDC), Dr. P. Orr (AMMI Canada), Ms. S. Pelletier (CHICA), Ms. K. Pielak (CNCI), Dr. P. Plourde (CATMAT), Dr. S. Rechner (CFPC), Dr. M. Salvadori (CPS), Dr. D. Scheifele (CAIRE), Dr. N. Sicard (CPHA), Dr. V. Senikas (SOGC).
Ex-Officio Representatives: Dr. S. Desai x(CIRID - Vaccine Preventable Diseases), Dr. P. Varughese (CIRID), Dr. R. Ramsingh (FNIHB), Dr. F. Hindieh (BGTD).
† This statement was prepared by Dr. Bryna Warshawsky, Dr. Shalini Desai and Dr. Joanne Langley and approved by NACI and the Public Health Agency of Canada. NACI gratefully acknowledges the work of Dr. Philippe De Wals for his contribution to the development of the statement.
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